76 results on '"Drago, F"'
Search Results
2. Effectiveness of telerehabilitation plus virtual reality (Tele-RV) in cognitive e social functioning: A randomized clinical study on Parkinson's disease.
- Author
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Maggio MG, Luca A, Cicero CE, Calabrò RS, Drago F, Zappia M, and Nicoletti A
- Subjects
- Humans, Social Interaction, Cognition, Telerehabilitation, Parkinson Disease psychology, Virtual Reality
- Abstract
Introduction: Telemedicine could represent an emerging and innovative approach to support cognitive and behavioral rehabilitation reducing the overload of healthcare facilities, favoring home care therapy. The present study aimed to assess the potential efficacy of Tele-VR apps in enhancing cognitive performance and improving social skills in patients with Parkinson's disease (PD)., Methods: Thirty-four patients with PD were included in the study. Patients were assigned to one of the following treatment groups: Experimental Group 1 (EG1) underwent a Tele-VR program using two cognitive rehabilitation applications (app) on smartphones (Neuronation-Brain Training and Train your Brain); Experimental Group 2 (EG2) received a Tele-VR program through one cognitive rehabilitation app (Neuronation-Brain Training) and one socio-cognitive rehabilitation App (The Sims) on smartphones; Active Control Group (aCG) performed a conventional training using pencil and paper exercises (Not-VR)., Results: At the end of the study, the aCG and EG1 presented an improvement in the executive, attentional and visuospatial cognitive domains. Mood and subjective memory also improved in the EG1. Moreover, in the EG2 group, a significant improvement was found in all cognitive domains, including social cognition skills (theory of mind). The inter-group comparison showed that both EG1 and EG2 had significantly greater improvements than aCG in MoCA score. Finally, both EG1 and EG2 showed a higher improvement in the FAB score, as compared to the aCG., Conclusion: Rehabilitation with smartphone apps could be more useful than conventional rehabilitation in improving cognitive and social cognition skills in patients with PD. Combining cognitive and social cognition training could improve the cognitive and affective domains, also aiding in the long-term maintenance of cognitive outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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3. Two cases of Monkeypox virus infection without detectable cutaneous/mucosal lesions.
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Ciccarese G, Brucci G, Di Biagio A, Drago F, Ogliastro M, Caccianotti B, Lo Caputo S, Santantonio T, and Serviddio G
- Subjects
- Humans, Skin, Monkeypox virus, Mpox (monkeypox) diagnosis
- Abstract
Competing Interests: Declaration of competing interest All authors declare no conflicts of interest.
- Published
- 2023
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4. The P2X7 receptor as a new pharmacological target for retinal diseases.
- Author
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Platania CBM, Drago F, and Bucolo C
- Subjects
- Adenosine Triphosphate, Humans, Quality of Life, Receptors, Purinergic P2X7, Diabetic Retinopathy drug therapy, Retinal Diseases drug therapy
- Abstract
Purinergic ionotropic receptors, such as the P2X7 receptor, are activated by extracellular adenosine triphosphate (ATP). The P2X7 receptor is a trimeric ATP-gated cation channel and its activation results in several downstream events, including the release of proinflammatory mediators and cell damage. The P2X7 receptor has been studied as a pharmacological target for inflammatory and neuroinflammatory diseases, and preclinical studies have recently provided evidence that P2X7 receptor activation is implicated in pathophysiology of several retinal age-related diseases. These diseases are devastating conditions that have an deep impact on the quality of life of patients and on the health systems of all countries. In this review, we discuss the role of the P2X7 receptor in retinal age-related conditions such as glaucoma, age-related macular degeneration, and diabetic retinopathy. Furthermore, we focus on the pharmacological modulation of the P2X7 receptor that could have a relevant clinical impact to prevent retinal diseases., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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5. Pharmacological significance of extra-oral taste receptors.
- Author
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D'Urso O and Drago F
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- Animals, Gastric Mucosa metabolism, Humans, Intestinal Mucosa metabolism, Lung metabolism, Pancreas metabolism, Skin metabolism, Taste Buds metabolism, Taste Perception physiology, Thyroid Gland metabolism, Receptors, G-Protein-Coupled metabolism
- Abstract
It has recently been shown that taste receptors, in addition to being present in the oral cavity, exist in various extra-oral organs and tissues such as the thyroid, lungs, skin, stomach, intestines, and pancreas. Although their physiological function is not yet fully understood, it appears that they can help regulate the body's homeostasis and provide an additional defense function against pathogens. Since the vast majority of drugs are bitter, the greatest pharmacological interest is in the bitter taste receptors. In this review, we describe how bitter taste 2 receptors (TAS2Rs) induce bronchodilation and mucociliary clearance in the airways, muscle relaxation in various tissues, inhibition of thyroid stimulating hormone (TSH) in thyrocytes, and release of glucagon-like peptide-1 (GLP-1) and ghrelin in the digestive system. In fact, substances such as dextromethorphan, chloroquine, methimazole and probably glimepiride, being agonists of TAS2Rs, lead to these effects. TAS2Rs and taste 1 receptors (TAS1R2/3) are G protein-coupled receptors (GPCR). TAS1R2/3 are responsible for sweet taste perception and may induce GLP-1 release and insulin secretion. Umami taste receptors, belonging to the same superfamily of receptors, perform a similar function with regard to insulin. The sour and salty taste receptors work in a similar way, both being channel receptors sensitive to amiloride. Finally, gene-protein coupled receptor 40 (GPR40) and GPR120 for fatty taste perception are also protein-coupled receptors and may induce GLP-1 secretion and insulin release, similar to those of other receptors belonging to the same superfamily., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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6. Circulating miRNAs in diabetic retinopathy patients: Prognostic markers or pharmacological targets?
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Trotta MC, Gesualdo C, Platania CBM, De Robertis D, Giordano M, Simonelli F, D'Amico M, Drago F, Bucolo C, and Rossi S
- Subjects
- Adult, Aged, Angiogenesis Inhibitors administration & dosage, Biomarkers blood, Computational Biology methods, Diabetic Retinopathy diagnostic imaging, Diabetic Retinopathy genetics, Female, Gene Regulatory Networks drug effects, Gene Regulatory Networks physiology, Humans, Male, MicroRNAs genetics, Middle Aged, Prognosis, Tomography, Optical Coherence methods, Diabetic Retinopathy blood, Diabetic Retinopathy drug therapy, Drug Delivery Systems methods, MicroRNAs blood
- Abstract
In this study we analyzed the expression of circulating miRNAs, in the serum of diabetic retinopathy (DR) patients. Five miRNAs (hsa-miR-195-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-27b-3p and hsa-miR-451a) were validated as biomarkers for stratification of DR stages, from the early non-proliferative (NPDR) to the late proliferative (PDR) phase. Furthermore, circulating levels of these miRNAs correlated with retinal hyper-reflective spots (HRS), assessed by optical coherence tomography (OCT). The number of HRS increased with worsening of DR stages. On the contrary, no significant vascular density differences between NPDR and PDR patients were detected by angio-OCT (OCTA). A post-hoc bioinformatics analysis associated these five miRNAs to target genes belonging to the "Tumor Necrosis Factor alfa signaling" pathway, and several molecules were predicted to modify miRNAs expression. In conclusion, correlation between specific circulating miRNAs and intraretinal hyper-reflective spots was demonstrated, confirming that these miRNAs were validated as prognostic biomarkers, and also as potential pharmacological targets, warranting further clinical evaluation to explore novel therapeutics for diabetic retinopathy., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
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7. P2X7 receptor antagonism preserves retinal ganglion cells in glaucomatous mice.
- Author
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Romano GL, Amato R, Lazzara F, Porciatti V, Chou TH, Drago F, and Bucolo C
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- Animals, Electroretinography methods, Glaucoma pathology, Mice, Mice, Inbred DBA, Niacinamide analogs & derivatives, Niacinamide metabolism, Niacinamide therapeutic use, Piperazines metabolism, Piperazines therapeutic use, Retinal Ganglion Cells pathology, Glaucoma drug therapy, Glaucoma metabolism, Purinergic P2X Receptor Antagonists metabolism, Purinergic P2X Receptor Antagonists therapeutic use, Receptors, Purinergic P2X7 metabolism, Retinal Ganglion Cells metabolism
- Abstract
To investigate the role of P2X7 receptor to preserve retinal ganglion cells (RGCs) structure and function in a genetic mouse model (DBA/2J mouse) of age-related glaucomatous neurodegeneration. Chronic treatment with P2X7 receptor antagonist eye drops was carried out in order to assess RGCs function and density by pattern electroretinogram (PERG) and RBPMS immunostaining, respectively. Further, microglia activation was assessed in flat-mounted retina by using Iba-1 immunostaining. Untreated glaucomatous eyes displayed significant microglia activation, alteration of PERG signal, and RGCs loss. In the P2X7 receptor antagonist-treated eyes, the PERG signal was significantly (p < 0.05) improved compared to controls, along with a significant (p < 0.05) reduction in terms of retinal microglial activation, and remarkable preservation of RGCs density. Altogether, these findings demonstrated that topical treatment with a P2X7 receptor antagonist has a neuroprotective effect on RGCs in glaucomatous mice, suggesting an appealing pharmacological approach to prevent retinal degenerative damage in optic neuropathy., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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8. Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR).
- Author
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Platania CBM, Ronchetti S, Riccardi C, Migliorati G, Marchetti MC, Di Paola L, Lazzara F, Drago F, Salomone S, and Bucolo C
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- Animals, Anti-Inflammatory Agents pharmacology, Antibodies, Monoclonal pharmacology, Binding Sites, CD3 Complex antagonists & inhibitors, CD3 Complex immunology, Gene Expression Regulation, Glucocorticoid-Induced TNFR-Related Protein chemistry, Glucocorticoid-Induced TNFR-Related Protein deficiency, Glucocorticoid-Induced TNFR-Related Protein immunology, High-Throughput Screening Assays, Interleukin-17 genetics, Interleukin-17 immunology, Interleukins genetics, Interleukins immunology, Male, Mice, Mice, Knockout, Minocycline pharmacology, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 immunology, Oxytetracycline pharmacology, Primary Cell Culture, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Spleen cytology, Spleen drug effects, Spleen immunology, T-Lymphocytes cytology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Tumor Necrosis Factors immunology, Anti-Inflammatory Agents chemistry, Glucocorticoid-Induced TNFR-Related Protein antagonists & inhibitors, Minocycline chemistry, Oxytetracycline chemistry, Tumor Necrosis Factors chemistry
- Abstract
The tumor necrosis factor (TNF) superfamily (TNFSF) includes about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Receptors of the tumor necrosis factor (TNF) superfamily (TNFSFRs) are pharmacological targets for treatment of inflammatory and autoimmune diseases. Currently, drugs targeting TNFSFR signaling are biological drugs (monoclonal antibodies, decoy receptors) aimed at binding and sequestering TNFSFR ligands. The glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) signaling is involved in a series of inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Our study aimed at repurposing FDA approved small molecules as protein-protein disruptors at the GITR ligand (GITRL) trimer, in order to inhibit the binding of GITRL to its receptor (GITR). A structure based molecular modeling approach was carried out to identify, through high throughput virtual screening, GITRL monomer-monomer disruptors. We used a database of ~8,000 FDA approved drugs, and after virtual screening, we focused on two hit compounds, minocycline and oxytetracycline. These two compounds were tested for their capability to modulate IL-17, IL-21 and RORγT expression in T lymphocytes, isolated from wild-type and GITR knock-out (GITR
-/- ) mice. Minocycline showed immunomodulatory effects specific to GITR activation and could represent a novel pharmacological tool to treat inflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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9. Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.
