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Copyright of Arquivos de Neuro-Psiquiatria is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ABSTRACT Decalcification of mineralized tissues is an essential step during tissue processing in the routine histopathology. The time required for complete decalcification, and the effect of decalcifier on cellular and tissue morphology are important parameters which influence the selection of decalcifying agents. In this study, we compared a decalcifying solution (ETDA) composed of both acid and chelating agents to a classical and well-known decalcifying agent (EDTA). To this purpose, the optic density of bone radiographs, residual calcium analysis, bone sample weight, and histological and immunohistochemical analysis were performed. Our data suggest that, similarly to EDTA, the ETDA solution completely removes the calcium ions from the samples enabling easy sectioning. However, unlike the EDTA, this agent takes much less time. Furthermore, both agents showed comparable decalcification efficacy, and similarly, they did not produce cellular, tissue or antigenicity impairments. Therefore, ETDA may be a suitable option when it is necessary an association between a rapid and complete removal of calcium minerals, and a suitable preservation of structure and antigenicity of tissues. Microsc. Res. Tech. 78:111-118, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Rationale: Nitric oxide (NO) modulates the dopamine uptake and release processes and appears to be implicated in dopamine-related pathologies, such as schizophrenia. However, it is unclear whether there is excess or deficient NO synthesis in schizophrenia pathophysiology. Analyses of the intracellular pathways downstream of NO system activation have identified the cyclic nucleotide cyclic guanosine monophosphate (cGMP) as a possible target for drug development. Defects in the sensorimotor gating of the neural mechanism underlying the integration and processing of sensory information have been detected across species through prepulse inhibition (PPI). Objectives: The aim of this study was to investigate the effects of NO/cGMP increase on sensorimotor gating modulation during dopamine hyperfunction. Methods: Mice were treated with NO donors and subjected to the PPI test. Treatment with the NO donor sodium nitroprusside was preceded by pretreatment with a soluble guanylate cyclase (sGC) inhibitor. Additionally, the mice were treated with NO donors and phosphodiesterases inhibitors prior to amphetamine treatment. Results: Pretreatment with the NO donors enhanced the PPI response and attenuated the amphetamine-disruptive effects on the PPI. The sGC inhibitor did not modify the sodium nitroprusside effects. Additionally, the cGMP increase induced by a specific phosphodiesterase inhibitor did not modify the amphetamine-disruptive effect. Conclusions: This study provides the first demonstration that an increase in NO can improve the PPI response and block the amphetamine-disruptive effects on the PPI response. Our data are consistent with recent clinical results. However, these effects do not appear to be related to an increase in cGMP levels, and further investigation is thus required. [ABSTRACT FROM AUTHOR]

