Search

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., Competing Interests: Conflict of Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pharmacological manipulation of nitric oxide (NO) has been suggested as a promising treatment for schizophrenia symptoms. A single infusion of sodium nitroprusside, a NO donor with short half-life, was found to improve schizophrenia symptoms. However, an increasing number of preclinical studies have demonstrated the potential beneficial effects of both NO donors and inhibitors. We investigated the potential synergistic effect of sub-effective doses of the NO donor sodium nitroprusside or the NO inhibitor 7-Nitroindazole (7NI) combined with clozapine, a standard atypical antipsychotic, on counteracting amphetamine or MK-801-induced psychosis-like behaviors. The impact of sodium nitroprusside and 7NI on cAMP regulation in the prefrontal cortex and striatum was also evaluated. Confirming previous results, we found that both NO donors and inhibitors prevented amphetamine-induced effects (prepulse inhibition [PPI] disruption and hyperlocomotion). In addition, we observed a synergistic effect of sodium nitroprusside and clozapine on antagonizing the disruptive effects of amphetamine, but not MK-801, in the PPI test. The sub-effective dose of 7NI tested did not prevent amphetamine or MK-induced PPI effects when combined with clozapine. Interestingly, cAMP levels were significantly decreased in the prefrontal cortex after treatment with sodium nitroprusside. In the striatum, both sodium nitroprusside and 7NI blocked the amphetamine-induced increase of cAMP. Our data corroborate previous findings on the dopaminergic mechanisms involved in the action of sodium nitroprusside. It is likely that the differential effects of sodium nitroprusside are related to its ability to modify cAMP levels in the prefrontal cortex., (Copyright © 2018 Elsevier Inc. All rights reserved.)

There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega-3 polyunsaturated fatty acid, was tested in streptozotocin-diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L-arginine (L-Arg) or nNOS inhibitor 7-nitroindazole (7-NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle-treated DBT animals exhibited a more pronounced anxiogenic-like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7-NI or L-Arg in VEH-treated DBT animals induced an anxiogenic-like and anxiolytic-like effect, respectively; the previous treatment with both L-Arg and 7-NI in FO-DBT animals abolished the anxiolytic-like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic-like effect., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Inflammatory mechanisms are proposed to play a role in L-DOPA-induced dyskinesia. Cyclooxygenase-2 (COX2) contributes to inflammation pathways in the periphery and is constitutively expressed in the central nervous system. Considering that inhibition of nitric oxide (NO) formation attenuates L-DOPA-induced dyskinesia, this study aimed at investigating if a NO synthase (NOS) inhibitor would change COX2 brain expression in animals with L-DOPA-induced dyskinesia. To this aim, male Wistar rats received unilateral 6-hydroxydopamine microinjection into the medial forebrain bundle were treated daily with L-DOPA (21 days) combined with 7-nitroindazole or vehicle. All hemi-Parkinsonian rats receiving l-DOPA showed dyskinesia. They also presented increased neuronal COX2 immunoreactivity in the dopamine-depleted dorsal striatum that was directly correlated with dyskinesia severity. Striatal COX2 co-localized with choline-acetyltransferase, calbindin and DARPP-32 (dopamine-cAMP-regulated phosphoprotein-32), neuronal markers of GABAergic neurons. NOS inhibition prevented L-DOPA-induced dyskinesia and COX2 increased expression in the dorsal striatum. These results suggest that increased COX2 expression after L-DOPA long-term treatment in Parkinsonian-like rats could contribute to the development of dyskinesia., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, the long-term use of L-DOPA causes, in combination with disease progression, the development of motor complications termed L-DOPA-induced dyskinesia (LID). LID is the result of profound modifications in the functional organization of the basal ganglia circuitry. There is increasing evidence of the involvement of non-dopaminergic systems on the pathophysiology of LID. This raises the possibility of novel promising therapeutic approaches in the future, including agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in preclinical testing or clinical development. Herein, we summarize the current knowledge of the pharmacology of LID in PD. More importantly, this review attempts to highlight the role of nitric oxide (NO) in PD and provide a comprehensive picture of recent preclinical findings from our group and others showing its potential involvement in dyskinesia.