- Author
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Stark T, Di Bartolomeo M, Di Marco R, Drazanova E, Platania CBM, Iannotti FA, Ruda-Kucerova J, D'Addario C, Kratka L, Pekarik V, Piscitelli F, Babinska Z, Fedotova J, Giurdanella G, Salomone S, Sulcova A, Bucolo C, Wotjak CT, Starcuk Z Jr, Drago F, Mechoulam R, Di Marzo V, and Micale V
- Subjects
- Animals, Antipsychotic Agents pharmacology, Brain diagnostic imaging, Cannabidiol chemistry, Cerebrovascular Circulation, Disease Models, Animal, Female, Gene Expression Regulation, Haloperidol chemistry, Haloperidol pharmacology, Magnetic Resonance Imaging, Male, Methylazoxymethanol Acetate toxicity, Models, Molecular, Molecular Dynamics Simulation, Pregnancy, Prenatal Exposure Delayed Effects, Puberty, Rats, Sprague-Dawley, Receptors, Dopamine D2 chemistry, Receptors, Dopamine D2 genetics, Receptors, Dopamine D2 metabolism, Receptors, Dopamine D3 chemistry, Receptors, Dopamine D3 metabolism, Schizophrenia chemically induced, Schizophrenia diagnostic imaging, Schizophrenia genetics, Brain drug effects, Cannabidiol pharmacology, Receptors, Dopamine D3 genetics, Schizophrenia drug therapy
- Abstract
Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol., Competing Interests: Declaration of Competing Interest VD is a consultant for GW Pharmaceuticals, UK, and FAI, FP and VD receive funding from GW Pharmaceuticals, UK. CTW is employed by Boehringer Ingelheime Pharma & Co KG which did not influence design, analysis and interpretation of the study., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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10. Novel indole derivatives targeting HuR-mRNA complex to counteract high glucose damage in retinal endothelial cells.
- Author
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Platania CBM, Pittalà V, Pascale A, Marchesi N, Anfuso CD, Lupo G, Cristaldi M, Olivieri M, Lazzara F, Di Paola L, Drago F, and Bucolo C
- Subjects
- Binding Sites physiology, ELAV-Like Protein 1 chemistry, Endothelial Cells drug effects, Endothelial Cells pathology, Glucose administration & dosage, Humans, Indoles chemistry, Inflammation Mediators antagonists & inhibitors, Inflammation Mediators metabolism, Protein Structure, Secondary, Protein Structure, Tertiary, RNA, Messenger chemistry, Retina drug effects, Retina pathology, ELAV-Like Protein 1 metabolism, Endothelial Cells metabolism, Glucose toxicity, Indoles administration & dosage, RNA, Messenger metabolism, Retina metabolism
- Abstract
The ELAVL1 (or human antigen R - HuR) RNA binding protein stabilizes the mRNA, with an AU-rich element, of several genes such as growth factors (i.e. VEGF) and inflammatory cytokines (i.e. TNFα). We hereby carried out a virtual screening campaign in order to identify and test novel HuR-mRNA disruptors. Best-scored compounds were tested in an in-vitro model of diabetic retinopathy, namely human retinal endothelial cells (HRECs) challenged with high-glucose levels (25 mM). HuR, VEGF and TNFα protein contents were evaluated by western-blot analysis in total cell lysates. VEGF and TNFα released from HRECs were measured in cell medium by ELISA. We found that two derivatives bearing indole moiety, VP12/14 and VP12/110, modulated HuR expression and decreased VEGF and TNF-α release by HREC exposed to high glucose (HG) levels. VP12/14 and VP12/110 inhibited VEGF and TNF-α release in HRECs challenged with high glucose levels, similarly to dihydrotanshinone (DHTS), a small molecule known to interfere with HuR- TNFα mRNA binding. The present findings demonstrated that VP12/14 and VP12/110 are innovative molecules with anti-inflammatory and anti-angiogenic properties, suggesting their potential use as novel candidates for treatment of diabetic retinopathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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11. Blood-retinal barrier protection against high glucose damage: The role of P2X7 receptor.
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Platania CBM, Lazzara F, Fidilio A, Fresta CG, Conti F, Giurdanella G, Leggio GM, Salomone S, Drago F, and Bucolo C
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- Blood-Retinal Barrier drug effects, Cell Line, Endothelial Cells drug effects, Humans, Niacinamide analogs & derivatives, Niacinamide pharmacology, Piperazines pharmacology, Retina cytology, Retina drug effects, Tight Junctions drug effects, Tight Junctions metabolism, Blood-Retinal Barrier metabolism, Endothelial Cells metabolism, Glucose toxicity, Receptors, Purinergic P2X7 physiology, Retina metabolism
- Abstract
Blood retinal barrier (BRB) breakdown is a hallmark of diabetic retinopathy, whose occurrence in early or later phases of the disease has not yet been completely clarified. Recent evidence suggests that hyperglycemia induces activation of the P2X7 receptor (P2X7R) leading to pericyte cell death. We herein investigated the role of P2X7R on retinal endothelial cells viability and expression of tight- and adherens-junctions following high glucose (HG) exposure. We found that HG elicited P2X7R activation and expression and release of the pro-inflammatory cytokine IL-1β in human retinal endothelial cells (HRECs). Furthermore, HG exposure caused a decrease in HRECs viability and a damage of the BRB. JNJ47965567, a P2X7R antagonist, protected HRECs from HG-induced damage (LDH release) and preserved the BRB, as shown by transendothelial electrical resistance and cell junction morphology (ZO-1, claudin-5 and VE-cadherin). Moreover, JNJ47965567 treatment significantly decreased IL-1β expression and release, elicited by HG. These data indicate that P2X7R plays an important role to regulate BRB integrity, in particular the block of this receptor was useful to counteract the damage elicited by HG in HRECs, and warranting further clinical evaluation of P2X7R antagonists for the treatment of diabetic macular edema., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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12. Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway.
- Author
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Lazzara F, Fidilio A, Platania CBM, Giurdanella G, Salomone S, Leggio GM, Tarallo V, Cicatiello V, De Falco S, Eandi CM, Drago F, and Bucolo C
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Cells, Cultured, Computer Simulation, Endothelial Cells drug effects, Extracellular Signal-Regulated MAP Kinases genetics, Humans, Mice, Models, Biological, Models, Molecular, Protein Binding, Protein Conformation, Protein Domains, Rats, Receptors, Vascular Endothelial Growth Factor, Retina cytology, Extracellular Signal-Regulated MAP Kinases metabolism, Glucose toxicity, Inflammation drug therapy, Membrane Proteins metabolism, Recombinant Fusion Proteins pharmacology, Retinal Diseases drug therapy
- Abstract
Diabetic retinopathy (DR) is a secondary complication of diabetes. DR can cause irreversible blindness, and its pathogenesis is considered multifactorial. DR can progress from non-proliferative DR to proliferative DR, characterized by retinal neovascularization. The main cause of vision loss in diabetic patients is diabetic macular edema, caused by vessel leakage and blood retinal barrier breakdown. Currently, aflibercept is an anti-VEGF approved for diabetic macular edema. Aflibercept can bind several members of vascular permeability factors, namely VEGF-A, B, and PlGF. We analyzed the aflibercept-PlGF complex at molecular level, through an in silico approach. In order to explore the role of PlGF in DR, we treated primary human retinal endothelial cells (HRECs) and mouse retinal epithelial cells (RPEs) with aflibercept and an anti-PlGF antibody. We explored the hypothesis that aflibercept has anti-inflammatory action through blocking of PlGF signaling and the ERK axis in an in vitro and in vivo model of DR. Both aflibercept and the anti-PlGF antibody exerted protective effects on retinal cells, by inhibition of the ERK pathway. Moreover, aflibercept significantly decreased (p < 0.05) the expression of TNF-α in an in vitro and in vivo model of DR. Therefore, our data suggest that inhibition of PlGF signaling, or a selective blocking, may be useful in the management of early phases of DR when the inflammatory process is largely involved., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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13. Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: Clinical presentation and phylogenesis of CV-A6 strains.
- Author
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Broccolo F, Drago F, Ciccarese G, Genoni A, Puggioni A, Rosa GM, Parodi A, Manukyan H, Laassri M, Chumakov K, and Toniolo A
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- Adolescent, Adult, Communicable Diseases, Emerging epidemiology, Communicable Diseases, Emerging virology, Disease Outbreaks, Enterovirus A, Human classification, Exanthema virology, Female, Genome, Viral, Hand, Foot and Mouth Disease epidemiology, Hand, Foot and Mouth Disease virology, Hospitalization statistics & numerical data, Humans, Italy epidemiology, Male, Middle Aged, Antibodies, Viral blood, Enterovirus A, Human genetics, Hand, Foot and Mouth Disease diagnosis, Phylogeny
- Abstract
Background: Typically, hand-foot-and-mouth disease (HFMD) is a mild childhood illness associated with coxsackievirus (CV)-A16, CV-A6, enterovirus (EV)-A71., Objectives: To identify the viral agents associated with severe cases of atypical HFMD in Italy., Study Design: Epidemiologically unrelated cases of severe atypical HFMD admitted to the Emergency Room (ER) of IRCCS San Martino IST (Genoa, Italy) in 2014-2016 were investigated. Serologic screening for viral positivity was performed against exanthem-inducing agents. Ten cases with serology indicative of recent EV infection were selected. Molecular assays were used to detect viral genomes in blood [EVs, Parvovirus B19 (PVB19), herpesviruses (CMV; EBV, HHV-6, -7, -8)]., Results: CV-A6 was detected in 10 cases of severe atypical HFMD. Two cases were also infected with PVB19. Herpesviruses were not detected. Phylogenetic analysis mapped the CV-A6 strains into a single cluster related to two recent isolates from a German and an Asian child. Fever, systemic symptoms, severe vasculitis-like rash, and enanthem were predominant at presentation. Spontaneous recovery occurred in 1-3 weeks., Conclusions: CV-A6 is emerging as a frequent cause of severe atypical HFMD in Italian adults. This viral agent is disseminating worldwide. Dermatologists must identify the manifold alterations caused by EVs and understand the diagnostic power of current virology methods., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2019
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14. Computational systems biology approach to identify novel pharmacological targets for diabetic retinopathy.
- Author
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Platania CBM, Leggio GM, Drago F, Salomone S, and Bucolo C
- Subjects
- Animals, Databases, Genetic, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism, Diabetic Retinopathy drug therapy, Diabetic Retinopathy metabolism, Gene Regulatory Networks drug effects, Gene Regulatory Networks physiology, Humans, Hypoglycemic Agents administration & dosage, Mice, Mice, Inbred C57BL, Rats, Rats, Long-Evans, Rats, Sprague-Dawley, Diabetes Mellitus, Experimental genetics, Diabetic Retinopathy genetics, Drug Delivery Systems methods, Gene Expression Profiling methods, Systems Biology methods
- Abstract
Diabetic retinopathy was included by the World Health Organization in the eye disease priority list. Up to now, only proliferative diabetic retinopathy can be treated with approved drugs, such as intravitreal anti-vascular endothelial growth factor (VEGF) agents or steroids. In this perspective, there is the urgent need to explore novel pharmacological targets for treatment of diabetic retinopathy. Drug discovery todays exploits the noticeable ability of computational systems biology methods to identify novel drug targets in complex pathologies bearing multifactorial etiology and wide and varying symptomatology. This is especially true for diseases, where the identification of specific molecular mechanisms, and thus drug targets, is a challenging, when not impossible, task. Within this framework, we applied a systems biology approach to identify novel drug targets for diabetic retinopathy. The complexity of diabetic retinopathy was investigated through the analysis of transcriptomics data, retrieved from Gene Expression Omnibus Dataset repository (GEO) datasets. Analysis of GEO datasets was carried out with an enrichment-information approach, which gave as output a series of complex gene-pathway and drug-gene networks. Analysis of these networks identified genes and biological pathways related with inflammation, fibrosis and G protein-coupled receptors that are potentially involved in development of the disease. This analysis provided new clues on novel pharmacological targets, useful to treat diabetic retinopathy., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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15. Endocannabinoid system, stress and HPA axis.
