Aspectos farmacológicos, efeitos anticonvulsivantes e neuroprotetores da buspirona / Pharmacological study of buspirone and its anticonvulsant and neuroprotective effects

A buspirona é o primeiro fármaco da classe das azapironas e a única comercializada no Brasil. O objetivo do presente trabalho foi conduzir uma revisão de literatura sobre os aspectos farmacológicos da buspirona, bem como demonstrar seus efeitos anticonvulsivantes e neuroprotetores no modelo de convulsão induzido por pilocarpina. Para tanto, foi realizada uma revisão da literatura usando as palavras-chaves buspirone, action mechanism, pharmacokinetics, indications, adverse effects, nomenclature e structure, por intermédio do MEDLINE e LILACS, bem como foram inseridos os resultados experimentais encontrados em camundongos pré-tratados com buspirona no modelo de convulsão induzido por pilocarpina. A busca incluiu todos os artigos completos, resumos, estudos de caso, pré-clínicos e clínicos nos idiomas português e inglês compreendidos entre os anos de 1982 e 2010. Com base na revisão, pode se perceber que ainda existem muitas questões sem respostas sobre a farmacologia da buspirona. Somente a descrição do mecanismo de ação é insuficiente para explicar todos os efeitos produzidos pela buspirona. Além disso, em nossos estudos farmacológicos demonstramos que a buspirona apresenta efeitos anticonvulsivantes e neuroprotetores em camundongos no modelo de convulsão induzido por pilocarpina. Existem poucas informações na literatura sobre o mecanismo de ação que explicaria os efeitos adversos da buspirona, bem como suas propriedades anticonvulsivantes e neuroprotetoras. Dessa forma, são necessários mais estudos para fornecer as informações necessárias, bem como para esclarecer as suas propriedades farmacológicas, contribuindo com o conhecimento dos profissionais, a fim de prevenir os efeitos adversos durante o tratamento clínico com a buspirona.

Buspirone was the first drug in the class of azapirones and is the only one marketed in Brazil. The objective of this study was to conduct a literature review on the pharmacology of buspirone, as well as to demonstrate its neuroprotective and anticonvulsant effects in the model of seizures induced by pilocarpine. To this end, we employed the keywords buspirone, action mechanism, pharmacokinetics, indications, adverse effects, nomenclature and structure to perform a search of the literature, through MEDLINE and LILACS, and inserted the experimental results obtained in mice pretreated with buspirone in the model of seizures induced by pilocarpine. The search included all full articles, abstracts, case studies, pre-clinical and clinical studies in Portuguese and English, between the years 1982 and 2010. The review revealed that there are still many unanswered questions about the pharmacology of buspirone. A description of the mechanism of action alone is insufficient to explain all the effects produced by buspirone. Moreover, our pharmacological studies have shown that buspirone has anticonvulsant and neuroprotective effects in a mouse model of seizures induced by pilocarpine. There is little information in the literature about mechanisms that would explain either the adverse effects of buspirone or its anticonvulsant and neuroprotective properties. Thus, further studies are needed to provide the necessary information, as well as to clarify its pharmacological properties, in order to enable professionals to prevent adverse effects during clinical treatment with buspirone.

Alterations on monoamines concentration in rat hippocampus produced by lipoic acid.

The purposes of the present study were to verify monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9% saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and in their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, in DOPAC and HVA levels did not show any significant change. The alterations in hippocampal monoamines can be suggested as a possible of brain mechanism of action from this antioxidant. The outcome of the study may have therapeutic implications in the treatment of neurodegenerative diseases.

Alterations on monoamines concentration in rat hippocampus produced by lipoic acid / Alterações na concentração de monoaminas no hipocampo de ratos produzidas pelo ácido lipóico

The purposes of the present study were to verify monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9 percent saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and in their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, in DOPAC and HVA levels did not show any significant change. The alterations in hippocampal monoamines can be suggested as a possible of brain mechanism of action from this antioxidant. The outcome of the study may have therapeutic implications in the treatment of neurodegenerative diseases.

