RESUMO
There is evidence that excitotoxicity and prolonged microglial activation are involved in neuronal death in neurodegenerative disorders. Activated microglia express various molecules, including the translocator protein 18 kDa (TSPO; formerly known as the peripheral benzodiazepine receptor) on the outer mitochondrial membrane. The TSPO is a novel target for neuroprotective treatments which aim to reduce microglial activation. The effect of PK 11195 and three other TSPO ligands on the level of microglial activation and neuronal survival was evaluated in a quinolinic acid (QUIN) rat model of excitotoxic neurodegeneration. All three ligands were neuroprotective at a level comparable to PK 11195. All of the ligands decreased microglial activation following the injection of QUIN but had no effect on astrogliosis. Interestingly, we also observed neuroprotective effects from the vehicle, dimethyl sulfoxide (DMSO).
Assuntos
Proteínas de Transporte/metabolismo , Morte Celular/efeitos dos fármacos , Isoquinolinas/farmacologia , Ativação de Macrófagos/fisiologia , Microglia/metabolismo , Neostriado/fisiologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ácido Quinolínico/antagonistas & inibidores , Ácido Quinolínico/toxicidade , Receptores de GABA-A/metabolismo , Animais , Proteínas de Transporte/efeitos dos fármacos , Dimetil Sulfóxido/metabolismo , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Isoquinolinas/química , Masculino , Microinjeções , Fármacos Neuroprotetores/química , Veículos Farmacêuticos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacosRESUMO
Much recent work is investigating the role of oxidative stress and inflammatory mechanisms in the aetiology of neurodegeneration in Parkinson's disease. The present study evaluated whether the green tea constituent epigallocatechin gallate (EGCG) which has both anti-oxidant and anti-inflammatory properties, exerts neuroprotection and symptomatic effects when administered orally as a pre-treatment prior to 6-hydroxydopamine (6-OHDA) lesions. Groups of rats were given either 1mg/kg, 2mg/kg EGCG or vehicle solution for 14 days. Sham or 6-OHDA surgery was performed on day 11 of the drug administration protocol. Behavioural analysis was conducted before drugs/vehicle solution, again during the treatment period and then repeated at fortnightly intervals for 2 months post-operatively. Whilst some subtle behavioural improvements in postural abnormalities and ability to cross a narrow beam were observed in lesioned rats after EGCG (vs. vehicle) there was no evidence of neuroprotection on post-mortem quantification of degree of nigral dopaminergic neuronal loss when comparing the lesioned groups given the various treatments.