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Brown spider monkeys Ateles hybridus are one of the most threatened primates in the Neotropics. Most of the remaining populations of this species already live either in forest fragments or in areas that face imminent anthropogenic disturbance. Understanding how these animals cope with the challenge of living in small fragments, while at the same time being a large, frugivorous mammal is crucial to design effective conservation and management strategies. We studied the diet of wild A. hybridus and measured forest productivity in a small (~65 ha) fragment in the Magdalena Region of northern Colombia over a period of 26 mo. Spider monkeys at this site spent far less time feeding on fruits than reported in previous studies of Ateles spp. living in less fragmented sites. Moreover, we registered a high consumption of leaves in every month (on average 37% of their feeding time) as well as the consistent inclusion of decayed wood in the diet. Ficus trees can be considered staple feeding items, as they were present in high proportions in the monkeysí diet throughout the study. Although wild populations of spider monkeys can have flexible diets that include large proportions of leaves over long periods of time, they may also be exposed to a suboptimal diet which may have negative implications for their reproduction and well-being in the long run, further compromising the viability of wild populations living in disturbed habitats.

The β -secretase-1 enzyme (BACE-1) performs a key role in the production of beta-Amyloid protein (Aβ), which is associated with the development of Alzheimer's disease (AD). The inhibition of BACE-1 has been an important pharmacological strategy in the treatment of this neurodegenerative disease. This study aims to identify new potential candidates for the treatment of Alzheimer's with the help of in silico studies, such as molecular docking and ADME prediction, from a broad list of candidates provided by the DrugBank database. From this analysis, 1145 drugs capable of interacting with the enzyme with a higher coupling energy than Verubecestat were obtained, subsequently only 83 presented higher coupling energy than EJ7. Applying the oral route of administration as inclusion criteria, only 41 candidates met this requirement; however, 6 of them are associated with diagnostic tests and not treatment, so 33 candidates were obtained. Finally, five candidates were identified as possible BACE-1 inhibitors drugs: Fluphenazine, Naratriptan, Bazedoxifene, Frovatriptan, and Raloxifene. These candidates exhibit pharmacophore-specific features, including the indole or thioindole group, and interactions with key amino acids in BACE-1. Overall, this study provides insights into the potential use of in silico methods for drug repurposing and identification of new candidates for the treatment of Alzheimer's disease, especially those targeting BACE-1.

It is now well recognized that a bidirectional relationship between gut microbiota and the brain, referred to as the gut-brain axis, plays a prominent role in maintaining homeostasis and that a disruption in this axis can result in neuroinflammatory response and neurological disorders such as Parkinson's disease (PD). The protective action of probiotics such as Bifidobacterium animalis ssp. lactis Bb12 and Lactobacillus rhamnosus GG in various animal models of PD has been reported. Therefore, in this study, we used an inflammatory model of PD to assess the effects of a combination of these two probiotics (Microbiot ® ) on motor behavior as well as on the response of microglia, including microglia morphology, to gain a better understanding of their mechanism of action. Microbiot ® (300 µL) was administered orally once daily for 15 days in a lipopolysaccharide-induced PD model using male Wistar rats. Although LPS-induced motor asymmetry in cylinder test was not affected by Microbiot ® , impairment of motor coordination in the narrow-beam test was significantly reduced by this probiotic. Moreover, Microbiot ® treatment reduced microglial activation suggesting an anti-inflammatory effect. While further mechanistic investigation of Microbiot ® in neurodegenerative diseases is warranted, our results support the potential utility of probiotics in PD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Paroxetine (PX) is a widely used antidepressant with side effects such as weakness, dizziness, and trouble sleeping. In search of novel compounds with better efficacy and fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects., Methods: In silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In vivo studies utilized an animal model of comorbid depression-Parkinson disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test, and tyrosine hydroxylase-positive neurons in substantia nigra pars compacta and Iba-1-positive stained microglia in ipsilateral striatum were measured., Results: In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX., Conclusion: The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Gut dysbiosis is considered a risk factor for Parkinson's disease (PD), and chronic treatment with probiotics could prevent it. Here we report the assessment of a probiotic mixture [Lacticaseibacillus rhamnosus GG (LGG), and Bifidobacterium animalis lactis BB-12 (BB-12)] administered to male rats 2 weeks before and 3 weeks after injecting 6-hydroxydopamine (6-OHDA) into the right striatum, a model that mimics the early stages of PD. Before and after lesion, animals were subjected to behavioral tests: narrow beam, cylinder test, and apomorphine (APO)-induced rotations. Dopaminergic (DA) denervation and microglia recruitment were assessed with tyrosine hydroxylase (TH + ) and ionized calcium-binding protein-1 adapter (Iba1 + ) immunostaining, respectively. Post 6-OHDA injury, rats treated with sunflower oil (probiotics vehicle) developed significant decrease in crossing speed and increases in contralateral paw slips (narrow beam), forepaw use asymmetry (cylinder), and APO-induced rotations. In striatum, 6-OHDA eliminated ≈2/3 of TH + area and caused significant increase of Iba1 + microglia population. Retrograde axonal degeneration suppressed ≈2/5 of TH + neurons in the substantia nigra pars compacta (SNpc). In hemiparkinsonian rats, probiotics treatment significantly improved the crossing speed, and also reduced paw slips (postlesion days 14 and 21), the loss of TH + neurons in SNpc, and the loss of TH + area and of Iba1 + microglia count in striatum, without affecting the proportion of microglia morphological phenotypes. Probiotics treatment did not attenuate forepaw use asymmetry nor APO-induced rotations. These results indicate that the mixture of probiotics LGG and BB-12 protects nigrostriatal DA neurons against 6-OHDA-induced damage, supporting their potential as preventive treatment of PD., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

