多奈哌齐和加兰他敏对氧糖剥夺/复氧导致的神经元损伤的保护作用及机制

Protective effects and the mechanisms of donepezil and galantamine on neuronal injury induced by glucose deprivation/reoxygenation

已有研究表明乙酰胆碱酯酶抑制剂多奈哌齐和加兰他敏具有减轻氧糖剥夺导致的神经元损伤并减小脑缺血动物的脑梗死体积的作用,但它们的这种作用可能并不完全依赖于其胆碱酯酶抑制活性。为了进一步研究多奈哌齐和加兰他敏对脑缺血后神经元损伤的作用,本课题组成功建立了体外大鼠神经元-星形胶质细胞共培养模型,并在该共培养模型的基础上研究多奈哌齐和加兰他敏对氧糖剥夺/复氧(oxygen-glucose deprivation/reoxygenation,OGD/R)后神经元凋亡的作用及其可能的作用机制。结果表明,多奈哌齐和加兰他敏可以明显减轻OGD/R后共培养体系中的神经元凋亡,同时,促进共培养体系中星形胶质细胞合成和分泌BDNF和NGF,并激活星形胶质细胞内的PI3K/Akt通路和ERK通路,促进核转录因子CREB的磷酸化。以上结果说明多奈哌齐和加兰他敏对OGD/R导致的神经元损伤具有保护作用,其机制可能与激活星形胶质细胞内的PI3K/Akt通路和ERK通路,促进核转录因子CREB的磷酸化,进而促进星形胶质细胞合成和分泌BDNF和NGF有关。

Studies have shown that acetylcholinesterase inhibitors donepezil and galantamine have effects of reducing neuronal damage caused by glucose deprivation and reducing the cerebral infarction volume of cerebral ischemic animals, but their effects may not be entirely dependent on its inhibition of cholinesterase activity. In order to study the effects of donepezil and galantamine on neuronal injury of cerebral ischemia, the rat neuron-astrocyte co-culture model was successfully established in this study. In this model, we studied the effects of donepezil and galantamine on neuron apoptosis induced by oxygen-glucose deprivation/reoxygenation （OGD/R） and investigated the mechanism. The results showed that donepezil and galantamine significantly reduced the neuron apoptosis, and promoted the synthesis and secretion of BDNF and NGF in astrocytes in the co-culture system. Donepezil and galantamine activated the PI3K/Akt pathway and ERK pathway, and promoted the phosphorylation of the nuclear transcription factor CREB. These results suggest that donepezil and galantamine exhibit protective effects on neuronal damage induced by OGD/R. The mechanism may be related to activation of PI3K/Akt pathway and ERK pathway in astrocytes and promote phosphorylation of CREB, which lead to the synthesis and secretion of BDNF and NGF from astrocytes.