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Micale V and Drago F
- Subjects
- Animals, Humans, Signal Transduction, Stress, Psychological pathology, Stress, Psychological physiopathology, Endocannabinoids metabolism, Hypothalamus metabolism, Hypothalamus pathology, Hypothalamus physiopathology, Pituitary-Adrenal System metabolism, Pituitary-Adrenal System pathology, Pituitary-Adrenal System physiopathology, Stress, Psychological metabolism
- Abstract
The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆
9 -tetrahydrocannabinol (∆9 -THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9 -THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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16. Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome.
- Author
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Caraci F, Iulita MF, Pentz R, Flores Aguilar L, Orciani C, Barone C, Romano C, Drago F, and Cuello AC
- Subjects
- Alzheimer Disease diagnosis, Alzheimer Disease drug therapy, Animals, Biomarkers metabolism, Down Syndrome drug therapy, Humans, Alzheimer Disease metabolism, Down Syndrome metabolism
- Abstract
Individuals with Down syndrome are at increased risk of developing Alzheimer's disease due to increase gene dosage resulting from chromosome 21 triplication. Although virtually all adults with Down syndrome will exhibit the major neuropathological hallmarks that define Alzheimer's disease, not all of them will develop the clinical symptoms associated with this disorder (i.e. dementia). Therefore, a good understanding of the pathophysiology of Alzheimer's disease in Down syndrome will be crucial for the identification of novel pharmacological targets to develop disease-modifying therapies for the benefit of Down syndrome individuals and for Alzheimer's sufferers alike. The study of biomarkers will also be essential for the development of better screening tools to identify dementia at its incipient stages. This review discusses the best-validated pharmacological targets for the treatment of cognitive impairment and Alzheimer's disease in Down syndrome. We further examine the relevance of newly discovered biological markers for earlier dementia diagnosis in this population., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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17. Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE.
- Author
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Giurdanella G, Lazzara F, Caporarello N, Lupo G, Anfuso CD, Eandi CM, Leggio GM, Drago F, Bucolo C, and Salomone S
- Subjects
- Blood-Retinal Barrier enzymology, Blood-Retinal Barrier metabolism, Cell Survival drug effects, Cells, Cultured, Diabetic Retinopathy metabolism, Diabetic Retinopathy prevention & control, Glycosaminoglycans isolation & purification, Humans, Primary Cell Culture, Blood-Retinal Barrier drug effects, Cyclooxygenase 2 metabolism, Glycation End Products, Advanced metabolism, Glycosaminoglycans pharmacology, Phospholipases A2 metabolism, Receptor for Advanced Glycation End Products metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE
2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA2 , an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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18. P2X7 receptor antagonism: Implications in diabetic retinopathy.
- Author
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Platania CBM, Giurdanella G, Di Paola L, Leggio GM, Drago F, Salomone S, and Bucolo C
- Subjects
- Allosteric Site drug effects, Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Apoptosis drug effects, Biomarkers metabolism, Cells, Cultured, Computational Biology, Databases, Chemical, Databases, Protein, Diabetic Retinopathy immunology, Diabetic Retinopathy metabolism, Diabetic Retinopathy pathology, Expert Systems, Humans, Ligands, Molecular Conformation, Molecular Docking Simulation, Niacinamide chemistry, Niacinamide metabolism, Niacinamide pharmacokinetics, Niacinamide pharmacology, Pericytes immunology, Pericytes metabolism, Pericytes pathology, Piperazines chemistry, Piperazines metabolism, Piperazines pharmacokinetics, Purinergic P2X Receptor Antagonists chemistry, Purinergic P2X Receptor Antagonists metabolism, Purinergic P2X Receptor Antagonists pharmacokinetics, ROC Curve, Receptors, Purinergic P2X7 chemistry, Structural Homology, Protein, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Diabetic Retinopathy drug therapy, Models, Molecular, Niacinamide analogs & derivatives, Pericytes drug effects, Piperazines pharmacology, Purinergic P2X Receptor Antagonists pharmacology, Receptors, Purinergic P2X7 metabolism
- Abstract
Diabetic retinopathy (DR) is the most frequent complication of diabetes and one of leading causes of blindness worldwide. Early phases of DR are characterized by retinal pericyte loss mainly related to concurrent inflammatory process. Recently, an important link between P2X7 receptor (P2X7R) and inflammation has been demonstrated indicating this receptor as potential pharmacological target in DR. Here we first carried out an in silico molecular modeling study in order to characterize the allosteric pocket in P2X7R, and identify a suitable P2X7R antagonist through molecular docking. JNJ47965567 was identified as the hit compound in docking calculations, as well as for its absorption, distribution, metabolism and excretion (ADME) profile. As an in vitro model of early diabetic retinopathy, human retinal pericytes were exposed to high glucose (25mM, 48h) that caused a significant (p<0.05) release of IL-1β and LDH. The block of P2X7R by JNJ47965567 significantly (p<0.05) reverted the damage elicited by high glucose, detected as IL-1β and LDH release. Overall, our findings suggest that the P2X7R represents an attractive pharmacological target to manage the early phase of diabetic retinopathy, and the compound JNJ47965567 is a good template to discover other P2X7R selective antagonists., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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19. TGF-β1 prevents rat retinal insult induced by amyloid-β (1-42) oligomers.
- Author
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Fisichella V, Giurdanella G, Platania CB, Romano GL, Leggio GM, Salomone S, Drago F, Caraci F, and Bucolo C
- Subjects
- Animals, Cytoprotection drug effects, Humans, Male, Protein Structure, Secondary, Proto-Oncogene Proteins c-bcl-2 metabolism, Rats, Rats, Sprague-Dawley, Retina cytology, bcl-2-Associated X Protein metabolism, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides toxicity, Peptide Fragments chemistry, Peptide Fragments toxicity, Protein Multimerization, Retina drug effects, Transforming Growth Factor beta1 pharmacology
- Abstract
To set up a retinal degenerative model in rat that mimics pathologic conditions such as age-related macular degeneration (AMD) using amyloid-β (Aβ) oligomers, and assess the effect of TGF-β1. Sprague-Dawley male rats were used. Human Aβ1-42 oligomers were intravitreally (ITV) injected (10µM) in the presence or in the absence of recombinant human TGF-β1 (1ng/μl ITV injected). After 48h, the animals were sacrificed and the eyes removed and dissected. The apoptotic markers Bax and Bcl-2 were assessed by western blot analysis in retina lysates. Gene-pathway network analysis was carried out in order to identify pathways involved in AMD. Treatment with Aβ oligomers induced a strong increase in Bax protein level (about 4-fold; p<0.01) and a significant reduction in Bcl-2 protein level (about 2-fold; p<0.05). Co-injection of TGF-β1 triggered a significant reduction of Bax protein induced by Aβ oligomers. Bioinformatic analysis revealed that Bcl-2 and PI3K-Akt are the most connected nodes, for genes and pathways respectively, in the enriched gene-pathway network common to AMD and Alzheimer disease (AD). Overall, these data indicate that ITV injection of Aβ1-42 oligomers in rat induces molecular changes associated with apoptosis in rat retina, highlighting a potential pathogenetic role of Aβ oligomers in AMD. Bioinformatics analysis confirms that apoptosis pathways can take part in AMD. Furthermore, these findings suggest that human recombinant TGF-β1 can prevent retinal damage elicited by Aβ oligomers., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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20. Astroglial type-1 cannabinoid receptor (CB1): A new player in the tripartite synapse.
- Author
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Oliveira da Cruz JF, Robin LM, Drago F, Marsicano G, and Metna-Laurent M
- Subjects
- Animals, Brain metabolism, Humans, Memory, Short-Term physiology, Neuronal Plasticity physiology, Astrocytes metabolism, Neurons metabolism, Receptor, Cannabinoid, CB1 metabolism, Synapses metabolism, Synaptic Transmission physiology
- Abstract
The endocannabinoid system is an important regulator of physiological functions. In the brain, this control is mainly exerted through the type-1-cannabinoid (CB1) receptors. CB1 receptors are abundant at neuron terminals where their stimulation inhibits neurotransmitter release. However, CB1 receptors are also expressed in astrocytes and recent studies showed that astroglial cannabinoid signaling is a key element of the tripartite synapse. In this review we discuss the different mechanisms by which astroglial CB1 receptors control synaptic transmission and plasticity. The recent involvement of astroglial CB1 receptors in the effects of cannabinoids on memory highlights their key roles in cognitive processes and further indicates that astrocytes are central active elements of high-order brain functions., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2016
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21. Gianotti-Crosti syndrome as presenting sign of cytomegalovirus infection: A case report and a critical appraisal of its possible cytomegalovirus etiology.
- Author
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Drago F, Javor S, Ciccarese G, and Parodi A
- Subjects
- Child, Preschool, Cytomegalovirus Infections pathology, Female, Humans, Acrodermatitis etiology, Acrodermatitis pathology, Cytomegalovirus Infections complications, Cytomegalovirus Infections diagnosis
- Abstract
Gianotti-Crosti syndrome (GCS) is a self-limiting exanthem of acute onset with a characteristic acral distribution, usually occurring in children. It is characterized by symmetric pink to red-brown papular or papulovesicular lesions that are a few millimetres in diameter, distributed on the face, buttocks and limbs. It may be accompanied by low-grade fever, hepato-splenomegaly and lymphadenopathy. GCS is considered a unique cutaneous response to viral infection, mostly associated with hepatitis B virus and Epstein-Barr virus (EBV), but other viruses, bacterial infections and recent immunizations may be inciting factors. We report a case of a 3-year-old girl presenting generalized, pruritic, papulovesicular eruption on the face and extremities for one month. In our case, GCS was related to cytomegalovirus (CMV) primary infection and may be considered the presenting sign of the infection., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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22. Genetic blockade of the dopamine D3 receptor enhances hippocampal expression of PACAP and receptors and alters their cortical distribution.
- Author
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Marzagalli R, Leggio GM, Bucolo C, Pricoco E, Keay KA, Cardile V, Castorina S, Salomone S, Drago F, and Castorina A
- Subjects
- Analysis of Variance, Animals, Cerebral Cortex anatomy & histology, Hippocampus anatomy & histology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuroimaging, Neurons metabolism, Receptors, Dopamine D3 genetics, Receptors, Vasoactive Intestinal Peptide, Type II metabolism, Receptors, Vasoactive Intestinal Polypeptide, Type I metabolism, Cerebral Cortex metabolism, Gene Expression Regulation genetics, Hippocampus metabolism, Pituitary Adenylate Cyclase-Activating Polypeptide metabolism, Receptors, Dopamine D3 deficiency, Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide metabolism
- Abstract
Dopamine D3 receptors (D3Rs) are implicated in several aspects of cognition, but their role in aversive conditioning has only been marginally uncovered. Investigations have reported that blockade of D3Rs enhances the acquisition of fear memories, a phenomenon tightly linked to the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP). However, the impact of D3R ablation on the PACAPergic system in regions critical for the formation of new memories remains unexplored. To address this issue, levels of PACAP and its receptors were compared in the hippocampus and cerebral cortex (CX) of mice devoid of functional D3Rs (D3R(-/-)) and wild-types (WTs) using a series of comparative immunohistochemical and biochemical analyses. Morphometric and stereological data revealed increased hippocampal area and volume in D3R(-/-) mice, and augmented neuronal density in CA1 and CA2/3 subfields. PACAP levels were increased in the hippocampus of D3R(-/-) mice. Expression of PACAP receptors was also heightened in mutant mice. In the CX, PACAP immunoreactivity (IR), was restricted to cortical layer V in WTs, but was distributed throughout layers IV-VI in D3R(-/-) mice, along with increased mRNAs, protein concentration and staining scores. Consistently, PAC1, VPAC1 and VPAC2 IRs were variably redistributed in CX, with a general upregulation in cortical layers II-IV in knockout animals. Our interpretation of these findings is that disturbed dopamine neurotransmission due to genetic D3R blockade may enhance the PACAP/PAC1-VPAC axis, a key endogenous system for the processing of fear memories. This could explain, at least in part, the facilitated acquisition and consolidation of aversive memories in D3R(-/-) mice., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2016
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23. Atypical exanthems associated with HHV-6 reactivation after hematopoietic cell transplantation.