Nitric oxide synthase inhibitors reduce l-3, (Del-Bel et al., Cell Mol Neurobiol 25(2):371-392, ) 4-dihydroxyphenylalanine ( l-DOPA)-induced abnormal motor effects subsequent to depletion of dopaminergic neurons in rodents and non-human primates. The present study used quantitative high-performance liquid chromatography to analyze, for the first time, dopamine metabolism in striatum of rats in order to elucidate the mechanism of action of the nitric oxide synthase inhibitors. Adult male Wistar rats received unilateral microinjection of saline (sham) or 6-hydroxydopamine (6-OHDA-lesioned) in the medial forebrain bundle. Past 3 weeks, rats were treated during 21 days with l-DOPA/benserazide (30 mg/kg/7.5 mg/kg, respectively, daily). On the 22nd day rats received an intraperitoneal (i.p.) injection of either vehicle or 7-nitroindazole, a preferential neuronal nitric oxide synthase inhibitor before l-DOPA. Abnormal involuntary movements and rotarod test were assessed as behavioral correlate of motor responses. Lesion intensity was evaluated through tyrosine hydroxylase immunohystochemical reaction. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and an extent of dopamine striatal tissue levels/dopamine metabolism were measured in the striatum. Lesion with 6-OHDA decreased dopamine, DOPAC, and DOPAC/dopamine ratio in the lesioned striatum. l-DOPA treatment induced abnormal involuntary movements and increased DOPAC/dopamine ratio (nearly five times) in the lesioned striatum. l-DOPA-induced dyskinesia was mitigated by 7-nitroindazole, which also decreased dopamine turnover, dopamine and DOPAC levels. Our results revealed an almost two times increase in dopamine content in the non-lesioned striatum of 6-OHDA-lesioned rats. Reduction of striatal DOPAC/dopamine ratio in dyskinetic rats may suggest an increase in the dopamine availability. Our data confirm contribution of nitrergic transmission in the pathogenesis of l-DOPA-induced dyskinesia with potential utilization of nitric oxide synthase inhibitors for treatment. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1 % of the population older than 60 years. The administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice is the most widely used approach to elucidate the mechanisms of cell death involved in PD. However, the magnitude of the PD-like neurodegeneration induced by MPTP depends on many variables, including the regimen of its administration. It has been demonstrated that intranasal (i.n.) administration of MPTP constitutes a new route of toxin delivery to the brain that mimics environmental exposure to neurotoxins. Previous data showed that mice submitted to chronic and acute i.n. MPTP treatment displayed a robust (~80 %) and moderate (~55 %) loss of striatal dopamine, respectively. However, little is known about the neurodegenerative and neuroinflammatory processes following a subacute i.n. MPTP administration in mice. Here, the C57BL/6 mice were infused intranasally with MPTP (1 mg/nostril/day) during 4 consecutive days. At 7 and 28 days after the last administration, the subacute i.n. MPTP regime decreased the tyrosine hydroxylase (TH)-labeling in the striatum (40-50 %) and substantia nigra (25-30 %) and increased the astrogliosis in such brain areas at both time points. Taken together, our data showed that the subacute administration of MPTP into the nasal cavity of C57BL/6 mice induces long-lasting neurodegeneration and neuroinflammation in the nigrostriatal pathway, thus representing a valuable animal model for the investigation of neuroprotective strategies in PD. [ABSTRACT FROM AUTHOR]

Abstract: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L-NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose-dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders. [Copyright &y& Elsevier]

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ9-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca2+) increase, etc.), on CBD behavioural effects. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5 s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20 mg/kg) immediately before, 3 h after and daily for 6 days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion + vehicle, day 1: zero, day 7: four, and lesion + Cannabidiol 20 mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions. [ABSTRACT FROM AUTHOR]

There are currently few clinical strategies in place, which provide effective neuroprotection and repair, despite an intense international effort over the past decades. One possible explanation for this is that a deeper understanding is required of how endogenous mechanisms act to confer neuroprotection. This mini-review reports the proceedings of a recent workshop 'Neuroprotection and Neurorepair: New Strategies' (Iguazu Falls, Misiones, Argentina, April 11-13, 2011, Satellite Symposium of the V Neurotoxicity Society Meeting, 2011) in which four areas of active research were identified to have the potential to generate new insights into this field. Topics discussed were (i) metallothionein and other multipotent neuroprotective molecules; (ii) oxidative stress and their signal mediated pathways in neuroregeneration; (iii) neurotoxins in glial cells, and (iv) drugs of abuse with neuroprotective effects. [ABSTRACT FROM AUTHOR]

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson’s disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD. [ABSTRACT FROM AUTHOR]