l-3, 4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease but can induce debilitating abnormal involuntary movements (dyskinesia). Here we show that the development of L-DOPA-induced dyskinesia in the rat is accompanied by upregulation of an inflammatory cascade involving nitric oxide. Male Wistar rats sustained unilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. After three weeks animals started to receive daily treatment with L-DOPA (30 mg/kg plus benserazide 7.5 mg/kg, for 21 days), combined with an inhibitor of neuronal NOS (7-nitroindazole, 7-NI, 30 mg/kg/day) or vehicle (saline-PEG 50%). All animals treated with L-DOPA and vehicle developed abnormal involuntary movements, and this effect was prevented by 7-NI. L-DOPA-treated dyskinetic animals exhibited an increased striatal and pallidal expression of glial fibrillary acidic protein (GFAP) in reactive astrocytes, an increased number of CD11b-positive microglial cells with activated morphology, and the rise of cells positive for inducible nitric oxide-synthase immunoreactivity (iNOS). All these indexes of glial activation were prevented by 7-NI co-administration. These findings provide evidence that the development of L-DOPA-induced dyskinesia in the rat is associated with activation of glial cells that promote inflammatory responses. The dramatic effect of 7-NI in preventing this glial response points to an involvement of nitric oxide. Moreover, the results suggest that the NOS inhibitor prevents dyskinesia at least in part via inhibition of glial cell activation and iNOS expression. Our observations indicate nitric oxide synthase inhibitors as a therapeutic strategy for preventing neuroinflammatory and glial components of dyskinesia pathogenesis in Parkinson's disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

According to classical thinking about Parkinson's disease, loss of dopaminergic input from the substantia nigra pars compacta leads to overactivity and underactivity of the indirect and direct output pathways, respectively, in the basal ganglia. Administration of the dopamine precursor L-DOPA (l-3, 4-dihydroxyphenylalanine) is proposed to induce changes in the opposite directions. L-DOPA is the most used drug to treat Parkinson`s disease symptoms. After repeated treatment with this compound, however, disabling secondary effects such as the abnormal involuntary movements usually appear. Nitric oxide is a free radical that can also act as an atypical neurotransmitter and influences dopamine-mediated neurotransmission. In this paper we will briefly review the role of nitric oxide on motor control and in Parkinson's disease, particularly a possible role of nitric oxide in L-DOPA induced dyskinesia in rodents. Recent results show that nitric oxide synthase inhibition reduces L-DOPA-induced dyskinesia in rats and mice. The effect is dose-dependent, does not suffer tolerance nor interferes with L-DOPA positive motor effects. These preclinical findings suggest that nitric oxide is a promising therapeutic target for the reduction of L-DOPA-induced dyskinesia.

Irreversible pulpitis has been associated with pain and an increase in the number of pulp inflammatory cells. Based on the action of nitric oxide (NO) elsewhere, NO may possibly participate in the sensory and autonomic innervation of the dental pulp, and may influence local inflammatory responses. The purpose of this study was to analyze normal and inflamed human dental pulp for the presence of NADPH-diaphorase (NADPH-d), as an index of NO system activity. Six non-carious second premolar pulp tissue samples were obtained from young patients who required extractions for orthodontic reasons and six inflamed samples were obtained from symptomatic carious second premolars clinically diagnosed with irreversible pulpitis. Pulp tissue was carefully removed, fixed by immersion in a cold 4% PFA buffered solution for 120 min, rinsed in cold phosphate buffer, and quickly-frozen for cryostat sectioning. Pulp tissue was sectioned perpendicularly to the vertical axis of the tooth at 20 microm and processed for histochemistry. Sections of each specimen were stained with hematoxylin-eosin and other sections were subjected to histochemical NADPH-d detection. Results indicated the presence of NADPH reactivity within the pulps of both normal and carious teeth. In the normal teeth NADPH-d activity was detected in a small number of vascular endothelial cells and fibroblasts. The inflammatory response of the pulp from carious premolars was detected in connective tissue by the presence of an increased number of fibroblasts, angioblasts and collagen fibers. It was possible to determine the extent of odontoblast reactivity since the odontoblast layer was usually absent in these split-peel preparations. There were no obvious signs of stained pulpal nerve fibers. Overall NADPH-d staining was significantly more intense within inflamed pulp tissues compared to normal healthy samples (Mann-Whitney test, p<0.002). These results suggest that NADPH-d may be used as a marker of inflammatory activity in pulpitis and provide the basis for further studies aiming to clarify the possible functions of NO in human dental pulp in pathophysiological situations.