The recombinant carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) exerts neuroprotective and neurorestorative effects on the dopaminergic system of animal models of Parkinson's disease (PD). The present study aimed to determine the effect of the Hc-TeTx fragment on the markers of oxidative stress and nitrosative stress generated by the acute toxicity of 1-methyl-4-phenylpyridinium (MPP + ). For this purpose, the Hc-TeTx fragment was administered once a day in three 20 μg/kg consecutive injections into the grastrocnemius muscle of the rats, with an intra-striatal unilateral injection of 1 μL of MPP + [10 μg/mL] then administered in order to cause a dopaminergic lesion. The results obtained show that the rats treated with Hc-TeTx plus MPP + presented an increase in the expression of tyrosine hydroxylase (TH), a significantly greater decrease in the levels of the markers of oxidative stress, nitrosative stress, and neurodegeneration than that observed for the group injured with only MPP + . Moreover, it was observed that total superoxide dismutase (SOD) and copper/zinc SOD activity increased with the administration of Hc-TeTx. Finally, immunoreactivity levels were observed to decrease for the levels of 3-nitrotyrosine and the glial fibrillary acidic protein in the ipsilateral striatum of the rats treated with Hc-TeTx plus MPP + , in contrast with those lesioned with MPP + alone. Our results demonstrate that the recombinant Hc-TeTx fragment may be a potent antioxidant and, therefore, could be suggested as a therapeutic tool against the dopaminergic neuronal impairment observed in the early stages of PD., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

The design, stereoselective synthesis and in vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported herein. Among the novel synthesized compounds, three showed an antiallodynic effect, while (R,R)-3HPX was found to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats. Consequently, the current investigation not only discloses a novel promising analgesic drug, but also reveals that functionalization at the C3 position of paroxetine could be as effective as the common functionalization at either C4 or within the sesamol group., (© 2020 Wiley-VCH GmbH.)

Pain is a usual and troublesome non-motor symptom of Parkinson's disease, with a prevalence of 29-82%. Therefore, it's vital to find pharmacological treatments for managing PD-associated pain symptoms, to improve patients' quality of life. For this reason, we tested the possible synergy between L-DOPA and celecoxib in decreasing allodynia and hyperalgesia induced by unilateral lesioning with 6-OHDA into the SNpc in rats. We also tested whether the antiallodynic and antihyperalgesic effect induced by combination of L-DOPA and celecoxib is mediated by the NO-cGMP-ATP-sensitive K + channel pathway. Tactile allodynia and mechanical hyperalgesia were evaluated using von Frey filament. Isobolographic analyses were employed to define the nature of the drug interaction using a fixed dose ratio (0.5: 0.5). We found that acute and sub-acute (10-day) treatment with a single dose of L-DOPA (3-25 mg/kg, i. p.) or celecoxib (2.5-20 mg/kg, i. p.) induced a dose-dependent antiallodynic and antihyperalgesic effect in parkinsonian rats. Isobolographic analysis revealed that the ED 50 values obtained by L-DOPA + celecoxib combination was significantly less than calculated additive values, indicating that co-administration of L-DOPA with celecoxib produces synergistic interactions in its antiallodynic and antihyperalgesic effect in animals with nigrostriatal lesions. Moreover, the antiallodynic and antihyperalgesic effects induced by L-DOPA + celecoxib combination were blocked by intrathecal pre-treatment with L-NAME, ODQ, and glibenclamide. Taken together, the data suggest that L-DOPA + celecoxib combination produces an antiallodynic and antihyperalgesic synergistic interaction at the systemic level, and these effects are mediated, at the central level, through activation of the NO-cGMP-ATP-sensitive K + channel pathway., (Copyright © 2020. Published by Elsevier B.V.)