The objective of the present study was to assess the influence of decortication of the posterior elements of the vertebra (recipient bed) and the nature of the bone graft (cortical or cancellous bone) on graft integration and bone, cartilage and fiber neoformation in the interface between the vertebral recipient bed and the bone graft. Seventy-two male Wistar rats were divided into four experimental groups according to the presence or absence of decortication of the posterior vertebral elements and the use of a cortical or cancellous bone graft. Group I—the posterior elements were decorticated and cancellous bone used. Group II—the posterior elements were decorticated and cortical graft was used. Group III—the posterior elements were not decorticated and cancellous graft was used. Group IV—the posterior elements were not decorticated and cortical graft was used. The animals were killed 3, 6 and 9 weeks after surgery and the interface between the posterior elements and the bone graft was subjected to histomorphometric evaluation. Mean percent neoformed bone was 40.8% in group I (decortication and cancellous graft), 39.13% in group II (decortication and cortical graft), 6.13% in group III (non-decorticated and cancellous graft), and 9.27% in group IV (non-decorticated and cortical graft) for animals killed at 3 weeks ( P = 0.0005). For animals killed at 6 weeks, the mean percent was 38.53% for group I, 40.40% for group II, 10.27% for group III, and 7.6% for group IV ( P = 0.0005), and for animals killed at 9 weeks, the mean was 25.93% for group I, 30.6% for group II, 16.4% for group III, and 18.73% for group IV ( P = 0.0026). The mean percent neoformed cartilage tissue was 8.36% for group I, 7.46% for group II, 11.1% for group III, and 9.13% for group IV for the animals killed at 3 weeks ( P = 0.6544); 6.6% for group I, 8.07% for group, 7.47% for group III and 6.13% for group IV ( P = 0.4889) for animals killed at 6 weeks, and 3.13% for group I, 4.06% for group II, 10.53% for group III and 12.07% for group IV ( P = 0.0006) for animals killed at 9 weeks. Mean percent neoformed fibrous tissue was 11% for group I, 6.13% for group II, 26.27% for group III and 21.87% for group IV for animals killed at 3 weeks ( P = 0.0008); 7.67% for group I, 7.1% for group II, 9.8% for group III and 10.4% for group IV ( P = 0.7880) for animals killed at 6 weeks, and 3.73% for group I, 4.4% for group II, 6.67% for group III and 6.8% for group IV ( P = 0.0214) for animals killed at 9 weeks. The statistically significant differences in percent tissue formation were related to decortication of the posterior elements. The use of a cortical or cancellous graft did not influence tissue neoformation. Ossification in the interface of the recipient graft bed was of the intramembranous type in the decorticated animals and endochondral type in the non-decorticated animals. [ABSTRACT FROM AUTHOR]

Nitric oxide synthase (NOS) has been reported to be involved with both bone healing and bone metabolism. The aim of this study was to test the null hypothesis that there is no correlation between new bone formation during mandibular distraction osteogenesis and NOS expression in the trigeminal ganglion of rats. Newly formed tissue during distraction osteogenesis and trigeminal NOS expression measured by the NADPH-diaphorase (NADPH-d) reaction were evaluated in 72 male Wistar rats by histomorphometric and histochemical methods. In animals submitted to 0.5 mm/day distraction osteogenesis, the percentage of bone tissue was higher in the basal area of the mandibles compared with the center and significantly increased through the experimental periods ( P < 0.05). At the sixth postoperative week, the difference in bone formation between the continuous and acute distraction osteogenesis groups was the highest. Significant correlation between new bone formation by distraction osteogenesis and NADPH-d-reactive neurons was found, varying according to neuronal cell size ( r = −0.6, P = 0.005, small cells strongly stained; r = 0.5, P = 0.018, large cells moderately stained). The results suggest that NOS may play a role in the bone healing process via neurogenic pathways, and the phenomenon seems to be neuronal cell morphotype-dependent. Further studies are now warranted to investigate the mechanistic link between the expression of trigeminal NOS and mandibular new bone formation by distraction osteogenesis. [ABSTRACT FROM AUTHOR]

Aim: To investigate the hypothesis supporting the link between periodontitis and dopaminergic neuron degeneration. Materials and Methods: Adult male Wistar rats were used to induce dopaminergic neuronal injury with 6‐hydroxydopamine (6‐OHDA) neurotoxin and experimental periodontitis via ligature placement. Motor function assessments were conducted before and after periodontitis induction in controls and 6‐OHDA‐injury‐induced rats. Tissue samples from the striatum, jaw and blood were collected for molecular analyses, encompassing immunohistochemistry of tyrosine hydroxylase, microglia and astrocyte, as well as micro‐computed tomography, to assess alveolar bone loss and for the analysis of striatal oxidative stress and plasma inflammatory markers. Results: The results indicated motor impairment in 6‐OHDA‐injury‐induced rats exacerbated by periodontitis, worsening dopaminergic striatal degeneration. Periodontitis alone or in combination with 6‐OHDA‐induced lesion was able to increase striatal microglia, while astrocytes were increased by the combination only. Periodontitis increased striatal reactive oxygen species levels and plasma tumour necrosis factor‐alpha levels in rats with 6‐OHDA‐induced lesions and decreased the anti‐inflammatory interleukin‐10. Conclusions: This study provides original insights into the association between periodontitis and a neurodegenerative condition. The increased inflammatory pathway associated with both 6‐OHDA‐induced dopaminergic neuron lesion and periodontal inflammatory processes corroborates that the periodontitis‐induced systemic inflammation may aggravate neuroinflammation in Parkinson's‐like disease, potentially hastening disease progression. [ABSTRACT FROM AUTHOR]