Strong evidence obtained from in vivo and ex-vivo studies suggests the existence of interaction between dopaminergic and nitrergic systems. Some of the observations suggest a possible implication of nitric oxide (NO) in dopamine (DA) uptake mechanism. The present work investigated the interaction between both systems by examining the effect of an NO donor, sodium nitroprusside (SNP), associated with the indirect DA agonist, amphetamine (AMPH) on tritiated DA uptake in cultures of embryonic mesencephalic neurons. Consistent with the literature, both AMPH (1, 3 and 10 microM) and SNP (300 microM and 1 mM) inhibited DA uptake in a dose-dependent manner. In addition, the inhibition of DA uptake by AMPH (1 and 3 microM) was significantly increased by the previous addition of SNP (300 microM). The implication of NO in this interaction was supported by the fact that the free radical scavenger N-acetyl-L-Cysteine (500 microM) significantly increased DA uptake and completely abolished the effect of SNP, leaving unaffected that from AMPH on DA uptake. Further, double-labeling immunohistochemistry showed the presence of tyrosine hydroxylase- (TH, marker for dopaminergic neurons) and neuronal NO synthase- (nNOS, marker for NO containing neurons) expressing neurons in mesencephalic cultures. Some dopaminergic neurons also express nNOS giving further support for a pre-synaptic interaction between both systems. This is the first work demonstrating in mesencephalic cultured neurons a combined effect of an NO donor and an indirect DA agonist on specific DA uptake.

Although insects lack the adaptive immune response of the mammalians, they manifest effective innate immune responses that include both cellular and humoral components. Cellular responses are mediated by hemocytes and humoral responses include the activation of proteolytic cascades that initiate many events, including NO production. In this work, we determined NO production in Chrysomya megacephala hemolymph and hemocytes after yeast inoculation. Assays were performed with non-infected controls (NIL), saline-injected larvae (SIL) or larvae injected with Saccharomyces cerevisiae (YIL). The hemolymph of injected groups was collected 0.5, 1, 2, 4, 12, 24 or 48h post-injection. NO levels in SIL were comparable to those measured in NIL until 12h, which might be considered the basal production, increasing at 24 and 48h post-injection, probably in response to the increased larval fragility after cuticle rupture. YIL exhibited significantly higher levels of NO than were found in other groups, peaking at 24h. l-NAME and EDTA caused a significant reduction of NO production in YIL at this time, suggesting the activity of a Ca(2+)-dependent NOS. Plasmatocytes and granular cells phagocytosed the yeasts. Plasmatocytes initiated the nodule formation and granular cells were the only hemocyte type to produce NO. These results permit us to conclude that yeasts induced augmented NO production in C. megacephala hemolymph and granular cells are the hemocyte type involved with the generation of this molecule.