- Author
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Drago F, Ciccarese G, Broccolo F, Cozzani E, and Parodi A
- Subjects
- Adult, Female, Herpesvirus 6, Human isolation & purification, Humans, Male, Middle Aged, Exanthema pathology, Hematopoietic Stem Cell Transplantation adverse effects, Herpesvirus 6, Human physiology, Roseolovirus Infections pathology, Virus Activation
- Published
- 2015
- Full Text
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24. Diversity, specificity and speciation in larval Diplostomidae (Platyhelminthes: Digenea) in the eyes of freshwater fish, as revealed by DNA barcodes.
- Author
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Locke SA, Al-Nasiri FS, Caffara M, Drago F, Kalbe M, Lapierre AR, McLaughlin JD, Nie P, Overstreet RM, Souza GT, Takemoto RM, and Marcogliese DJ
- Subjects
- Animals, Cluster Analysis, DNA, Ribosomal Spacer genetics, Electron Transport Complex IV genetics, Eye Diseases parasitology, Fresh Water parasitology, Genetic Variation, Larva, Life Cycle Stages genetics, Molecular Sequence Data, Phylogeny, Sequence Analysis, DNA, Species Specificity, Trematoda classification, Trematoda isolation & purification, DNA Barcoding, Taxonomic methods, Eye Diseases veterinary, Fish Diseases parasitology, Trematoda genetics
- Abstract
Larvae (metacercariae) in some species of Diplostomidae (Platyhelminthes: Digenea) inhabit fish eyes and are difficult to identify to species based on morphology. DNA barcoding has clarified the diversity and life cycles of diplostomids in North America, Europe and Africa, but has seldom been used in parasites sampled in large numbers or at large spatial scales. Here, distance-based analysis of cytochrome c oxidase 1 barcodes and, in some specimens, internal transcribed spacer (ITS-1, 5.8S, ITS-2) sequences was performed for over 2000 diplostomids from Africa, the Middle East, Europe, Asia and the Americas. Fifty-two species of Diplostomum, Tylodelphys and Austrodiplostomum (Digenea: Diplostomidae) were distinguished. The 52 species comprise 12 identified species, six species in two species complexes and 34 putative species, and 33/52 had been delineated in previous studies. Most (23/40) of the unidentified, putative species distinguished by cytochrome c oxidase 1 distances were supported by at least one additional line of evidence. As the intensity of sampling of the 52 species increased, variation in cytochrome c oxidase 1 decreased between and increased within species, while the spatial scale at which species were sampled had no effect. Nonetheless, variation between species always exceeded variation within species. New life-cycle linkages, geographic and host records, and genetic data were recorded in several species, including Tylodelphys jenynsiae, Tylodelphys immer and Diplostomum ardeae. Species of Diplostomum inhabiting the lens are less host-specific and less numerous than those infecting other tissues, suggesting that reduced immune activity in the lens has influenced rates of speciation., (Copyright © 2015 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2015
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25. Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity.
- Author
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Caraci F, Pappalardo G, Basile L, Giuffrida A, Copani A, Tosto R, Sinopoli A, Giuffrida ML, Pirrone E, Drago F, Pignatello R, and Guccione S
- Subjects
- Amyloid beta-Peptides toxicity, Animals, Cell Death drug effects, Cells, Cultured, Cerebral Cortex cytology, Peptide Fragments toxicity, Rats, Amides pharmacology, Monoamine Oxidase Inhibitors pharmacology, Neurons drug effects, Neuroprotective Agents pharmacology, Tranylcypromine pharmacology
- Abstract
Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer's disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-β (Aβ)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Aβ-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 µM. TCP-But was maximally protective in mixed neuronal cultures at 1 µM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Aβ toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Aβ aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Aβ(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Aβ(1-42) oligomers with TCP-Ac was able to almost completely prevent Aβ-induced neurodegeneration. These results suggest that inhibition of Aβ oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
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26. Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway.
- Author
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Giurdanella G, Anfuso CD, Olivieri M, Lupo G, Caporarello N, Eandi CM, Drago F, Bucolo C, and Salomone S
- Subjects
- Arachidonic Acids pharmacology, Bevacizumab, Cell Count, Cell Survival drug effects, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Enzyme Inhibitors pharmacology, Feedback, Physiological, Gene Expression Regulation, Glucose toxicity, Humans, Pericytes cytology, Pericytes metabolism, Phospholipases A2 genetics, Phospholipases A2 metabolism, Phosphorylation drug effects, Primary Cell Culture, Ranibizumab, Retina cytology, Retina metabolism, Signal Transduction, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 genetics, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Angiogenesis Inhibitors pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Glucose antagonists & inhibitors, Pericytes drug effects, Receptors, Vascular Endothelial Growth Factor pharmacology, Recombinant Fusion Proteins pharmacology, Retina drug effects
- Abstract
Diabetic retinopathy, a major cause of vision loss, is currently treated with anti-VEGF agents. Here we tested two hypotheses: (i) high glucose damages retinal pericytes, the cell layer surrounding endothelial cells, via VEGF induction, which may be counteracted by anti-VEGFs and (ii) activation of PLA2/COX-2 pathway by high glucose might be upstream and/or downstream of VEGF in perycites, as previously observed in endothelial cells. Human retinal pericytes were treated with high glucose (25mM) for 48h and/or anti-VEGFs (40μg/ml aflibercept, 25μg/ml bevacizumab, 10μg/ml ranibizumab). All anti-VEGFs significantly prevented high glucose-induced cell damage (assessed by LDH release) and improved cell viability (assessed by MTT and Evans blue). High glucose-induced VEGF-A expression, as detected both at mRNA (qPCR) and protein (ELISA) level, while receptor (VEGFR1 and VEGFR2) expression, detected in control condition, was unaffected by treatments. High glucose induced also activation of PLA2/COX-2 pathway, as revealed by increased phosphorylation of cPLA2, COX-2 expression and PGE2 release. Treatment with cPLA2 (50μM AACOCF3) and COX-2 (5μM NS-392) inhibitors prevented both cell damage and VEGF-A induced by high glucose. Finally, challenge with exogenous VEGF-A (10ng/ml) induced VEGF-A expression, while anti-VEGFs reduced VEGF-A expression induced by either high glucose or exogenous VEGF-A. These data indicate that high glucose directly damages pericytes through activation of PLA2/COX-2/VEGF-A pathway. Furthermore, a kind of feed-forward loop between cPLA2/COX-2/PG axis and VEGF appears to operate in this system. Thus, anti-VEGFs afford protection of pericytes from high glucose by inhibiting this loop., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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27. Effects of novel hybrids of caffeic acid phenethyl ester and NSAIDs on experimental ocular inflammation.
- Author
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Pittalà V, Salerno L, Romeo G, Siracusa MA, Modica MN, Romano GL, Salomone S, Drago F, and Bucolo C
- Subjects
- Animals, Caffeic Acids adverse effects, Caffeic Acids chemical synthesis, Inflammation drug therapy, Inflammation pathology, Male, Phenylethyl Alcohol adverse effects, Phenylethyl Alcohol chemical synthesis, Phenylethyl Alcohol chemistry, Phenylethyl Alcohol pharmacology, Rabbits, Anti-Inflammatory Agents, Non-Steroidal chemistry, Aspirin chemistry, Caffeic Acids chemistry, Caffeic Acids pharmacology, Eye Diseases drug therapy, Eye Diseases pathology, Indomethacin chemistry, Phenylethyl Alcohol analogs & derivatives
- Abstract
In this study, we report the design and synthesis of novel hybrids of caffeic acid phenetyl ester (CAPE) and non-steroidal anti-inflammatory drugs (NSAIDs). We assessed their effects on an experimental ocular inflammation in New Zealand rabbits. The formulations of CAPE-aspirin and CAPE-indomethacin hybrids were topical instilled in the rabbit׳s eye. Afterwards, the anti-inflammatory activity was evaluated by grading the clinical signs and by assessing the inflammatory cell count, protein, PGE2 and TNFα levels in the aqueous humor. Furthermore, ocular tolerability of hybrids formulations was evaluated in a separate set of animals by using a modified Draize test. The ocular inflammation in the control group was significantly higher than in both the hybrid-treated groups, as indicated by clinical grading and biomarkers assessment. However, only the CAPE-aspirin hybrid reduced, in a significant dose-dependent manner, the ocular inflammation elicited by paracentesis. CAPE-indomethacin hybrid was able to significantly attenuate the clinical grading and the PGE2 aqueous levels only at the highest dose (0.1%). CAPE-aspirin significantly reduced PGE2 and TNFα levels in the aqueous humor as well as proteins and PMNs. Finally, all formulations showed no ocular irritation compared with vehicle-treated group. In conclusion, CAPE-aspirin shows full anti-inflammatory efficacy in experimental model of ocular inflammation demonstrating an optimal pharmacological and safety profile. Taken together these data indicate that CAPE-aspirin hybrid represents a valid and safe new chemical entity potentially useful for the treatment of ocular inflammation., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
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28. Regulation of vascular tone in rabbit ophthalmic artery: cross talk of endogenous and exogenous gas mediators.
- Author
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Salomone S, Foresti R, Villari A, Giurdanella G, Drago F, and Bucolo C
- Subjects
- Animals, Cyclic GMP biosynthesis, Ophthalmic Artery metabolism, Ophthalmic Artery physiology, Rabbits, Carbon Monoxide pharmacology, Hydrogen Sulfide pharmacology, Muscle Tonus, Nitric Oxide pharmacology, Ophthalmic Artery drug effects
- Abstract
Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S) modulate vascular tone. In view of their therapeutic potential for ocular diseases, we examined the effect of exogenous CO and H2S on tone of isolated rabbit ophthalmic artery and their interaction with endogenous and exogenous NO. Ophthalmic artery segments mounted on a wire myograph were challenged with cumulative concentrations of phenylephrine (PE) in the presence or absence of NG-nitro-L-arginine (LNNA) to inhibit production of NO, the CO-releasing molecules CORMs or the H2S-donor GYY4137. The maximal vasoconstriction elicited by PE reached 20-30% of that induced by KCl but was dramatically increased by incubation with LNNA. GYY4137 significantly raised PE-mediated vasoconstriction, but it did not change the response to PE in the presence of LNNA or the relaxation to sodium nitroprusside (SNP). CORMs concentration-dependently inhibited PE-induced constriction, an effect that was synergistic with endogenous NO (reduced by LNNA), but insensitive to blockade of guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-α]quinoxalin-1-one (ODQ). In vascular tissues cyclic GMP (cGMP) levels seemed reduced by GYY4137 (not significantly), but were not changed by CORM. These data indicate that CO is able per se to relax isolated ophthalmic artery and to synergize with NO, while H2S counteracts the effect of endogenous NO. CO does not stimulate cGMP production in our system, while H2S may reduce cGMP production stimulated by endogenous NO. These findings provide new insights into the complexities of gas interactions in the control of ophthalmic vascular tone, highlighting potential pharmacological targets for ocular diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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29. The saliva quantitative PCR assay is inadequate to detect and monitor human herpesvirus-7 and -6 reactivation in patients with Pityriasis rosea.