We used mouse microglial cells in culture activated by lipopolysaccharide (LPS) or α-synuclein amyloid aggregates (αSa) to study the anti-inflammatory effects of COL-3, a tetracycline derivative without antimicrobial activity. Under LPS or αSa stimulation, COL-3 (10, 20 µM) efficiently repressed the induction of the microglial activation marker protein Iba-1 and the stimulated-release of the pro-inflammatory cytokine TNF-α. COL-3′s inhibitory effects on TNF-α were reproduced by the tetracycline antibiotic doxycycline (DOX; 50 µM), the glucocorticoid dexamethasone, and apocynin (APO), an inhibitor of the superoxide-producing enzyme NADPH oxidase. This last observation suggested that COL-3 and DOX might also operate themselves by restraining oxidative stress-mediated signaling events. Quantitative measurement of intracellular reactive oxygen species (ROS) levels revealed that COL-3 and DOX were indeed as effective as APO in reducing oxidative stress and TNF-α release in activated microglia. ROS inhibition with COL-3 or DOX occurred together with a reduction of microglial glucose accumulation and NADPH synthesis. This suggested that COL-3 and DOX might reduce microglial oxidative burst activity by limiting the glucose-dependent synthesis of NADPH, the requisite substrate for NADPH oxidase. Coherent with this possibility, the glycolysis inhibitor 2-deoxy-D-glucose reproduced the immunosuppressive action of COL-3 and DOX in activated microglia. Overall, we propose that COL-3 and its parent compound DOX exert anti-inflammatory effects in microglial cells by inhibiting glucose-dependent ROS production. These effects might be strengthened by the intrinsic antioxidant properties of DOX and COL-3 in a self-reinforcing manner. [ABSTRACT FROM AUTHOR]

The 5-lipoxygenase/leukotriene system has been implicated in both physiological and pathological states within the central nervous system. Understanding how this system interacts with the dopaminergic system could provide valuable insights into dopamine-related pathologies. This study focused on examining both motor and non-motor dopamine-related responses in 5-lipoxygenase/leukotriene-deficient mice. We used pharmacological agents such as amphetamine, apomorphine, and reserpine to challenge the dopaminergic system, evaluating their effects on prepulse inhibition reaction (PPI), general motor activity, and oral involuntary movements. Additionally, we analyzed striatal glial marker expression (GFAP and Iba-1) in reserpine-treated mice. The 5-lipoxygenase/leukotriene-deficient mice exhibited increased spontaneous locomotor activity, including both horizontal and vertical exploration, along with stereotyped behavior compared to wild-type mice. This hyperactivity was reduced by acute apomorphine treatment. Although basal PPI responses were unchanged, 5-lipoxygenase/leukotriene-deficient mice displayed a significant reduction in susceptibility to amphetamine-induced PPI disruption. Conversely, these mice were more vulnerable to reserpine-induced involuntary movements. There were no significant differences in the basal expression of striatal GFAP and Iba-1 positive cells between 5-lipoxygenase/leukotriene-deficient and wild-type mice. However, reserpine treatment significantly increased GFAP immunoreactivity in wild-type mice, an effect not observed in 5-lipoxygenase-deficient mice. Additionally, the percentage of activated microglia was significantly higher in reserpine-treated wild-type mice, an effect absents in 5-lipoxygenase/leukotriene-deficient mice. Our findings suggest that 5-lipoxygenase/leukotriene deficiency leads to a distinctive dopaminergic phenotype, indicating that leukotrienes may influence the modulation of dopamine-mediated responses. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. Methods: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. Results: 6-OHDA-lesioned rats exhibited memory impairments and despair-like behaviour in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. CBD decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behaviour that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favoured the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. Conclusion: The present findings suggest a potential beneficial effect of CBD on non-motor symptoms induced by intra-nigral 6-OHDA infusion in rats. [ABSTRACT FROM AUTHOR]

