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1.
Neuropharmacology ; 123: 261-273, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28495374

RESUMO

The status epilepticus (SE) induced by lithium-pilocarpine is a well characterized rodent model of the human temporal lobe epilepsy (TLE) which is accompanied by severe brain damage. Stress and glucocorticoids markedly contribute to exacerbate neuronal damage induced by seizures but the underlying mechanisms are poorly understood. Herein we sought to investigate whether a single administration of metyrapone (150 mg/kg, i.p.), an 11ß-hydroxylase inhibitor, enzyme involved in the peripheral and central synthesis of corticosteroids, had neuroprotective properties in this model. Two experiments were carried out. In exp. 1, metyrapone was administered 3 h before pilocarpine injection whereas in exp. 2, metyrapone administration took place at the onset of the SE. In both experiments, 3 days after the insult, brain metabolism was assessed by in vivo 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET). Brains were processed for analyses of markers of hippocampal integrity (Nissl staining), neurodegeneration (Fluoro-Jade C), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and, for a marker of activated microglia by in vitro autoradiography with the TSPO (18 kDa translocator protein) radioligand [18F]GE180. The SE resulted in a consistent hypometabolism in hippocampus, cortex and striatum and neuronal damage, hippocampal neurodegeneration, neuronal death and gliosis. Interestingly, metyrapone had neuroprotective effects when administered before, but not after the insult. In summary, we conclude that metyrapone administration prior but not after the SE protected from brain damage induced by SE in the lithium-pilocarpine model. Therefore, it seems that the effect of metyrapone is preventive in nature and likely related to its antiseizure properties.


Assuntos
Encéfalo/efeitos dos fármacos , Metirapona/farmacologia , Fármacos Neuroprotetores/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Carbazóis , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fluordesoxiglucose F18 , Gliose/tratamento farmacológico , Gliose/metabolismo , Gliose/patologia , Glucose/metabolismo , Imuno-Histoquímica , Compostos de Lítio , Masculino , Pilocarpina , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia
2.
CNS Neurol Disord Drug Targets ; 16(6): 694-704, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27989232

RESUMO

BACKGROUND: Epilepsy is a central disorder associated with neuronal damage and brain hypometabolism. It has been reported that antidepressant drugs show anticonvulsant and neuroprotective effects in different animal models of seizures and epilepsy. AIMS: The purpose of this study was to investigate the eventual short-term brain impairment induced by a single low convulsant dose of the potassium channel blocker 4-aminopyridine (4-AP) and the eventual neuroprotective effects exerted by fluoxetine, a prototypical selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). METHOD: In vivo 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and several histological assessments were carried out in adult male rats after i.p. administration of 3 mg/kg 4-AP for evaluating eventual brain metabolism impairment and signs of hippocampal damage. We also evaluated the effects of a short-term fluoxetine treatment (10 mg/kg, i.p. for 7 days) in this seizure model. RESULTS: [18F]FDG PET analysis revealed no changes in the regional brain metabolism on day 3 after 4-AP injection. The histological assessments revealed signs of damage in the hippocampus, a brain area usually affected by seizures. Thus, reactive gliosis and a significant increase in the expression of caspase-9 were found in the aforementioned brain area. By contrast, we observed no signs of neurodegeneration or neuronal death. Regarding the effects of fluoxetine, this SSRI showed beneficial neurologic effects, since it significantly increased the seizure latency time and reduced the abovementioned 4-AP-induced hippocampal damage markers. CONCLUSION: Overall, our results point to SSRIs and eventually endogenous 5-HT as neuroprotective agents against convulsant-induced hippocampal damage.


Assuntos
4-Aminopiridina/toxicidade , Lesões Encefálicas , Convulsivantes/toxicidade , Fluoxetina/uso terapêutico , Hipocampo/patologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/patologia , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fluoresceínas/metabolismo , Fluordesoxiglucose F18/farmacocinética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/induzido quimicamente , Gliose/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Masculino , Fosfopiruvato Hidratase/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos
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