- Author
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Broccolo F, Ciccarese G, Oggioni M, Rebora A, Parodi A, and Drago F
- Subjects
- Adolescent, Adult, DNA, Viral analysis, DNA, Viral isolation & purification, Female, Herpesvirus 6, Human genetics, Herpesvirus 6, Human physiology, Herpesvirus 7, Human genetics, Herpesvirus 7, Human physiology, Humans, Male, Plasma virology, Viral Load, Young Adult, Herpesvirus 6, Human isolation & purification, Herpesvirus 7, Human isolation & purification, Pityriasis Rosea virology, Real-Time Polymerase Chain Reaction methods, Saliva virology, Virus Activation
- Published
- 2014
- Full Text
- View/download PDF
30. Role of phospholipases A2 in diabetic retinopathy: in vitro and in vivo studies.
- Author
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Lupo G, Motta C, Giurdanella G, Anfuso CD, Alberghina M, Drago F, Salomone S, and Bucolo C
- Subjects
- Animals, Blood-Retinal Barrier immunology, Blood-Retinal Barrier pathology, Cattle, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Coculture Techniques, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental immunology, Diabetes Mellitus, Experimental pathology, Diabetic Retinopathy etiology, Diabetic Retinopathy immunology, Diabetic Retinopathy pathology, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells enzymology, Glucose pharmacology, Male, Microscopy, Confocal, Pericytes cytology, Pericytes drug effects, Pericytes enzymology, Phospholipase A2 Inhibitors pharmacology, Phospholipases A2 biosynthesis, Rats, Rats, Sprague-Dawley, Streptozocin pharmacology, Vascular Endothelial Growth Factor A metabolism, Blood-Retinal Barrier enzymology, Diabetes Mellitus, Experimental enzymology, Diabetic Retinopathy enzymology, Phospholipases A2 metabolism
- Abstract
Diabetic retinopathy is one of the leading causes of blindness and the most common complication of diabetes with no cure available. We investigated the role of phospholipases A2 (PLA2) in diabetic retinopathy using an in vitro blood-retinal barrier model (BRB) and an in vivo streptozotocin (STZ)-induced diabetic model. Mono- and co-cultures of endothelial cells (EC) and pericytes (PC), treated with high or fluctuating concentrations of glucose, to mimic the diabetic condition, were used. PLA2 activity, VEGF and PGE2 levels and cell proliferation were measured, with or without PLA2 inhibition. Diabetes was induced in rats by STZ injection and PLA2 activity along with VEGF, TNFα and ICAM-1 levels were measured in retina. High or fluctuating glucose induced BRB breakdown, and increased PLA2 activity, PGE2 and VEGF in EC/PC co-cultures; inhibition of PLA2 in mono- or co-cultures treated with high or fluctuating glucose dampened PGE2 and VEGF production down to the levels of controls. High or fluctuating glucose increased EC number and reduced PC number in co-cultures; these effects were reversed after transfecting EC with small interfering RNA targeted to PLA2. PLA2 and COX-2 protein expressions were significantly increased in microvessels from retina of diabetic rats. Diabetic rats had also high retinal levels of VEGF, ICAM-1 and TNFα that were reduced by treatment with a cPLA2 inhibitor. In conclusion, the present findings indicate that PLA2 upregulation represents an early step in glucose-induced alteration of BRB, possibly upstream of VEGF; thus, PLA2 may be an interesting target in managing diabetic retinopathy., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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31. Dopamine D(3) receptor as a new pharmacological target for the treatment of depression.
- Author
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Leggio GM, Salomone S, Bucolo C, Platania C, Micale V, Caraci F, and Drago F
- Subjects
- Animals, Central Nervous System drug effects, Central Nervous System metabolism, Depression etiology, Depression metabolism, Depression microbiology, Dopamine metabolism, Humans, Depression drug therapy, Molecular Targeted Therapy methods, Receptors, Dopamine D3 metabolism
- Abstract
A substantial proportion of depressed patients do not respond to current antidepressant drug therapies. So far, antidepressant drugs have been developed based on the "monoaminergic hypothesis" of depression, which considers a synaptic deficiency in 5-hydroxytryptamine (5-HT; serotonin) or noradrenaline as main cause. More recently, the dopaminergic system has been implicated in the efficacy of some antidepressants, such as desipramine, amineptine, nomifensine. Dysfunction of dopaminergic neurotransmission within the mesolimbic system may contribute to anhedonia, loss of motivation and psychomotor retardation in severe depressive disorders. Dopamine D3 receptor subtype is located both pre- and postsynaptically in brain areas regulating motivation and reward-related behavior and has been implicated in depression-like behaviors. Activity of mesolimbic dopamine neurons in the reward circuit is a key determinant of behavioral susceptibility/resilience to chronic stress, which plays a central role in the pathogenesis of depression. Dopamine D3 receptor expression and function are both down-regulated in stress and depression, and these changes are reversed by antidepressant treatments, suggesting that enhanced dopaminergic neurotransmission mediated by dopamine D3 receptor participates in adaptive changes related to antidepressant activity. Of note, brain derived neurotrophic factor (BDNF) controls the expression of the dopamine D3 receptor in some brain areas and BDNF induction by antidepressant treatments is related to their behavioral activity. A number of experimental drugs in pre-clinical or clinical development, including aripiprazole and cariprazine, may act as antidepressants because of their partial agonist activity at dopamine D3 receptors. These preclinical and clinical data are discussed in the present review., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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32. Regulation of intraocular pressure in mice: structural analysis of dopaminergic and serotonergic systems in response to cabergoline.
- Author
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Platania CB, Leggio GM, Drago F, Salomone S, and Bucolo C
- Subjects
- Animals, Cabergoline, Dose-Response Relationship, Drug, Ergolines chemistry, Ergolines metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Docking Simulation, Molecular Dynamics Simulation, Ocular Hypertension chemically induced, Ocular Hypertension drug therapy, Ocular Hypertension physiopathology, Protein Conformation, Receptor, Serotonin, 5-HT1A chemistry, Receptor, Serotonin, 5-HT1A metabolism, Receptor, Serotonin, 5-HT2A metabolism, Receptor, Serotonin, 5-HT2B metabolism, Receptors, Dopamine D3 chemistry, Receptors, Dopamine D3 genetics, Receptors, Dopamine D3 metabolism, Sequence Alignment, Dopamine Agonists pharmacology, Ergolines pharmacology, Intraocular Pressure drug effects, Receptor, Serotonin, 5-HT2A chemistry, Receptor, Serotonin, 5-HT2B chemistry
- Abstract
Elevated intraocular pressure (IOP) is the main recognized risk factor of glaucoma. To investigate the contribution of dopaminergic and serotonergic systems in IOP regulation, we used cabergoline, a mixed dopamine and serotonin agonist, in C57BL/6J WT and dopamine D₃ receptor knock-out (D₃R⁻/⁻) mice with normal eye pressure or steroid-induced ocular hypertension. Furthermore, we studied the structural basis of the cabergoline-mediated activation of the dopaminergic and serotonergic systems by molecular modeling. Topical application of cabergoline, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice, both in an ocular normotensive group (-9, -5 and -2 mmHg with 5%, 1%, and 0.1%, respectively) and an ocular hypertensive group, with a prolonged effect in this latter group. No change of intraocular pressure was observed after topical application of cabergoline in D₃R⁻/⁻ mice. We modeled and optimized, with molecular dynamics, structures of hD₃, h5HT(1A) and h5HT(2A-C) receptors; thereafter we carried out molecular docking of cabergoline. Docking revealed that binding of cabergoline into D₃ and 5HT(1A) receptors is associated with a better desolvation energy in comparison to 5HT(2A-C) binding. In conclusion, the present study support the hypothesis that dopaminergic system is pivotal to regulate IOP and that D₃R represents an intriguing target in the treatment of glaucoma. Furthermore, the structure-based computational approach adopted in this study is able to build and refine structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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33. Dopamine D3 receptor deletion increases tissue plasminogen activator (tPA) activity in prefrontal cortex and hippocampus.
- Author
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Castorina A, D'Amico AG, Scuderi S, Leggio GM, Drago F, and D'Agata V
- Subjects
- Animals, Blotting, Western, Brain-Derived Neurotrophic Factor metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism, Fibrinolysin metabolism, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Immunohistochemistry, Learning physiology, Male, Memory physiology, Mice, Mice, Knockout, Oncogene Protein v-akt metabolism, Phosphorylation, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Ribosomal, 18S metabolism, Real-Time Polymerase Chain Reaction, Hippocampus metabolism, Prefrontal Cortex metabolism, Receptors, Dopamine D3 genetics, Receptors, Dopamine D3 physiology, Tissue Plasminogen Activator metabolism
- Abstract
Considerable evidence indicates that dopamine (DA) influences tissue plasminogen activator (tPA)-mediated proteolytic processing of the precursor of brain-derived neurotrophic factor (proBDNF) into mature BDNF (mBDNF). However, specific roles in this process for the dopamine D3 receptor (D3R) and the underlying molecular mechanisms are yet to be fully characterized. In the present study, we hypothesized that D3R deletion could influence tPA activity in the prefrontal cortex and hippocampus. Using D3R knockout (D3(-/-)) mice, we show that receptor inactivation is associated with increased tPA expression/activity both in the prefrontal cortex and, to a greater extent, in the hippocampus. Augmented tPA expression in D3(-/-) mice correlated with increased BDNF mRNA levels, plasmin/plasminogen protein ratio and the conversion of proBDNF into mBDNF, as well as enhanced tPA and mBDNF immunoreactivity, as determined by quantitative real time polymerase chain reaction (qRT-PCR), immunoblot and immunohistochemistry. In addition, when compared to wild-type controls, D3(-/-) mice exhibited increased basal activation of the canonical cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-driven Akt/cAMP-response element-binding protein (CREB) signaling cascade, as determined by the increased Akt phosphorylation both at Thr304 and Ser473 residues, of DA and cAMP-regulated protein of 32kDa (DARPP-32) at Thr34 and a phosphorylation state-dependent inhibition of glycogen synthetase kinase-3β (GSK-3β) at Ser9, a substrate of Akt whose constitutive function impairs normal CREB transcriptional activity through phosphorylation at its Ser129 residue. Accordingly, CREB phosphorylation at Ser133 was significantly increased in D3(-/-) mice, whereas the GSK-3β-dependent phosphorylation at Ser129 was diminished. Altogether, our finding reveals that mice lacking D3Rs show enhanced tPA proteolytic activity on BDNF which may involve, at least in part, a potentiated Akt/CREB signaling, possibly due to hindered GSK-3β activity., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2013
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34. Reversible inhibition of vasoconstriction by thiazolidinediones related to PI3K/Akt inhibition in vascular smooth muscle cells.