Stimulation of the hippocampal formation can modulate nociceptive mechanisms, whereas painful stimuli can activate this structure. Stress exposure can produce plastic changes in the hippocampus. Nitric oxide (NO) is an important neuroregulatory agent present in the hippocampus. The objective of the present study was to investigate the effects of intrahippocampal administration of N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of NO synthase (NOS), on nociceptive processes in stressed and nonstressed rats. Male Wistar rats (n=6-11/group) received unilateral microinjection of L-NAME (50-300 nmol/0.2 microl) into the dentate gyrus (DG) of the dorsal hippocampus. Immediately after the injection tail-flick reflex latency was measured. Stressed animals were submitted to 2 h of restraint and tested immediately or 1, 2, 5 or 10 days later. L-NAME failed to modify nociception in nonstressed rats. However, 5 days after, restraint L-NAME, at all doses tested, produced an antinociceptive effect (ANOVA, P<.05). The dose-response curve had an inverted U shape. L-NAME antinociceptive effect was antagonized by previous treatment with L-arginine (150 nmol/0.2 microl, P<.05). The results suggest that the modulation of nociceptive processes by NO in the dorsal hippocampus is dependent on previous stress exposure and on poststress interval.

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]

Citrus fragrances have been used in aromatherapy for the treatment of anxiety, and the essential oil of Citrus sinensis (sweet orange) has shown promising results, although its mechanism of action was not known. The objective of this study was to evaluate the involvement of nitric oxide (NO) neurotransmission in the anxiolytic-like effect of C. sinensis essential oil. Swiss male mice were submitted to 15 min of C. sinensis essential oil inhalation (1%, 2.5%, 5%, and 10%) and tested in the marble-burying test, neophobia-induced hypophagia, and light/dark test. Locomotor activity was evaluated in an automated locomotor activity box. The coadministration of C. sinensis essential oil with L-arginine (200 mg/kg, i.p.), an NO precursor, was used for the behavioral evaluation of nitrergic system mediation. Additionally, the NO synthase activity was measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) analysis in the cerebral cortex. C. sinensis essential oil exerted anxiolytic-like effect at dose that did not change locomotor activity. Moreover, L-arginine pretreatment prevented this anxiolytic-like effect on marble-burying test. Finally, C. sinensis essential oil reduced the NADPH-d positive cells. Thus, the nitrergic neurotransmission plays a relevant role in the anxiolytic-like effect C. sinensis essential oil. [ABSTRACT FROM AUTHOR]

The nitric oxide (NO) system has been proven to be a valuable modulator of L‐DOPA‐induced dyskinesia in Parkinsonian rodents. NO activates the enzyme soluble guanylyl cyclase and elicits the synthesis of the second‐messenger cGMP. Although we have previously described the anti‐dyskinetic potential of NO synthase inhibitors on L‐DOPA‐induced dyskinesia, the effect of soluble guanylyl cyclase inhibitors remains to be evaluated. The aim of this study was to analyze whether the clinically available non‐selective inhibitor methylene blue, or the selective soluble guanylyl cyclase inhibitor ODQ (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one), could mitigate L‐DOPA‐induced dyskinesia in 6‐hydroxydopamine‐lesioned rats. Here, we demonstrated that methylene blue was able to reduce L‐DOPA‐induced dyskinesia incidence when chronically co‐administered with L‐DOPA during 3 weeks. Methylene blue chronic (but not acute) administration (2 weeks) was effective in attenuating L‐DOPA‐induced dyskinesia in rats rendered dyskinetic by a previous course of L‐DOPA chronic treatment. Furthermore, discontinuous methylene blue treatment (e.g., co‐administration of methylene blue and L‐DOPA for 2 consecutive days followed by vehicle and L‐DOPA co‐administration for 5 days) was effective in attenuating dyskinesia. Finally, we demonstrated that microinjection of methylene blue or ODQ into the lateral ventricle effectively attenuated L‐DOPA‐induced dyskinesia. Taken together, these results demonstrate an important role of NO‐soluble guanylyl cyclase‐cGMP signaling on L‐DOPA‐induced dyskinesia. The clinical implications of this discovery are expected to advance the treatment options for patients with Parkinson's disease. In this work, we demonstrated an important role of striatal neuronal nitric oxide synthase (nNOS) – nitric oxide (NO) – soluble guanylyl cyclase (sGC) signaling pathway on L‐DOPA‐induced dyskinesia. Our data indicate that inhibition of nNOS/sGC with methylene blue and the specific inhibition of sGC with ODQ were able to attenuate L‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat model of Parkinson's disease. [ABSTRACT FROM AUTHOR]