Aggregated forms of the synaptic protein α-synuclein (αS) have been proposed to operate as a molecular trigger for microglial inflammatory processes and neurodegeneration in Parkinson´s disease. Here, we used brain microglial cell cultures activated by fibrillary forms of recombinant human αS to assess the anti-inflammatory and neuroprotective activities of the antibiotic rifampicin (Rif) and its autoxidation product rifampicin quinone (RifQ). Pretreatments with Rif and RifQ reduced the secretion of prototypical inflammatory cytokines (TNF-α, IL-6) and the burst of oxidative stress in microglial cells activated with αS fibrillary aggregates. Note, however, that RifQ was constantly more efficacious than its parent compound in reducing microglial activation. We also established that the suppressive effects of Rif and RifQ on cytokine release was probably due to inhibition of both PI3K- and non-PI3K-dependent signaling events. The control of oxidative stress appeared, however, essentially dependent on PI3K inhibition. Of interest, we also showed that RifQ was more efficient than Rif in protecting neuronal cells from toxic factors secreted by microglia activated by αS fibrils. Overall, data with RifQ are promising enough to justify further studies to confirm the potential of this compound as an anti-parkinsionian drug. [ABSTRACT FROM AUTHOR]

Levodopa (L‐DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L‐DOPA‐induced dyskinesias (LIDs). Dysregulation of the nitric oxide–cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham‐operated and 6‐hydroxydopamine‐lesioned rats chronically treated with vehicle or L‐DOPA, respectively. In sham‐operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6‐hydroxydopamine‐lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L‐DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDs) are a group of chronic, progressive disorders characterized by the gradual loss of neurons that affect specific regions of the brain, which leads to deficits in specific functions (e.g., memory, movement, cognition). The mechanism that drives chronic progression of NDs remains elusive. Among the proposed underlying pathophysiological mechanisms, aggregation and accumulation of misfolded proteins and neuroinflammation have been credited to contribute to extensive neural loss. Therapeutic agents that confer neuroprotection by downregulating these shared characteristics could therefore have beneficial effects on a wide range of NDs. In this regard, a commonly used antibiotic, doxycycline (Doxy), has been shown to reduce the progression and severity of disease in different experimental models of neurodegeneration by counteracting these common features. This review will focus on the effects reported for Doxy regarding its neuroprotective properties, the "off-target" effects, thereby supporting its evaluation as a new therapeutic approach for diseases associated with a neurodegeneration. [ABSTRACT FROM AUTHOR]

Doxycycline is an antibiotic that has shown neuroprotective, anti-inflammatory, and antidepressant-like effects. Low doses of doxycycline revert the behavioral and neuroinflammatory responses induced by lipopolysaccharide treatment in a mice model of depression. However, the molecular mechanisms involved in the antidepressant action of doxycycline are not yet understood. Doxycycline inhibits the synthesis of nitric oxide (NO), which increases after stress exposure. Inducible NO synthase (iNOS) inhibition also causes antidepressant-like effects in animal models sensitive to antidepressant-like effects such as the forced swimming test (FST). However, no direct study has yet investigated if the antidepressant-like effects of doxycycline could involve changes in NO-mediated neurotransmission. Therefore, this study aimed at investigating: i) the behavioral effects induced by doxycycline alone or in association with ineffective doses of a NO donor (sodium nitroprusside, SNP) or an iNOS inhibitor (1400 W) in mice subjected to the FST; and ii) doxycycline effects in NO metabolite levels in the prefrontal cortex and hippocampus these animals. Male mice (8 weeks) received i.p. injection of saline or doxycycline (10, 30, and 50 mg/kg), alone or combined with SNP (0.1, 0.5, and 1 mg/kg) or 1400 W (1, 3, and 10 µg/kg), and 30 min later were submitted to the FST. Animals were sacrificed immediately after, and NO metabolites nitrate/nitrite (NOx) were measured in the prefrontal cortex and hippocampus. Doxycycline (50 mg/kg) reduced both the immobility time in the FST and NOx levels in the prefrontal cortex of mice compared to the saline group. The antidepressant-like effect of doxycycline in the FST was prevented by SNP (1 mg/kg) pretreatment. Additionally, sub-effective doses of doxycycline (30 mg/kg) associated with 1400 W (1 µg/kg) induced an antidepressant-like effect in the FST. Altogether, our data suggest that the reducing NO levels in the prefrontal cortex through inhibition of iNOS could be related to acute doxycycline treatment resulting in rapid antidepressant-like effects in mice. [ABSTRACT FROM AUTHOR]

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as l-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model. [ABSTRACT FROM AUTHOR]