Pain is the non-motor symptom with the highest prevalence in patients with Parkinson's Disease (PD) affecting 40-85%. This study aimed to investigate the development of tactile allodynia and mechanical hyperalgesia after the nigrostriatal dopaminergic lesion induced by the unilateral 6-hydroxydopamine (6-OHDA) injection at different doses in the substantia nigra pars compacta (SNpc). Moreover, we studied the possible antiallodynic and antihyperalgesic effect with the acute and the subacute treatment of the pramipexole (PPX) in rats. First, dopaminergic lesion was realized by the unilateral injection of 6-OHDA (6, 10 and 16 μg/μl) into the SNpc. To know the establishment of motor deficits, we measure several turns and forelimb-use asymmetry by rotational behavior and cylinder, respectively. On the other hand, to investigate allodynia and hyperalgesia induced by 6-OHDA, we used the von Frey filaments. Moreover, antiallodynic and antihyperalgesic effect induced by PPX (0.03, 0.3 and 3 mg/kg, s.c.) was examined on acute and subacute conditions. We found that major dopaminergic lesion with 16 μg/μl of 6-OHDA caused the highest allodynia and hyperalgesia effects in both paws, as well as the major motor deficits. In addition, the treatment with PPX at 0.3 mg/kg reverts the allodynia and the hyperalgesia induced by 6-OHDA. In conclusion, the dopaminergic lesion into SNpc induce allodynia and hyperalgesia in both paws; interestingly the treatment with PPX can be suggested as an analgesic drug for patients with PD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is an idiopathic and progressive neurodegenerative disease characterized by the loss of ~ 80% of dopaminergic neurons in substantia nigra pars compacta (SNpc). Because activation of the innate cellular immune response, mediated by microglia, has been linked to the neurodegeneration in PD, in the present study, we evaluated the effects of lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) on microglia's morphology, reflective of their activity, as well as tyrosine hydroxylase (TH)-positive neurons in SNpc and motor behavior. Adult male Wistar rats were stereotactically injected with LPS or 6-OHDA into the left dorsolateral striatum. Control groups received appropriate vehicle. The morphological changes of microglial cells and neurotoxic effects were examined at 1, 7, and 14 post-injection days. Both LPS and 6-OHDA caused activation and morphological changes in microglial cells as well as loss of dopaminergic neurons in SNpc. These effects were maximal at 14 days post-injection where motor impairments were also evident. However, our findings indicate that 6-OHDA causes a low degree of microglia activation compared to LPS. Hence, it may be concluded that LPS model of PD might be a better representation of inflammatory involvement in this devastating disease.

The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) may be of therapeutic potential in motor impairments associated with Parkinson disease (PD). Since depression is a common co-morbid condition with PD, we undertook this study to determine whether Hc-TeTx might also show antidepressant-like properties and whether central brain-derived neurotrophic factor (BDNF) and/or tumor necrosis factor (TNF)-alpha are also affected by it. Adult male Wistar-Kyoto rats, a putative animal model of depression, were treated with various doses of Hc-TeTx (0, 20, 40 and 60 μg/kg, IM) and their performance in the open field locomotor activity (OFLA) as well as in the forced swim test (FST) was evaluated at 24 h, one week and two weeks after the single injection. A separate group of rats were injected with 60 μg/kg Hc-TeTx and sacrificed 24 h later for neurochemical evaluations. Hc-TeTx resulted in a dose-dependent decrease in immobility score after 24 h, whereas OFLA was not affected. Concomitant with the 24 h behavioral effects, the levels of hippocampal and frontal cortical BDNF were significantly increased, whereas the levels of TNF-alpha in both these areas were significantly decreased. The decrease in immobility scores following higher doses of Hc-TeTx were still evident after one week, but not 2 weeks of rest. These results indicate long lasting antidepressant effects of a single Hc-TeTx dose and suggest potential utility of Hc-TeTx in PD-depression co-morbidity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Reports indicate that striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson's disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. The purpose of this study was to gain some understanding of the actions of each drug, including potential antioxidant and anti-inflammatory effects and importantly, to determine whether the combination of the two drugs would be superior to each alone. Adult male Wistar rats were administered 6-OHDA into the dorso-lateral striatum, and the effects of Hc-TeTx fragment (20 μg/kg i.m. every 24 h) for 3 days; PPX (1 mg/kg p.o., every 12 h) for 30 days and their combination on various motor and neurochemical parameters were evaluated. Behavioral tests were carried out at 15 and 30 days post-treatments. At day 31, the animals were sacrificed and the levels of tyrosine hydroxylase (TH), reflecting dopaminergic activity in both striatum and substantia nigra, were evaluated. In addition, indices of astrogliosis, microgliosis, as well as oxidative stress in the striatum were determined. Both Hc-TeTx and PPX ameliorated the motor and neurochemical deficits induced by 6-OHDA lesion; however, the combination of the two drugs was not superior to each alone. Hence, at concentrations used in this study, no significant advantage in combining Hc-TeTx with PPX was noted. Although the results suggest similar neurochemical effects of the two compounds, further evaluation of different concentrations of Hc-TeTx and PPX as potential intervention in PD is warranted.