In Parkinson's disease (PD), l-DOPA therapy leads to the emergence of motor complications including l-DOPA-induced dyskinesia (LID). LID relies on a sequence of pre- and postsynaptic neuronal events, leading to abnormal corticostriatal neurotransmission and maladaptive changes in striatal projection neurons. In recent years, additional non-neuronal mechanisms have been proposed to contribute to LID. Among these mechanisms, considerable attention has been focused on l-DOPA-induced inflammatory responses. Microglia and astrocytes are the main actors in neuroinflammatory responses, and their double role at the interface between immune and neurophysiological responses is starting to be elucidated. Both microglia and astrocytes express a multitude of neurotransmitter receptors and via the release of several soluble molecules modulate synaptic function in neuronal networks. Here we review preclinical and clinical evidence of glial overactivation by l-DOPA, supporting a role of microglia and astrocytes in the development of LID. We propose that in PD, chronically and abnormally activated microglia and astrocytes lead to an aberrant neuron-glia communication, which affect synaptic activity and neuroplasticity contributing to the development of LID. [ABSTRACT FROM AUTHOR]

Inflammation in Parkinson's disease (PD) is a new concept that has gained ground due to the potential of mitigating dopaminergic neuron death by decreasing inflammation. The solution to this question is likely to be complex. We propose here that the significance of inflammation in PD may go beyond the nigral cell death. The pathological process that underlies PD requires years to reach its full extent. A growing body of evidence has been accumulated on the presence of multiple inflammatory signs in the brain of PD patients even in very late stages of the disease. Because neuron-microglia-astrocyte interactions play a major role in the plasticity of neuronal response to l-DOPA in post-synaptic neurons, we focused this review on our recent results of l-DOPA-induced dyskinesia in rodents correlating it to significant findings regarding glial cells and neuroinflammation. We showed that in the rat model of PD/ l-DOPA-induced dyskinesia there was an increased expression of inflammatory markers, such as the enzymes COX2 in neurons and iNOS in glial cells, in the dopamine-denervated striatum. The gliosis commonly seem in PD was associated with modifications in astrocytes and microglia that occur after chronic treatment with l-DOPA. Either as a cause, consequence, or promoter of progression of neuronal degeneration, inflammation plays a role in PD. The key aims of current PD research ought to be to elucidate (a) the time sequence in which the inflammatory factors act in PD patient brain and (b) the mechanisms by which neuroinflammatory response contributes to the collateral effects of l-DOPA treatment. [ABSTRACT FROM AUTHOR]

Background Nitric oxide (NO) is a gaseous molecule that modulates several physiological processes, including signal transmission in the central nervous system. There is evidence supporting NO as a major neurotransmitter involved in motor and emotion/behavior control. We investigated the distribution and morphology of nitrergic neurons in the two main input structures of the basal ganglia of human brain: the striatum and subthalamic nucleus. Methods We studied samples of striatum (caudate and putamen) and subthalamic nucleus of 20 human brains from subjects without neurological/psychiatric diseases. The tissues were stained by histochemistry for nicotinamide adenine dinucleotide phosphate diaphorase activity and by immunohistochemistry for neuronal NO synthase (nNOS). Subsequently, we analyzed the nitrergic neuronal profile and its morphometric parameters. Results Our data corroborate that approximately 2% of neurons in striatum express nNOS and these exhibited morphology characteristic of interneurons. Posterior regions of the striatum have a higher nitrergic neuronal profile than anterior regions of this nucleus suggesting an anteroposterior gradient of nitrergic neurons. Posterior limbic-associated areas of the striatum have a higher nitrergic neuronal profile compared to other functional subdivisions. Also, approximately 90% of neurons in the subthalamic nucleus express nNOS. Conclusions A remarkable presence of nitrergic neurons in the human striatum and subthalamic nucleus suggests that NO may play a critical role in the physiology of these nuclei. [ABSTRACT FROM AUTHOR]

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.)