O objetivo do presente estudo foi verificar a concentração das monoaminas (dopamina (DA), norepinefrina (NA), serotonina (5-HT)), e seus metabólitos (ácido 3,4-hidroxifenil (DOPAC), ácido homovanílico (HVA) e 5 ácido hydroxiindolacético (5-HIAA)) no hipocampo de ratos após administração do ácido lipóico (AL). Ratos Wistar foram tratados com solução salina 0,9 por cento (i.p., grupo controle) e AL (10, 20 ou 30 mg/kg, i.p., AL10, AL20 e AL30 grupos, respectivamente). Após os tratamentos todos os grupos foram observados durante 24 h. O conteúdo de DA no hipocampo de ratos foi aumentado apenas com AL na dose de 20 mg/kg dose. A concentração de serotonina e do seu metabólito 5-HIAA também foi diminuída com esta dose de AL. Por outro lado, os níveis de DOPAC e de HVA não mostrram nenhuma mudança significativa. As alterações na concentração das monoaminas hipocampais podem ser sugeridas como um possível mecanismo de ação cerebral deste antioxidante. O resultado do estudo pode ter implicações terapêuticas no tratamento de doenças neurodegenerativas.

Oxidative stress in rat hippocampus caused by pilocarpine-induced seizures is reversed by buspirone.

Temporal lobe epilepsy is the most common form of epilepsy in humans. Oxidative stress is a mechanism of cell death induced by seizures. Buspirone presents anxyolitic and antidepressant effects due to their ability to stimulate 5-HT(1A) receptor. We studied the buspirone effects on oxidative stress in rat hippocampus after seizures and status epilepticus (SE) induced by pilocarpine. In pilocarpine group there was a significant increase in lipid peroxidation and nitrite levels. However, no alteration was observed in superoxide dismutase and catalase activities. Buspirone pretreatment produces significantly reduction of the lipid peroxidation level (60%) and nitrite content (44%) as well as increased the superoxide dismutase (47%) and catalase (40%) activities in rat hippocampus after seizures, when compared with the pilocarpine group. The intraperitoneal injection of buspirone prior to pilocarpine suppressed the behavioral seizure occurrence. According to our results, the oxidative stress is present during seizures. Buspirone exerted anticonvulsant effects associated with the inhibition of the development of oxidative stress. These results suggest a therapeutic use potential of buspirone in epilepsy treatment.

Effects of ubiquinone on hydroperoxide concentration and antioxidant enzymatic activities in the rat hippocampus during pilocarpine-induced seizures.

Recent researches have shown that antioxidant compounds may have certain neuroprotective effect against the neurotoxicity of seizures at cellular level. Ubiquinone (UQ), an antioxidant compound, exhibits a wide range of therapeutic effects that are attributed to its potent antioxidant capacity. The objective of the present study was to evaluate the neuroprotective effects of UQ in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with either 0.9% saline (i.p., control group), UQ (5, 10 or 20 mg/kg, i.p., UQ5, UQ10 and UQ20 groups), pilocarpine (400 mg/kg, i.p., P400 group), or co-administration of pilocarpine with UQ group rats 30 min prior to UQ administration. After the treatments all groups were observed for 24 h. The antioxidant enzymatic activities as well as the hydroperoxide concentrations were measured using spectrophotometric methods and the results were analyzed. In pilocarpine group there was a significant increase in hydroperoxides concentration and glutathione peroxidase activity. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the hydroperoxide content and increased the superoxide dismutase, catalase and glutathione peroxidase activities in rat hippocampus during seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, which indicates that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences. Our result also suggests that ubiquinone can exert significant neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.

Lipoic acid blocks seizures induced by pilocarpine via increases in delta-aminolevulinic dehydratase and Na+, K+-ATPase activity in rat brain.

In the present study we investigated the effects of lipoic acid (LA) on delta-aminolevulinic dehydratase (delta-ALA-D) and Na(+), K(+)-ATPase activities in rat brain after seizures induction by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (10mg/kg, i.p., LA group), pilocarpine (400mg/kg, i.p., pilocarpine group), or the combination of LA (10mg/kg, i.p.) with pilocarpine (400mg/kg, i.p.), 30 min before administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 1h. The enzyme activities (delta-ALA-D and Na(+), K(+)-ATPase) were measured using spectrophotometric methods, and the results were compared with that obtained from saline and pilocarpine-treated animals. Neuroprotective effects of LA against seizures were evaluated based on those enzyme activities. The pilocarpine group showed a reduction in delta-ALA-D and Na(+), K(+)-ATPase activities after seizures. In turn, LA plus pilocarpine abolished the appearance of seizures and reversed the decreased in delta-ALA-D and Na(+), K(+)-ATPase activities produced by seizures, when compared to the pilocarpine seizing group. The results from the present study demonstrate that preadministration of LA abolished seizure episodes induced by pilocarpine in rat, probably by increasing delta-ALA-D and Na(+), K(+)-ATPase activities in rat brain during seizures.