- Author
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Sinagra T, Tamburella A, Urso V, Siarkos I, Drago F, Bucolo C, and Salomone S
- Subjects
- Anilides pharmacology, Animals, Chromans pharmacology, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Femoral Artery, Male, Muscle, Smooth, Vascular physiology, Myocytes, Smooth Muscle physiology, Nitroarginine pharmacology, PPAR gamma antagonists & inhibitors, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Pioglitazone, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Rats, Rats, Sprague-Dawley, Rosiglitazone, Troglitazone, Muscle, Smooth, Vascular cytology, Myocytes, Smooth Muscle drug effects, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Thiazolidinediones pharmacology, Vasoconstriction drug effects
- Abstract
Thiazolidinediones (also referred to as glitazones), agonists for Peroxisome Proliferator-Activated Receptor gamma (PPARγ), are used for treating type 2 diabetes mellitus, where they decrease insulin resistance and cardiovascular risk. Compounds bearing the thiazolidinedione structure have also been shown to inhibit phosphoinositide 3-kinase (PI3K). Here we tried to elucidate the poorly defined role of PI3K/Akt in the physiology of vascular smooth muscle cell contraction and tested the hypothesis that thiazolidinediones, by affecting the PI3K/Akt pathway, may influence vascular physiology. Isolated rat femoral arteries segments were mounted in a wire myograph and challenged with 100mM KCl or phenylephrine (PE), in the absence or presence of troglitazone, rosiglitazone, pioglitazone, LY294002 (PI3K inhibitor) and 10-DEBC (Akt inhibitor). All these compounds dose-dependently inhibited vasoconstriction to KCl or PE; their effect was reversible (after 60-120 min washout) and not affected by GW9662 (a PPARγ antagonist) or by N(G)-nitro-L-arginine (LNNA, an inhibitor of NO biosynthesis). Analysis of phospho-Akt (ser 473) in lysates from rat arteries (by immunoblot) revealed that thiazolidinediones, LY294002 and 10-DEBC, at the same concentration and kinetics inhibiting vasoconstriction, produced a similar decrease of Akt phosphorylation. PI3K/Akt pathway therefore appears to be an important, fast acting, modulator of contraction of vascular smooth muscle. Thiazolidinediones decrease vasoconstriction of isolated vessels possibly by inhibiting PI3K/Akt pathway. Such an effect of glitazones, if occurring in vivo, may impact cardiovascular syndromes related to vasospasm in diabetic patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2013
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35. Eriodictyol prevents early retinal and plasma abnormalities in streptozotocin-induced diabetic rats.
- Author
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Bucolo C, Leggio GM, Drago F, and Salomone S
- Subjects
- Animals, Antioxidants administration & dosage, Antioxidants chemistry, Blood-Retinal Barrier immunology, Blood-Retinal Barrier metabolism, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental immunology, Diabetic Retinopathy blood, Diabetic Retinopathy etiology, Diabetic Retinopathy immunology, Dose-Response Relationship, Drug, Flavanones administration & dosage, Flavanones chemistry, Lipid Peroxidation drug effects, Male, Molecular Structure, Oxidative Stress drug effects, Rats, Rats, Sprague-Dawley, Retina drug effects, Retina immunology, Retina metabolism, Antioxidants therapeutic use, Blood-Retinal Barrier drug effects, Diabetes Mellitus, Experimental drug therapy, Diabetic Retinopathy prevention & control, Flavanones therapeutic use, Lipid Peroxides blood
- Abstract
Diabetic retinopathy is a complex disease that has potential involvement of inflammatory and oxidative stress-related pathways in its pathogenesis. We hypothesized that eriodictyol, one of the most abundant dietary flavonoids, could be effective against diabetic retinopathy, which involves significant oxidative stress and inflammation. The aim of the present study was to investigate the effects of eriodictyol in early retinal and plasma changes of streptozotocin-induced diabetic rats. The effect of eriodictyol treatment (0.1, 1, 10 mg/kg daily for 10 days) was evaluated by TNF-α, ICAM-1, VEGF, and eNOS protein levels measurement in the retina, plasma lipid peroxidation, and blood-retinal barrier (BRB) integrity. Increased amounts of cytokines, adhesion molecule, and nitric oxide synthase were observed in retina from diabetic rats. Eriodictyol treatment significantly lowered retinal TNF-α, ICAM-1, VEGF, and eNOS in a dose-dependent manner. Further, treatment with eriodictyol significantly suppressed diabetes-related lipid peroxidation, as well as the BRB breakdown. These data demonstrated that eriodictyol attenuates the degree of retinal inflammation and plasma lipid peroxidation preserving the BRB in early diabetic rats., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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36. The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats.
- Author
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Tamburella A, Micale V, Mazzola C, Salomone S, and Drago F
- Subjects
- Aging, Animals, Animals, Newborn, Atomoxetine Hydrochloride, Attention Deficit Disorder with Hyperactivity chemically induced, Avoidance Learning drug effects, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Female, Male, Memory drug effects, Motor Activity drug effects, Neurotransmitter Uptake Inhibitors administration & dosage, Pregnancy, Propylamines administration & dosage, Random Allocation, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Attention Deficit Disorder with Hyperactivity drug therapy, Disease Models, Animal, Neurotransmitter Uptake Inhibitors therapeutic use, Norepinephrine antagonists & inhibitors, Prenatal Exposure Delayed Effects, Propylamines therapeutic use, Trimethyltin Compounds toxicity
- Abstract
This study was carried out to assess the behavioral effects of the non-psychostimulant drug atomoxetine, in rats prenatally-exposed to the organic compound trimethyltin chloride (TMT) and in spontaneously hypertensive rat (SHR), two rodent models of Attention Deficit/Hyperactivity Disorder (ADHD). At birth, neonatal reflexes (righting, cliff aversion, forelimb placing, forelimb grasping, bar holding and startle) had an earlier onset (i.e. percent of appearance) and completion (maximum appearance, i.e. 100% of the brood exhibiting each reflex) in prenatally TMT-exposed and SHR pups as compared to control groups. Two months after birth, TMT-exposed and SHR rats showed impaired cognitive performances in both the step-through passive avoidance test and the shuttle box active avoidance test. Atomoxetine (1, 3 and 6 mg/kg, i.p.), already at the lowest dose tested, improved learning and memory capacity of prenatally TMT-exposed rats and SHR; while methylphenidate (1, 3 and 6 mg/kg, i.p.), used here as positive control, elicited a significant cognitive enhancing effect only at the higher doses. In the open field test, both TMT-exposed rats and SHR displayed enhanced locomotor activity. Methylphenidate further increased locomotor activity in all groups, whereas atomoxetine reduced the enhanced locomotor activity of TMT-exposed rats and SHR down to the level of controls. These results suggest that prenatal TMT-exposure could be considered as a putative experimental model of ADHD and further support the effectiveness of atomoxetine in the ADHD pharmacotherapy. Furthermore, despite the similar effect of the two drugs on cognitive tasks, they exhibit distinct profiles of activity on locomotion, in ADHD models., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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37. Dopamine-₃ receptor modulates intraocular pressure: implications for glaucoma.
- Author
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Bucolo C, Leggio GM, Maltese A, Castorina A, D'Agata V, and Drago F
- Subjects
- Animals, Chromatography, High Pressure Liquid, Dopamine Agonists pharmacology, Dose-Response Relationship, Drug, Glaucoma drug therapy, Glaucoma prevention & control, Indans pharmacology, Intraocular Pressure drug effects, Male, Mice, Mice, Knockout, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Dopamine D3 agonists, Receptors, Dopamine D3 antagonists & inhibitors, Receptors, Dopamine D3 genetics, Reverse Transcriptase Polymerase Chain Reaction, Tetrahydronaphthalenes pharmacology, Glaucoma metabolism, Intraocular Pressure physiology, Receptors, Dopamine D3 metabolism
- Abstract
The aim of the present study was to investigate the role of D₃ receptor on intraocular pressure regulation using WT and KO D₃R⁻/⁻ mice. Both mice were used with normal eye pressure or steroid-induced ocular hypertension. As measured by tonometry, the topical application of 7-OH-DPAT, a dopamine D₃-preferring receptor agonist, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice both in an ocular normotensive group and an ocular hypertensive group. Pretreatment with U-99194A, a D₃ receptor antagonist, reverted 7-OH-DPAT induced ocular hypotension in WT mice. No change of intraocular pressure was observed after topical application of 7-OH-DPAT in KO D₃R⁻/⁻ mice. PCR analysis demonstrated the presence of all dopamine receptor genes in eye tissues obtained from WT mice, and the lack of D₃R mRNAs in KO mice. The present study identified the D₃R subtype as the most important receptor of the dopaminergic system to modulate intraocular pressure with relevant implications for glaucoma that represents one of the most crippling optic neuropathies., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2012
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38. The PKCbeta/HuR/VEGF pathway in diabetic retinopathy.
- Author
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Amadio M, Bucolo C, Leggio GM, Drago F, Govoni S, and Pascale A
- Subjects
- Animals, Antigens, Surface genetics, Blood Glucose, Diabetes Mellitus, Experimental, ELAV Proteins, ELAV-Like Protein 1, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation physiology, Male, Phosphorylation, Protein Kinase C beta, RNA-Binding Proteins genetics, Rats, Rats, Sprague-Dawley, Retina metabolism, Antigens, Surface metabolism, Diabetic Retinopathy metabolism, Protein Kinase C metabolism, RNA-Binding Proteins metabolism
- Abstract
We investigated whether the diabetes-related PKCbeta activation affects VEGF expression through the mRNA-stabilizing human embryonic lethal abnormal vision (ELAV) protein, HuR, in the retina of streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in rats by STZ injection. Retinal tissues were processed to detect PKCbetaI, PKCbetaII, VEGF and HuR contents, as well as HuR phosphorylation. Immunoprecipitation coupled to RT-PCR was employed to evaluate HuR binding to VEGF mRNA in RiboNucleoProteic (RNP) complexes. Statistical analysis was performed by ANOVA followed by an appropriate post hoc comparison test. Following experimental diabetes PKCbetaI and PKCbetaII levels were increased compared to sham; there was also a PKC-mediated phosphorylation/activation of HuR. These effects were blunted by the in vivo co-administration of a selective PKCbeta inhibitor. A specific binding between the HuR protein and the VEGF mRNA was also detected. The PKCbeta/HuR activation was accompanied by enhanced VEGF protein expression that was, again, blunted by the PKCbeta inhibitor. These findings first demonstrate the activation, in the retina, of the PKCbeta/HuR/VEGF pathway following experimental diabetes and disclose a new potential pharmacological target to counteract pathologies implicating VEGF deregulation, such as diabetic retinopathy., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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39. Depression and Alzheimer's disease: neurobiological links and common pharmacological targets.
- Author
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Caraci F, Copani A, Nicoletti F, and Drago F
- Subjects
- Alzheimer Disease complications, Alzheimer Disease metabolism, Animals, Depressive Disorder complications, Depressive Disorder metabolism, Humans, Inflammation complications, Inflammation metabolism, Inflammation physiopathology, Intracellular Signaling Peptides and Proteins metabolism, Alzheimer Disease drug therapy, Alzheimer Disease physiopathology, Depressive Disorder drug therapy, Depressive Disorder physiopathology
- Abstract
Depression is one of the most prevalent and life-threatening forms of mental illnesses, whereas Alzheimer's disease is a neurodegenerative disorder that affects more than 37 million people worldwide. Recent evidence suggests a strong relationship between depression and Alzheimer's disease. A lifetime history of major depression has been considered as a risk factor for later development of Alzheimer's disease. The presence of depressive symptoms can affect the conversion of mild cognitive impairment into Alzheimer's disease. Neuritic plaques and neurofibrillary tangles, the two major hallmarks of Alzheimer's disease brain, are more pronounced in the brains of Alzheimer's disease patients with comorbid depression as compared with Alzheimer's disease patients without depression. On the other hand, neurodegenerative phenomena have been observed in different brain regions of patients with a history of depression. Recent evidence suggests that molecular mechanisms and cascades that underlie the pathogenesis of major depression, such as chronic inflammation and hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis, are also involved in the pathogenesis of Alzheimer's disease. In particular, a specific impairment in the signaling of some neurotrophins such as transforming-growth-factor beta1 (TGF-beta1) and brain-derived neurotrophic factor (BDNF) has been observed both in depression and Alzheimer's disease. In the present review we will examine the evidence on the common molecular pathways between depression and Alzheimer's disease and we will discuss these pathways as new pharmacological targets for the treatment of both major depression and Alzheimer's disease.