Systemic administration of nitric oxide synthase (NOS) inhibitors induces catalepsy in a dose-dependent manner in male Albino-Swiss mice. The objective of the present work was to investigate if similar effects occur in rats and if these effects are centrally mediated. The results showed that systemic administration of NG-nitro-l-arginine (l-NOARG, 40–160 mg/kg, i.p.), a non-selective NOS inhibitor, induced catalepsy in rats. Similar effects were found after intracerebroventricular (i.c.v.) injection of l-NOARG (50–200 nmol) or NG-nitro-l-arginine methylester (l-NAME, 100–200 nmol). The dose–response curve of the former compound, however, had an inverted U shape. The effect of l-NOARG (100 nmol, i.c.v.) was completely prevented by pre-treatment with l-arginine (300 nmol, i.c.v.) but not by d-arginine (300 nmol, i.c.v.). Intra-striatal injection of NG-monomethyl-l-arginine (l-NMMA, 100 nmol), 7-nitroindazole (7-NIO, 100 nmol), l-NOARG (25–100 nmol) or l-NAME (50–200 nmol) also induced catalepsy. Similar to i.c.v. administration, the latter two compounds produced bell-shaped dose–response curves. The cataleptic effect of intra-striatal administration of l-NAME (100 nmol) was reversed by local treatment with l-arginine (100 nmol). These results suggest that interference with the striatal formation of nitric oxide may induce significant motor effects in rats. [Copyright &y& Elsevier]

Abstract: Synaptophysin is a protein involved in the biogenesis of synaptic vesicles and budding. It has been used as an important tool to investigate plastic effects on synaptic transmission. Nitric oxide (NO) can influence plastic changes in specific brain regions related to cognition and emotion. Experimental evidence suggests that NO and synaptophysin are co-localized in several brain regions and that NO may change synaptophysin expression. Therefore, the aim of the present work was to investigate if inhibition of NO formation would change synaptophysin mRNA expression in the hippocampal formation. Male Wistar rats received single or repeated (once a day for 4 days) i.p. injections of saline or l-nitro-arginine (l-NOARG, 40mg/kg), a non-selective inhibitor of nitric oxide synthase (NOS). Twenty-four hours after the last injection the animals were sacrificed and their brains removed for ‘in situ’ hybridization study using 35S-labeled oligonucleotide probe complementary to synaptophysin mRNA. The results were analyzed by computerized densitometry. Acute administration of l-NOARG induced a significant (p <0.05, ANOVA) increase in synaptophysin mRNA expression in the dentate gyrus, CA1 and CA3. The effect disappeared after repeated drug administration. No change was found in the striatum, cingulated cortex, substantia nigra or nucleus accumbens. These results reinforce the proposal that nitric oxide is involved in plastic events in the hippocampus. [Copyright &y& Elsevier]

We assessed the effect of nitric oxide (NO) synthase inhibition on plasma atrial natriuretic peptide (ANP) concentration and content in some brain structures [neurohypophysis (NH), adenohypophysis (AH), medial basal hypothalamus (MHB) and olfactory bulb (OB)] in rats before and after blood volume expansion (BVE). Male Wistar rats were injected i.p. with Nϖ-nitro-l-arginine (l-NNA), 25 mg/kg of body weight, 40 min before the experiment (acute treatment) or l-NNA at a dose of 25 mg/kg body weight, twice a day, for 4 days (chronic treatment). The acute treatment caused an increase in the blood pressure and plasma ANP concentration in rats under basal conditions and after BVE. A decrease in ANP content was observed in the OB and NH, whereas no significant changes were found in the AH or MBH. In chronically treated rats, we also found an increase in blood pressure and in plasma ANP concentration under basal conditions and after BVE. The ANP content increased in the OB, NH and AH. These results indicate that systemic NO synthase inhibition increases ANP concentration in plasma and in areas of the central nervous system. We hypothesize that ANP participates in the hypertension-induced by NO synthesis blockade acting by baroreceptors input to the brain to stimulate ANP release and synthesis that reduces NO prival hypertension. [Copyright &y& Elsevier]