Galectins are animal lectins that bind to β-galactosides, such as lactose and N-acetyllactosamine, contained in glycoproteins or glycolipids. Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are involved in pathologies associated with the inflammatory process, cell proliferation, adhesion, migration, and apoptosis. Recent evidence has shown that the administration of Amyloid-β 25-35 (Aβ 25-35 ) into the hippocampus of rats increases the inflammatory response that is associated with memory impairment and neurodegeneration. Galectins could participate in the modulation of the neuroinflammation induced by the Aβ 25-35 . The aim of this study was to evaluate the presence of Gal-1 and Gal-3 in the neuroinflammation induced by administration of Aβ 25-35 into the hippocampus and to examine spatial memory in the Morris water maze. After the administration of Aβ 25-35 , animals were tested for learning and spatial memory in the Morris water maze. Behavioral performance showed that Aβ 25-35 didn't affect spatial learning but did impair memory, with animals taking longer to find the platform. On the day 32, hippocampus was examined for astrocytes (GFAP), microglia (Iba1), Gal-1 and Gal-3 via immunohistochemical analysis, and the cytokines IL-1β, TNF-α, IFN-γ by ELISA. This study's results showed a significant increase in the expression of Gal-3 in the microglia and astrocytes, while Gal-1 didn't increase in the dorsal hippocampus. The expression of galectins is associated with increased cytokines in the hippocampal formation of Aβ 25-35 treated rats. These findings suggest that Gal-3 could participate in the inflammation induced by administration of Aβ 25-35 and could be involved in the neurodegeneration progress and memory impairment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration of action, poor protease selectivity, and low blood-brain barrier (BBB) permeability, which altogether limit their potential as drugs. Here, we describe the structure-based design of the first irreversible, selective, and brain-permeable POP inhibitors. At low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, both in vitro and in human cells. More importantly, they are >1,000-fold selective against two family-related proteases (DPPIV and FAP) and display high BBB permeability, as shown in both lipid membranes and MDCK cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Several studies have shown that intrastriatal application of 1-methyl-4-phenylpyridinium (MPP + ) produces similar biochemical changes in rat to those seen in Parkinson's disease (PD), such as dopaminergic terminal degeneration and consequent appearance of motor deficits, making the MPP + lesion a widely used model of parkinsonism in rodents. Previous results from our group have shown a neuroprotective effect of the carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) under different types of stress. In the present study, pretreatment with the intraperitoneal injection of Hc-TeTx in rats prevents the decrease of tyrosine hydroxylase immunoreactivity in the striatum due to injury with MPP + , when applied stereotaxically in the striatum. Similarly, striatal catecholamine contents are restored, as well as the levels of two other dopaminergic markers, the dopamine transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2). Additionally, uptake studies of [ 3 H]-dopamine and [ 3 H]-MPP + reveal that DAT action is not affected by Hc-TeTx, discarding a protective effect due to a reduced entry of MPP + into nerve terminals. Behavioral assessments show that Hc-TeTx pretreatment improves the motor skills (amphetamine-induced rotation, forelimb use, and adjusting steps) of MPP + -treated rats. Our results lead us to consider Hc-TeTx as a potential therapeutic tool in pathologies caused by impairment of dopaminergic innervation in the striatum, as is the case of PD.

Children with cancer are particularly vulnerable to malnutrition, which can affect their tolerance of chemotherapy and outcome. In Nicaragua approximately two-thirds of children diagnosed with cancer present with under-nutrition. A nutritional program for children with cancer has been developed at "La Mascota" Hospital. Results of this oral nutritional intervention including difficulties, benefits, and relevance for children treated for cancer in low- and middle-income countries are here reported and discussed., Competing Interests: Competing interests: The authors have declared that no competing interests exist.

Memory impairment by the Amyloid-β 25-35 (Aβ 25-35 ) peptide in animal models has provided an understanding of the causes behind the similar deterioration that occurs in Alzheimer's disease. However, it is uncertain if a decrease of dendritic spines and neurogenesis conduces to cognitive impairment by an impairment in the retrieval of stored memory. The aim of this study was to evaluate the consequences of impairment on spatial memory caused by the administration of the Aβ 25-35 peptide in the hippocampus, which is associated whit morphological changes and neurogenesis in the dentate gyrus (DG). The vehicle or Aβ 25-35 peptide (0.1μg/μL) were bilaterally administered in the CA1 subfield of the rat hippocampus. The animals were tested for spatial learning and memory in the Morris Water Maze. In the day's 11, 18 and 32 after administration of the Aβ 25-35 peptide were examined the morphological changes in the DG using a Golgi-Cox stain. In the day 32, the neurogenesis was evaluated by the immunoreactivity to 5-bromo-2'-deoxyuridine (BrdU; 100mg/kg, i.p.) that corresponding to cellular proliferation post damage, the neuronal specific nuclear protein (NeuN) and doublecortin (DCX). This study found a memory retrieval impairment occurring at day 17, a cognitive deficit which had increased significantly at day 31 after the administration of Aβ 25-35 peptide. These results are related to morphological changes in the granular cells of the DG, such as a shorter dendritic length and a decrease in the number of dendritic spines. In neurogenesis, the total number of cells positive to BrdU, NeuN and DCX in the hippocampal granule cell layer was found to have declined in animals treated with Aβ 25-35 . The results suggest that the Aβ 25-35 peptide impairs memory retrieval by decreasing the number of dendritic spines and altering neurogenesis in the DG., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Most children with cancer live in resource-limited countries where malnutrition is often prevalent. We identified the relationship between malnutrition and treatment-related morbidity (TRM), abandonment of therapy, and survival of children with cancer in Nicaragua to better inform targeted nutritional interventions., Procedure: We conducted a retrospective review of patients aged 6 months to 18 years with newly diagnosed acute lymphoblastic leukemia, acute myeloid leukemia (AML), Wilms tumor, Hodgkin lymphoma, or Burkitt lymphoma (BL) who were treated between January 1, 2004, and December 31, 2007 at Children's Hospital Manuel de Jesus Rivera in Managua, Nicaragua. Statistical analysis examined the relations among nutritional status and cancer type, risk category, TRM, and event-free survival (EFS)., Results: Sixty-seven percent of patients (189/282) were malnourished at diagnosis. Malnutrition was highest among patients with Wilms tumor (85.7%), BL (75%), and AML (74.3%). A total of 92.2% of patients (225/244) experienced morbidity during the first 90 days. Malnutrition was associated with severe infection (P = 0.033). Severely malnourished patients had ≥grade 3 TRM on more days (P = 0.023) and were more likely to experience severe TRM on >50% of days (P = 0.032; OR, 3.27 [95% CI, 1.05-10.16]). Malnourished patients had inferior median EFS (2.25 vs. 5.58 years; P = 0.049), and abandoned therapy more frequently (P = 0.015)., Conclusions: In Nicaragua, pediatric oncology patients with malnutrition at diagnosis experienced increased TRM, abandoned therapy more frequently, and had inferior EFS. Standardized nutritional evaluation of patients with newly diagnosed cancer and targeted provision of nutritional support are essential to decrease TRM and improve outcomes., (© 2017 Wiley Periodicals, Inc.)