- Published
- 2010
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40. Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases.
- Author
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Broccolo F, Drago F, Paolino S, Cassina G, Gatto F, Fusetti L, Matteoli B, Zaccaria E, Parodi A, Lusso P, Ceccherini-Nelli L, and Malnati MS
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Viral blood, Child, Cross-Sectional Studies, DNA, Viral genetics, Female, Herpesvirus 6, Human isolation & purification, Herpesvirus 7, Human isolation & purification, Herpesvirus 7, Human physiology, Humans, Male, Middle Aged, Polymerase Chain Reaction methods, Prevalence, Roseolovirus Infections virology, Viremia, Young Adult, Autoimmune Diseases virology, Connective Tissue Diseases complications, Connective Tissue Diseases virology, Herpesvirus 6, Human physiology, Roseolovirus Infections complications, Roseolovirus Infections epidemiology, Virus Activation
- Abstract
Background: Little is known about the involvement of human herpesviruses 6 and 7 (HHV-6 and HHV-7) in autoimmune connective tissue diseases (ACTD)., Objective: To determine the prevalence of active infection with HHV-6 and HHV-7 in patients with ACTD., Study Design: The presence and quantity of HHV-6 DNA was determined by quantitative real-time PCR in a cross-sectional study of serum, peripheral blood mononuclear cells, and tissues obtained from 58 ACTD patients and 38 healthy subjects (HS). Specific anti-HHV-6 antibody titer was also measured., Results: HHV-6 serum viremia occurred in a significantly higher proportion of ACTD patients compared to HS [26/58 (44.8%) vs. 1/38 (2.6%), p=0.001] with the highest reactivation frequency [7/10 (70%)] observed in patients with scleroderma. Moreover, HHV-6 in serum was associated with ACTD activity (22/38 vs. 4/20, p<0.05). Higher titers of HHV-6 antibodies were found in ACTD patients than in HS, although HHV-6 seroprevalence among patients with ACTD and HS was similar. HHV-7 viremia was not detected in any patients or HS controls., Conclusion: The frequent reactivation of HHV-6 in scleroderma and other ACTD, especially when active, suggests that HHV-6 may play a role in the pathogenesis of these diseases.
- Published
- 2009
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41. Behavioral effects of the beta3 adrenoceptor agonist SR58611A: is it the putative prototype of a new class of antidepressant/anxiolytic drugs?
- Author
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Consoli D, Leggio GM, Mazzola C, Micale V, and Drago F
- Subjects
- Adrenergic beta-3 Receptor Antagonists, Adrenergic beta-Antagonists administration & dosage, Analysis of Variance, Animals, Anti-Anxiety Agents administration & dosage, Anti-Anxiety Agents pharmacology, Antidepressive Agents administration & dosage, Antidepressive Agents pharmacology, Anxiety physiopathology, Anxiety prevention & control, Clomipramine administration & dosage, Clomipramine pharmacology, Depression physiopathology, Depression prevention & control, Disease Models, Animal, Dose-Response Relationship, Drug, Grooming drug effects, Injections, Intraperitoneal, Male, Maze Learning drug effects, Methysergide administration & dosage, Methysergide pharmacology, Mice, Motor Activity drug effects, Propanolamines administration & dosage, Propanolamines pharmacology, Rats, Rats, Wistar, Receptors, Adrenergic, beta-3 physiology, Serotonin Antagonists administration & dosage, Serotonin Antagonists pharmacology, Swimming, Tetrahydronaphthalenes administration & dosage, Adrenergic beta-3 Receptor Agonists, Adrenergic beta-Antagonists pharmacology, Behavior, Animal drug effects, Tetrahydronaphthalenes pharmacology
- Abstract
A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.
- Published
- 2007
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42. A novel adamantane derivative attenuates retinal ischemia-reperfusion damage in the rat retina through sigma1 receptors.
- Author
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Bucolo C, Marrazzo A, Ronsisvalle S, Ronsisvalle G, Cuzzocrea S, Mazzon E, Caputi A, and Drago F
- Subjects
- Adamantane analogs & derivatives, Adenosine Triphosphate metabolism, Animals, Anisoles pharmacology, Glucose metabolism, Lactic Acid metabolism, Male, Propylamines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, sigma agonists, Receptors, sigma antagonists & inhibitors, Retina drug effects, Retina metabolism, Retina pathology, Retinal Diseases etiology, Retinal Diseases physiopathology, Adamantane pharmacology, Receptors, sigma physiology, Reperfusion Injury complications, Retinal Diseases prevention & control
- Abstract
The effects of a novel N-methyladamantan-1-amine derivative [(-)-MR22] with high sigma1 receptor affinity were investigated on retinal degeneration using a rat model of ischemia-reperfusion injury. The animals were anaesthetized and retinal ischemia was induced by elevating the intraocular pressure to 120 mm Hg for 45 min. The drug was injected intraperitoneally before the ischemic damage. Retinal biochemical changes, i.e. increase of lactate content and decrease of glucose and ATP were significantly inhibited by the new and selective sigma1 receptor ligand compared to the ischemic control group. The effect of (-)-MR22 was antagonized by pre-treatment with the sigma1 site antagonist. The protective effect of (-)-MR22 on ischemic retina was confirmed by the histological analysis. These findings suggest that (-)-MR22 serves as a retinal neuroprotective agent and acts as a sigma1 receptor agonist.
- Published
- 2006
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43. Possible involvement of nitric oxide in morphine-induced miosis and reduction of intraocular pressure in rabbits.
- Author
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Bonfiglio V, Bucolo C, Camillieri G, and Drago F
- Subjects
- Animals, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Eye drug effects, Eye metabolism, Glutathione pharmacology, Miosis chemically induced, Miosis prevention & control, NG-Nitroarginine Methyl Ester pharmacology, Naloxone pharmacology, Narcotic Antagonists pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nitric Oxide Synthase metabolism, Rabbits, Receptors, Opioid, mu drug effects, Receptors, Opioid, mu metabolism, Time Factors, Analgesics, Opioid toxicity, Intraocular Pressure drug effects, Miosis metabolism, Morphine toxicity, Nitric Oxide metabolism
- Abstract
The role of mu3 opioid receptors in morphine-induced intraocular pressure (IOP) lowering effect and miosis was evaluated in conscious, dark-adapted New Zealand white (NZW) rabbits using a masked-design study. IOP and pupil diameter (PD) measurements were taken at just before and 0.5, 1, 2, 4, 6 h after monolateral instillation of morphine (10, 50 and 100 microg/30 microl) as compared to vehicle administered in the contralateral eye. Morphine-induced ocular effects were challenged by a pre-treatment with the non-selective opioid receptor antagonist, naloxone (100 microg/30 microl), the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME, 1%, 30 microl), or the non-selective mu3 opioid receptor inhibitor, reduced L-glutathione (GSH, 1%, 30 microl). Morphine induced a dose-dependent decrease in IOP and PD. Pre-treatment with naloxone totally prevented morphine-induced decrease in IOP and miosis. Ocular administration of L-NAME or GSH alone failed to affect IOP or PD of NZW rabbits. However, pre-treatment with either drugs significantly reduced, but not totally prevented ocular effects of morphine. These results suggest that biochemical mechanisms related to nitric oxide release are involved, at least in part, in morphine effects on the eye. Since the mu3 opioid receptor subtype is able to release nitric oxide and is sensitive to inactivation by GSH, it may be possible that mu3 opioid receptors are involved in morphine-induced miosis and reduction in IOP.
- Published
- 2006
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44. Stressors affect the response of male and female rats to clomipramine in a model of behavioral despair (forced swim test).
- Author
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Consoli D, Fedotova J, Micale V, Sapronov NS, and Drago F
- Subjects
- Animals, Antidepressive Agents, Tricyclic therapeutic use, Behavior, Animal physiology, Clomipramine therapeutic use, Corticosterone blood, Depression blood, Depression drug therapy, Disease Models, Animal, Electroshock, Estrous Cycle physiology, Female, Male, Rats, Rats, Wistar, Sex Factors, Stress, Physiological blood, Swimming, Antidepressive Agents, Tricyclic pharmacology, Behavior, Animal drug effects, Clomipramine pharmacology, Depression physiopathology, Stress, Physiological physiopathology
- Abstract
Aim of the present study was to evaluate the effects of physical stressors (electric foot-shocks) on effect of the antidepressant drug, clomipramine and plasma corticosterone levels in male and female rats tested in a model of behavioral despair (forced swim test,). Male and female rats of the Wistar strain were injected with clomipramine (50 mg/kg, i.p.) or saline. A group of animals also received electric shocks of different intensity and duration of 24, 5 and 1 h before being subjected to forced swim test. At the end of behavioral procedures, vaginal smears were assessed in all female animals and data on immobility time were plotted according to the ovarian cycle phase. After decapitation, corticosterone plasma levels were measured by radioimmunoassay in both male and female rats. Application of mild shocks (5 ms, 0.1 mA) significantly reduced immobility time in forced swim test of untreated male rats and augmented clomipramine effect on this parameter. Moderate shocks of higher intensity or duration (5 ms, 1.0 mA) also resulted in decreased immobility time of untreated male rats, but in reduced effect of clomipramine treatment. Furthermore, application of severe shocks (10 ms, 1.0 mA) increased the immobility time in untreated animals and totally abolished clomipramine effect in forced swim test. Untreated non-shocked female rats in proestrous and estrous phases exhibited a longer immobility time as compared to diestrous animals. Immobility time appeared to be generally higher when mild, moderate or severe shocks were applied prior to behavioral testing in proestrous and estrous animals, while the behavioral response of diestrous and metestrous animals did not differ from that of controls. Clomipramine effect on immobility time was generally reduced by application of shocks of every strengths. Stress-induced plasma corticosterone levels surge correlated with intensity and duration of shocks in both male and female rats, but clomipramine treatment generally blunted the hormonal response. However, severe shocks were followed by a surge of plasma corticosterone levels in both male and female clomipramine-treated rats. These results demonstrate that duration and intensity of stressful stimuli may deeply affect the behavioral response of rats in forced swim test and influence clomipramine effect in this behavioral model depending on gender-based variables, probably of the hormonal type. Plasma corticosterone levels correlate with the behavioral response to clomipramine treatment suggesting that reactivity of hypothalamus-pituitary-adrenal axis to stress may be involved in the antidepressant effect of this drug.
- Published
- 2005
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45. Effects of neurosteroids on ischemia-reperfusion injury in the rat retina: role of sigma1 recognition sites.