It is well known that nitric oxide (NO) interacts with dopamine (DA) within the striatal circuitry. The anti-dyskinetic properties of NO synthase (NOS) inhibitors demonstrate the importance of NO in L-3,4-dihydroxyphenylalanine ( l -DOPA)-induced dyskinesia (LID). Here, we investigated the ability of a daily co-treatment of the preferential neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI, 30 mg/kg), with l -DOPA (30 mg/kg) to counteract LID in unilaterally 6-OHDA-lesioned rats. We analyzed striatal nNOS-expressing interneurons, DA and 5-HT neurochemistry in the striatum and alterations of the Fos-B/ΔFosB expression in the corticostriatal, nigrostriatal and mesolimbic pathways. Prolonged administration of 7-NI inhibited the manifestation of chronic l -DOPA treatment-induced abnormal involuntary movements (AIMs). LID was associated with an up-regulation in the number of nNOS-expressing interneurons in the lateral but not medial striatum. nNOS inhibition reduced the number of nNOS-expressing interneurons. The anti-dyskinetic effects of 7-NI correlated with a reduction in DA and 5-HT turnover in the striatum. At postsynaptic striatal sites, 7-NI prevented l -DOPA-induced Fos-B/ΔFosB up-regulation in the motor cortex, nucleus accumbens and striatum. Finally, 7-NI blocked Fos-B/ΔFosB expression in nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d)-positive interneurons in the striatum. These results provide further evidence of the molecular mechanisms by which NOS-inhibiting compounds attenuate LID. The involvement of NO with DA and 5-HT neurochemistry may contribute to the understanding of this new, non-dopaminergic therapy for the management of LID. [ABSTRACT FROM AUTHOR]

Abstract: Rodents with lesion of dopaminergic pathway when receiving repeated l-3,4-dihydroxiphenylalanine (l-DOPA) treatment develop abnormal involuntary movements called dyskinesia. We demonstrated that nitric oxide synthase (NOS) inhibitors mitigate l-DOPA-induced dyskinesia in rodents. The aim of the present study was to verify if the in vivo preferential neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) affect the expression of the transcription factor FosB/ΔFosB in the lesioned striatum, an indicator of neuronal activity associated with dyskinesia. Male Wistar rats with unilateral microinjection (medial forebrain bundle) of either the neurotoxin 6-hydroxidopamine (6-OHDA; n =4–6/group) or saline (sham; n =6/group) were provided with l-DOPA (30mg/kg plus benserazide 7.5mg/kg/day, oral gavage), once a day during 22 days. 6-OHDA-lesioned animals developed abnormal involuntary movements (AIMs) classified as axial, limb, orofacial and locomotive dyskinesia and presented FosB/ΔFosB increase in the dopamine-depleted striatum. Administration of 7-NI (30mg/kg, i.p.), 30min prior to l-DOPA reduced the severity of AIMs (≈65% for axial, limb and orofacial and 74% for locomotive AIMs scores), without interfering with the rotarod performance. Simultaneously, 7-NI attenuated the expression of FosB/ΔFosB in dopamine-depleted striatum (≈65% in medial and ≈54% in lateral striatum, bregma 0.48mm). FosB/ΔFosB expression in lateral striatum was correlated with l-DOPA-induced dyskinesia. The findings described here corroborate a new approach to the management of l-DOPA-therapy in Parkinson's disease (PD) treatment. [Copyright &y& Elsevier]