Cognitive deficits are considered a key feature of schizophrenia, and they usually precede the onset of the illness and continue after psychotic symptoms appear. Current antipsychotic drugs have little or no effect on the cognitive deficits of this disorder. Prolyl oligopeptidase (POP) is an 81-kDa monomeric serine protease that is expressed in brain and other tissues. POP inhibitors have shown neuroprotective, anti-amnesic and cognition-enhancing properties. Here we studied the potential of IPR19, a new POP inhibitor, for the treatment of the cognitive symptoms related to schizophrenia. The efficacy of the inhibitor was evaluated in mouse models based on subchronic phencyclidine and acute dizocilpine administration, and in adult offspring from mothers with immune reaction induced by polyinosinic:polycytidylic acid administration during pregnancy. Acute IPR19 administration (5mg/kg, i.p.) reversed the cognitive performance deficits of the three mouse models in the novel object recognition test, T-maze, and eight-arm radial maze. The compound also ameliorates deficits of the prepulse inhibition response. The in vitro inhibitory efficacy and selectivity, brain penetration and exposure time after injection of IPR19 were also addressed. Our results indicate that the inhibition of POP using IPR19 may offer a promising strategy to develop drugs to ameliorate the cognitive deficits of schizophrenia., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson's disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment., Methods: For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment., Results: We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx., Conclusions: Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a peptide that has a neuroprotective action against dopaminergic damage by MPP(+), both in vitro and in vivo. The trophic effects of Hc-TeTx have been related to its ability to activate the pathways of the tropomyosin receptor kinase, which are crucial for survival process. Our group had previously shown neuroprotective effect of intramuscular Hc-TeTx treatment on animals with a dopaminergic lesion; however, there is no evidence indicating its restorative effects on advanced dopaminergic neurodegeneration. The aim of our study was to examine the restorative effects of an intramuscular injection of the Hc-TeTx fragment on the nigrostriatal system of hemiparkinsonian rats. The animals were administered with a vehicle or Hc-TeTx (20μg/kg) in the gastrocnemius muscle for three consecutive days post-dopaminergic lesion, which was made using 6-hydroxydopamine. Post-Hc-TeTx treatment, the hemiparkinsonian rats showed constant motor asymmetry. Moreover, the ipsilateral striatum of the post-Hc-TeTx group had a lower number of argyrophilic structures and a major immunorreactivity to Tyrosine Hydroxylase in the striatum and the substantia nigra pars compacta compared to the 6-OHDA group. Our results show the restorative effect of the Hc-TeTx fragment during the dopaminergic neurodegeneration caused by 6-OHDA., (Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

A screening of the natural product chlorogenic acid, isolated from the Brazilian medicinal plant Hypericum brasiliense, caffeic acid, cinnamic acid, and p-methoxycinnamic acid, and derivatives of caffeoylquinic, caffeoyl, and cinnamoyl against the enzymes prolyl oligopeptidase and dipeptidyl peptidase IV was carried out. Caffeoylquinic, caffeoyl, and cinnamoyl derivatives were prepared using simple derivatization procedures and through coupling reactions with the amino acid proline. The dipeptidyl peptidase IV assay showed inhibitory activity of the tested compounds at a high concentration (500 µM) in the range of 81.5-7.2 %. In contrast, the derivatives methyl ester and 1,7-acetonide obtained from chlorogenic acid, and caffeic acid and its methyl ester derivative showed selectivity and activity as prolyl oligopeptidase inhibitors, with IC50 values of 3 to 14 mM., (Georg Thieme Verlag KG Stuttgart · New York.)