- Author
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Bucolo C and Drago F
- Subjects
- Adenosine Triphosphate metabolism, Animals, Binding Sites, Dehydroepiandrosterone Sulfate administration & dosage, Estradiol administration & dosage, Ethylenediamines pharmacology, Glucose metabolism, Injections, Intraperitoneal, Lactates metabolism, Male, Morpholines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, sigma antagonists & inhibitors, Receptors, sigma metabolism, Reperfusion Injury complications, Retina metabolism, Retinal Degeneration etiology, Dehydroepiandrosterone Sulfate pharmacology, Estradiol pharmacology, Reperfusion Injury physiopathology, Retina drug effects, Retinal Degeneration prevention & control
- Abstract
The effects of neurosteroids, 17beta-estradiol and dehydroepiandrosterone-sulfate (DHEA-S), were investigated on retinal degeneration using a rat model of ischemia-reperfusion injury. The animals were anaesthetized and retinal ischemia was induced by elevating the intraocular pressure to 120 mm Hg for 45 min. Neurosteroids were injected intraperitoneally before ischemia and immediately after reperfusion. Retinal biochemical changes such as increase of lactate content and decrease of glucose and ATP were significantly inhibited by neurosteroids compared to the control ischemic group. The effects of 17beta-estradiol and DHEA-S were antagonized by pre-treatment with the sigma1 site antagonist. These findings suggest that 17beta-estradiol and dehydroepiandrosterone-sulfate may affect the metabolic state of surviving neurons and glial cells after ischemic injury and that they act, at least in part, through involvement of sigma1 recognition sites.
- Published
- 2004
- Full Text
- View/download PDF
46. Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade.
- Author
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Mazzola C, Micale V, and Drago F
- Subjects
- Amyloid beta-Peptides administration & dosage, Amyloid beta-Peptides antagonists & inhibitors, Animals, Avoidance Learning drug effects, Avoidance Learning physiology, Drug Administration Schedule, Injections, Intraperitoneal, Injections, Intraventricular, Male, Mice, Peptide Fragments administration & dosage, Peptide Fragments antagonists & inhibitors, Piperidines administration & dosage, Piperidines pharmacokinetics, Piperidines therapeutic use, Pyrazoles administration & dosage, Pyrazoles pharmacokinetics, Pyrazoles therapeutic use, Receptor, Cannabinoid, CB1 drug effects, Retention, Psychology drug effects, Retention, Psychology physiology, Rimonabant, Time Factors, Amnesia chemically induced, Amnesia prevention & control, Amyloid beta-Peptides adverse effects, Peptide Fragments adverse effects, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 physiology
- Abstract
Administration of drugs activating cannabinoid CB(1) receptors in the brain induces memory deficit in rodents, and blockade of these receptors may restore memory capacity in these animals. Central administration of beta-amyloid or beta-amyloid fragments may also lead to memory disturbances. This study was undertaken to study the involvement of cannabinoid CB(1) receptors in amnesia induced by beta-amyloid fragments in mice tested in a step-through passive avoidance paradigm. Pre-training intracerebroventricular (i.c.v.) injection of beta-amyloid fragments, beta-amyloid peptide-(25-35) (4, 8 or 16 nmol/mouse) or beta-amyloid peptide-(1-42) (200, 400, 800 pmol/mouse) 7 days prior to the learning trial reduced in a dose-dependent manner the retention of passive avoidance response. This effect was observed in two retention tests, 1 and 7 days after the learning trial. The two beta-amyloid fragments showed similar potency in reducing retention of passive avoidance behavior. This effect was counteracted by a single intraperitoneal (i.p.) injection of the cannabinoid CB(1) receptor antagonist, N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 1 mg/kg), made 30 min prior to the second retention test. The injection of SR141716A per se did not affect memory capacity of mice. The i.c.v. administration of beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) made 30 min prior to the learning trial failed to affect the retention capacity of mice as measured 1 and 7 days later. Also, the i.p. injection of SR 141716A (1 mg/kg) made 30 min prior to the learning trial did not influence the behavioral response of mice injected with beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) 7 days prior to the learning trial. These results show that beta-amyloid fragments induce a dose-dependent memory deficit. Their effect on memory retention depends upon the time of administration and seems to involve cannabinoid CB(1) receptors in the brain.
- Published
- 2003
- Full Text
- View/download PDF
47. Very low doses of ethanol induce behavioral changes involving dopamine D2 receptors.
- Author
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Castorina M, Marino R, Grassi M, and Drago F
- Subjects
- Administration, Oral, Animals, Avoidance Learning drug effects, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Dose-Response Relationship, Drug, Drug Interactions, Ethanol pharmacokinetics, Male, Phenethylamines pharmacology, Rats, Rats, Sprague-Dawley, Sulpiride pharmacology, Ultrasonics, Behavior, Animal drug effects, Ethanol administration & dosage, Ethanol pharmacology, Receptors, Dopamine D1 physiology
- Abstract
In male rats, pretreatment for 20 days with very low (0.5, 1%, v/v) but not with high (5, 10%, v/v) oral doses of ethanol delayed the initiation and reduced the duration of narcosis induced by an acute high intraperitoneal (i.p.) dose of the drug (3 g/kg in 25% saline solution). Furthermore, the treatment improved the acquisition of shuttle-box active avoidance response but did not affect the emission of ultrasonic calls, an index of emotional state of animals. These effects were inhibited by peripheral administration of the dopamine D2 receptor antagonist, sulpiride (1 mg/kg). A higher dose of sulpiride (10 mg/kg) prolonged the duration of narcosis in rats pretreated with high-dose ethanol and reduced the number of conditioned avoidance responses in the shuttle-box paradigm. The pretreatment with the dopamine D2 receptor agonist, (+/-)-2-(N-phenethyl-N-propylamino)-5-hydroxytetralin (PPHT, 0.1 mg/kg), enhanced the effects of ethanol very low doses in delaying the initiation and reducing the duration of narcosis induced by an acute i.p. dose of the drug. A pharmacokinetic study in ethanol-pretreated animals revealed that administration of 0.5% or 1% ethanol for 20 days did not modify significantly the bioavailability of acute ethanol administered i.p. in a dose of 3 g/kg in 25% saline solution. Thus, repeated administration of ethanol very low doses may have affected the sensitivity of presynaptic dopamine D2 receptors. The influence on dopamine release through an action on presynaptic receptors may be involved in these effects of small doses of ethanol.
- Published
- 2003
- Full Text
- View/download PDF
48. Long-lasting behavioral changes induced by pre- or neonatal exposure to diazepam in rats.
- Author
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Nicosia A, Giardina L, Di Leo F, Medico M, Mazzola C, Genazzani AA, and Drago F
- Subjects
- Animals, Animals, Newborn, Behavior, Animal physiology, Diazepam therapeutic use, Female, Male, Pregnancy, Rats, Rats, Wistar, Reaction Time physiology, Reflex physiology, Seizures prevention & control, Time, Behavior, Animal drug effects, Diazepam pharmacology, Prenatal Exposure Delayed Effects, Reaction Time drug effects, Reflex drug effects
- Abstract
Prenatal treatment with small doses of diazepam may counteract the effect of physical stress in rats, normalizing the time course of neonatal reflexes and the behavioral responses in adulthood. However, prenatal administration of diazepam in greater doses may induce desensitization of gamma-aminobutyric acid A (GABA(A)) receptors and induce hypersensitivity to convulsants. This study was designed to examine in rats the influence of prenatal or neonatal diazepam treatment on development of neonatal reflexes, as index of brain maturation, and susceptibility to pentylenetetrazol-induced convulsions in adulthood. Pregnant Wistar rats were injected with diazepam 2.5 mg/kg/day, intraperitoneally (i.p.) on days 14-21 of pregnancy. Offspring showed a delay in the appearing of neonatal reflexes (cliff aversion, forelimb placing, forelimb grasping and bar holding) except for righting and startle reflexes. At 50 days of age, male rats showed a greater sensitivity to pentylenetetrazol compared to controls. In contrast, females showed a decreased susceptibility to convulsions. The appearance of reflexes in pups exposed to diazepam during neonatal life appeared to be similar to that of controls. Only the appearance of cliff aversion and startle reflexes appeared to be delayed in animals exposed neonatally to diazepam as compared to controls. In adulthood, female rats exposed in early neonatal life to diazepam again showed a resistance to pentylenetetrazol-induced convulsions as compared to male animals. These data suggest that prenatal exposure to diazepam induces long-lasting behavioral changes, which may be influenced by sex-dependent factors.
- Published
- 2003
- Full Text
- View/download PDF
49. Mechanism and clinical significance of prostaglandin-induced iris pigmentation.
- Author
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Stjernschantz JW, Albert DM, Hu DN, Drago F, and Wistrand PJ
- Subjects
- Amides, Animals, Bimatoprost, Cloprostenol adverse effects, Dinoprost adverse effects, Gene Expression Regulation drug effects, Humans, Iris metabolism, Iris Diseases metabolism, Latanoprost, Lipids adverse effects, Melanocytes metabolism, Monophenol Monooxygenase genetics, Pigmentation Disorders metabolism, Prostaglandins F, Synthetic adverse effects, Receptors, Prostaglandin metabolism, Travoprost, Up-Regulation, Antihypertensive Agents adverse effects, Cloprostenol analogs & derivatives, Dinoprost analogs & derivatives, Eye Color drug effects, Iris drug effects, Iris Diseases chemically induced, Pigmentation Disorders chemically induced
- Abstract
The new glaucoma drugs latanoprost, isopropyl unoprostone, travoprost, and bimatoprost cause increased pigmentation of the iris in some patients. The purpose of the present article is to survey the available preclinical and clinical data on prostaglandin-induced iris pigmentation and to assess the phenomenon from a clinical perspective. Most of the data have been obtained with latanoprost, and it appears that there is a predisposition to latanoprost-induced iris pigmentation in individuals with hazel or heterochromic eye color. As latanoprost and travoprost are selective agonists for the prostaglandin F(2alpha) receptor, it is likely that the phenomenon is mediated by this receptor. Several studies indicate that latanoprost stimulates melanogenesis in iridial melanocytes, and transcription of the tyrosinase gene is upregulated. The safety aspects of latanoprost-induced iris pigmentation have been addressed in histopathologic studies, and no evidence of harmful consequences of the side effect has been found. Although a final assessment of the clinical significance of prostaglandin-induced iris pigmentation currently is impossible to make, it appears that the only clear-cut disadvantage is a potential heterochromia between the eyes in unilaterally treated patients because the heterochromia is likely to be permanent, or very slowly reversible.
- Published
- 2002
- Full Text
- View/download PDF
50. The "low-dose" concept and the paradoxical effects of prolactin on grooming and sexual behavior.
- Author
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Drago F and Lissandrello CO
- Subjects
- Animals, Dose-Response Relationship, Drug, Female, Male, Prolactin administration & dosage, Rats, Sex Characteristics, Grooming drug effects, Prolactin pharmacology, Sexual Behavior, Animal drug effects
- Abstract
The effects of prolactin on animal behavior include the stimulation of novelty-induced grooming in rats. This effect has been demonstrated in hyperprolactinaemic animals bearing pituitary homografts under the kidney capsule or after intracerebroventricular (i.c.v.) administration of prolactin. Since plasma prolactin levels in hyperprolactinaemic rats are similar to those of animals injected with low doses of rat prolactin, we studied the effects of this hormone injected subcutaneously (s.c.) in a dose range of 5-50 microg/kg. Novelty-induced grooming was enhanced only in rats injected with 5 or 10 microg/kg rat prolactin, whereas no effect was observed after the s.c. injection of the higher dose. The sexual behavior of male rats is also affected by prolactin. Male rats with normal mating activity showed enhanced sexual behavior when injected s.c. with rat prolactin (5, 10 or 50 microg/kg). In animals with poor sexual performance or in impotent rats, prolactin (5 or 10 microg/kg, but not 50 microg/kg) restored the full pattern of sexual behavior. An increased lordosis quotient was also observed in ovariectomized rats treated with prolactin 5 or 10 microg/kg. These results suggest that, besides the duration of hyperprolactinaemia, the effective level of plasma prolactin is important for the expression of the behavioral effects of this hormone.
- Published
- 2000
- Full Text
- View/download PDF
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