Less than 2% of all potential neurotherapeutics cross the blood-brain barrier (BBB). Here, we sought to build a construct with the capacity to cross this barrier, to behave as a chemical delivery system, and, once inside the central nervous system, to be transformed and then act as an enzyme inhibitor. With all this in mind, here, we describe the entire process to obtain such a compound, from the initial candidate selection to preparation of the compound library and posterior evaluation and final selection of the most promising candidates in terms of selectivity, serum stability, and BBB-transport., (Copyright © 2013 Wiley Periodicals, Inc.)

Schizophrenia is a serious life-long disease that affects a significant part of the adult population. Although there is considerably effective medication for the positive symptoms of the disease, none are available for the associated cognitive deficits. These deficits are a core feature of schizophrenia, and they severely impair the functionality and social integration of patients. POP is a promising target for the treatment of the cognitive deficits of schizophrenia. Inhibitors of this peptidase show cognition-enhancing properties, act through a complex mechanism and have suitable pharmacological properties. Nevertheless, several studies must be carried out in order to improve the design and clinical evaluation of these substances. Permeability to the brain, appropriate animal models and suitable indications are the main issues that must be addressed. However, current information supports the potential of POP as an interesting drug target for the treatment of the cognitive deficits related to schizophrenia.

There is evidence to support that an impaired energy metabolism and the excessive generation of reactive oxygen species (ROS) contribute to brain injury in neurodegenerative disorders such as Parkinson's disease (PD), whereas diets enriched in foods with an antioxidant action may modulate its progression. Several studies have proved that the antioxidant components produced by Spirulina, a microscopic blue-green alga, might prevent cell death by decreasing free radicals, inhibiting lipoperoxidation and upregulating the antioxidant enzyme systems. In our study, we investigated the protective effect of the Spirulina maxima (S. maxima) against the 6-OHDA-caused toxicity in the rat striatum. The S. maxima (700 mg/kg/day, vo) was administered for 40 days before and 20 days after a single injection of 6-OHDA (16 μg/2 μL) into the dorsal striatum. At 20-day postsurgery, the brain was removed and the striatum was obtained to evaluate the indicators of toxicity, such as nitric oxide levels, ROS formation, lipoperoxidation, and mitochondrial activity. These variables were found significantly stimulated in 6-OHDA-treated rats and were accompanied by declines in dopamine levels and motor activity. In contrast, the animals that received the chronic treatment with S. maxima had a restored locomotor activity, which is associated with the decreased levels of nitric oxide, ROS, and lipoperoxidation in the striatum, although mitochondrial functions and dopamine levels remained preserved. These findings suggest that supplementation with antioxidant phytochemicals (such as contained in S. maxima) represents an effective neuroprotective strategy against 6-OHDA-caused neurotoxicity vía free radical production to preserve striatal dopaminergic neurotransmission in vivo.

We have previously shown that the intrastriatal injection of the C-terminal domain of tetanus toxin (Hc-TeTx) protects the nigrostriatal-dopaminergic pathways and improves motor behavior in hemiparkinsonism-rat models caused by MPP(+) (1-methyl-4-phenylpyridinium). Here we have investigated the protective effects of the intramuscular application of the Hc-TeTx on motor asymmetry and neurodegeneration in the striatum of 6-hydroxydopamine (6-OHDA)-treated rats. Adult male rats were intramuscularly injected with the recombinant Hc-TeTx protein (0.1-20μg/kg, daily) 3days before the stereotaxic injection of 6-OHDA into the left striatum. Our results showed that the motor-improvement functions were extended for 4weeks in all Hc-TeTx-treated groups, obtaining the maximum performance with the highest dose of Hc-TeTx (20μg/kg). The improvements found were 97%, 87%, and 70% in the turning behavior, stepping test, and cylinder test, respectively. The striatal levels of dopamine and its metabolites did not vary compared to the control group. Moreover, the peripheral treatment with Hc-TeTx in rats prevents, for 30days, the neurodegeneration in the striatum caused by the toxicity of the 6-OHDA. Our results lead us to believe that the Hc-TeTx could be a potential therapeutic agent in pathologies caused by impairment of dopaminergic innervations such as Parkinson's disease., (Copyright © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Introduction: The serine exopeptidase DPP IV is a dual protein able to work as an enzyme and an interacting protein. The incretin molecules glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are hydrolyzed by DPP IV into inactive forms, which are unable to promote insulin secretion. Therefore, DPP IV is a validated target for the treatment of type 2 diabetes mellitus (T2DM), and a number of inhibitors have been reported in the literature as antidiabetic drugs., Areas Covered: DPP IV inhibitor patents from 2006 are included in this review. Documents are classified into chemical groups depending on the main claim. Groups are: i) pyrrolidines and thiazolidines; ii) cyclohexanes, piperidines, piperazines, pyridines and pyrimidines; iii) fused 5-carbon cycles; iv) pyridine, pyrimidine and pyrazine-based bicyclic structures; v) indoles, condensed-imidazoles and xanthines; vi) pyrido-pyrimidines, quinolones, isoquinolines, quinozalines, quinoxalines, naphthyridines, quinolones and quinazolinones; vii) benzoquinolizines, fused aminopiperidines and fused triazoles; viii) other heterocyclic structures and ix) peptidomimetics., Expert Opinion: Research in finding new DPP IV inhibitors is intense, despite the number of reported molecules. This is mainly because marketed compounds have been approved in the last 5 years and long-term side effects have not been detected. The perfect inhibitor for the T2DM treatment would therefore be a molecule that inhibits GLP-1 and GIP degradation by DPP IV, but does not affect the activity of the protease in other substrates, nor disturbs the communication of DPP IV with other proteins.

Sialic acid in glycoconjugates participates in important cellular functions associated with normal development, growth, and communication. Therefore we evaluated the sialylation pattern and memory deficits caused by the injection of Aβ((25-35)) into the hippocampus (Hp) of rats. The eight-arm maze spatial-learning and memory test indicated that the injection of Aβ((25-35)) into subfield CA1 of the Hp impaired both learning and memory. The sialylation pattern was examined using sialic acid-specific lectins. Our results showed that Maackia amurensis agglutinin (MAA, specific for Neu5Acα2,3Gal) showed reactivity in the CA1 and dentate gyrus (DG) subfields of the Hp mainly in the group injected with vehicle, whereas Macrobrachium rosenbergii lectin (MRL, specific for Neu5,9,7Ac) and Sambucus nigra agglutinin (SNA, specific for Neu5Acα2,6Gal-GalNAc) had increased reactivity in the CA1 and DG subfields of the Hp in the Aβ((25-35))-injected group. The staining pattern of the antibody specific for polysialic acid (a linear homopolymer of α-2,8-linked sialic acid) increased in the CA1 and DG subfields of the Hp of the Aβ((25-35)) group compared to the control group. Our results suggest that injection of Aβ((25-35)) causes impairment in spatial memory and alters the sialylation pattern in response to compensatory reorganization and-or sprouting of dendrites and axons of the surviving neurons., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The Aβ(25-35) fraction mimics the toxic effects of the complete peptide Aβ(1-42) because this decapeptide is able to cause memory impairment and neurodegenerative events. Recent evidence has shown that the injection of Aβ(25-35) into the temporal cortex (TCx) of the rat increases the nitric oxide (NO) pathways with several consequences, such as neuronal loss in rats. Our aim was to investigate the effects of each NOS isoform by the prior injection of NOS inhibitors before the injection of the Aβ(25-35). One month after the treatment, the animals were tested for their spatial memory in the radial maze. The hippocampus (Hp) and TCx were assessed for NO production, nitration of proteins (3-NT), astrocytosis (GFAP), and neuronal loss. Our findings show a significant impairment in the memory caused by Aβ25-35 injection. In contrast NOS inhibitors plus Aβ25-35 cause a protection yielding a high performance in the memory test and reduction of cell damage in the TCx and the Hp. Particularly, iNOS is the major source of NO and related to the inflammatory response leading to the memory deficits. The inhibition of iNOS is an important target for neuronal protection against the toxicity of the Aβ25-35 over the long term., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Herein we present the design, synthesis, and evaluation of a structurally novel library of 20 peptidyl 3-aryl vinyl sulfones as inhibitors of cathepsins L and B. The building blocks, described here for the first time, were synthesized in a highly efficient and enantioselective manner, starting from 3-aryl-substituted allyl alcohols. The corresponding vinyl sulfones were prepared by a new approach, based on a combination of solid-phase peptide synthesis using the Fmoc/tBu strategy, followed by solution-phase coupling to the corresponding (R)-3-amino-3-aryl vinyl sulfones as trifluoroacetate salts. The inhibitory activity of the resulting compounds against cathepsins L and B was evaluated, and the compound exhibiting the best activity was selected for enzymatic characterization. Finally, docking studies were performed in order to identify key structural features of the aryl substituent.

Alzheimer's disease (AD) is characterized by the amyloid-beta (Abeta) aggregation but it is unclear when this process begins. Previously, we showed that amyloid-beta(25-35) (Abeta(25-35)) increases the nitric oxide (NO) pathways and causes neurodegenerative effects in rats. The excessive increase of NO during brain development can promote a persistent oxidative stress, but the role of the Abeta(25-35) in the neonatal age and its effects over the long term is unclear. Our aim was to evaluate if the Abeta(25-35) injection on postnatal day 7 causes loss in spatial memory by NO pathways in adult rats. Our results showed that neonatal-Abeta(25-35) injection into the hippocampus (Hp) causes significant impairments in the spatial memory after 90 days. The NO levels were found increased and argynophilic in the Hp. Other evidence of neuronal damage was an increase of the immunoreactivity for 3-nitrotyrosine (3-NT) and the glial-fibrilar acid protein (GFAP) in the Hp of the Abeta(25-35) group. In contrast, these effects were blocked by the administration of L-NAME (inhibitor of nitric oxide synthase) before the injection of Abeta(25-35). The L-NAME plus Abeta(25-35) group showed a better performance in the spatial memory compared to the Abeta(25-35) group. In addition in this group we found a decrease of NO, 3-NT and neurodegeneration in the Hp compared to the Abeta(25-35) group. This finding is a novel result about the role of Abeta(25-35) during the neonatal stage that enhances the NO production, which appears to impair the spatial memory in adult rats.

Recently it has been shown that the C-terminus fragment of the tetanus toxin (Hc-TeTx) is transported retrogradely and had shown neuroprotective effects, preventing neuronal death by apoptosis. This could be a new alternative preventing ongoing cell death and restoring the motor function in Parkinson's disease (PD), which is characterized by dopaminergic neurodegeneration. Our aim was to evaluate the effects of local administration of Hc-TeTx on motor behavior and the dopamine (DA) levels in the striatum of MPP(+)-treated rats. In the rotational behavior task, the Hc-TeTx [2 microM]+MPP(+) group had a decreased number of contralateral rotations and the cylinder test improved for both forelimb-use asymmetry compared to the MPP(+) group. The staircase test showed that the Hc-TeTx+MPP(+) group had an improvement of fine motor skills compared to the same limb performance of the MPP(+) group. The group of animals with Hc-TeTx+MPP(+) had higher DA and metabolite levels compared to the MPP(+) group. Our study clearly shows that Hc-TeTx improves different motor behavior strongly, which favors the hypothesis of the Hc-TeTx fragment enhancing survival pathways that result in amelioration of the dopaminergic system of rats with a dopaminergic lesion.

Purpose: To evaluate eye care services from the user's perspective in a low income population from the east zone of the city of São Paulo--Brazil., Methods: A household survey was performed using cluster sampling in three low income districts of the city of São Paulo--Brazil. From July/2004 to January/2005, 1055 interviews with an adult household representative were carried and an eye care system responsiveness questionnaire was administered through individual interview., Results: 71.56% of the participants were women. Respondents' age ranged from 18 to 92 years (41.42 +/- 15.67 years). Regarding schooling, 525 (49.77%) had four years or less; 489 (46.35%) between five and eleven years, 40 (3.79%) had eleven or more years of study. Eye care services need was reported as 712 (67.49%) declaring themselves or someone else of the household needing and obtaining services and 135 (12.80%) had never needed eye care. The most frequently cited barriers to obtain the eye care service by respondents was cost (77.29%), followed by unsuccessful attempt to obtain eye care (42.21%). General satisfaction for the criteria contained in the questionnaire was 63.37%. In the 36.63% dissatisfied respondents, the most frequently cited claim was the amount of time waited before consultation., Conclusion: The main barriers to obtain eye care services were cost of medical appointment and lack of access to the services. 63.37% of the individuals in need who had received eye care in last 12 months were satisfied with the service provided.

The chemical alpha-asarone is an important active substance of the Acori graminei rhizome (AGR). It has pharmacological effects that include antihyperlipidemic, antiinflammatory, and antioxidant activity. Our aim was to study the effects alpha-asarone on nitric oxide (NO) levels in the hippocampus and temporal cortex of the rat after injection of the fraction 25-35 from amyloid-beta (Abeta((25-35))). In addition we examined the working spatial memory in an eight-arm radial maze. Our results showed a significant increase of nitrites in the hippocampus and temporal cortex of Abeta((25-35))-treated rats. Other evidence of neuronal damage was the expression of a glial-fibrillar-acid protein and a silver staining. There were impairments in the spatial memory evaluated in the eight-arm radial maze. We wanted to determine whether alpha-asarone improves the memory correlated with NO overproduction and neuronal damage caused by the injection of Abeta((25-35)) into rats. Then animals received a 16-day treatment of alpha-asarone before the Abeta((25-35)) injection. Our results show a significant decrease of nitrite levels in the hippocampus and temporal cortex, without astrocytosis and silver-staining cells, which correlates with memory improvement in the alpha-asarone-treated group. Our results suggest that alpha-asarone may protect neurons against Abeta((25-35))-caused neurotoxicity by inhibiting the effects of NO overproduction in the hippocampus and temporal cortex.

beta-Amyloid plays an important role in the neurodegeneration process of Alzheimer's disease (AD), but its neurotoxic mechanisms are not clear. It has been associated with the increase of oxidative stress and cognitive impairment because the beta-amyloid peptide 25-35 (Abeta((25-35))) has the critical neurotoxic properties of the full-length Abeta(1-42). Our present study shows the role of Abeta((25-35)) when injected into the temporal cortex on the nitric oxide pathways, 3-nitrotyrosine, neuronal death, and the spatial memory of rats 1 month after the injection. Our data showed that Abeta((25-35)) increases oxidative stress, causes neuronal damage, and decreases spatial memory in rats. Notably, the injection of the fraction Abeta((25-35)) caused an increase of nNOS and iNOS immunoreactivity in the temporal cortex and hippocampus. We demonstrated a significant increase of reactive astrocytosis, which was accompanied by neuronal damage in the temporal cortex and hippocampus of rats injected with Abeta((25-35)). These data suggest that the fraction Abeta((25-35)) injected into the temporal cortex might contribute to understanding the role of nitric oxide on the biological changes related to the neuropathological progression and the memory impairment in AD.