Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Pharmacol Biochem Behav. 2018 Dec;175:69-76. doi: 10.1016/j.pbb.2018.09.006. Epub 2018 Sep 12.
Donepezil is the first-line of treatment for Alzheimer's disease (AD), which improves cognitive impairment effectively, but whether it has an impact on cognitive impairment in schizophrenia remains unknown. In this study, we evaluated the effects and mechanisms of donepezil on schizophrenia-like cognitive deficits induced by phencyclidine (PCP). The cognitive deficits model of schizophrenia was established by injecting PCP into mice. Risperidone, an atypical antipsychotic drug, served as positive control drug. Three behavioral tests including novel object recognition (NOR) test, Morris Water Maze (MWM) and passive avoidance (PA) test were performed to evaluate the effect of donepezil on PCP-induced cognitive deficits. Furthermore, the content of BDNF and NGF in the hippocampus and cortex of mice was determined using ELISA. Expressions of p-GSK-3β/GSK-3β, p-Akt/Akt, Bcl-2/Bax and Caspase-3 in the hippocampus and cortex were detected by Western blot. Results revealed that donepezil has a protective effect on PCP-induced cognitive dysfunction. Moreover, donepezil can also improve PCP-induced schizophrenia-like cognitive deficits by inhibiting neuronal apoptosis and regulating synaptic plasticity, which was possible through the up-regulation of p-Akt, p-GSK-3β, Bcl-2 and the down-regulation of Bax, Caspase-3. The results indicated that donepezil might exhibit a beneficial effect on the treatment of cognitive dysfunction in schizophrenia.
多奈哌齐是治疗阿尔茨海默病（AD）的一线药物，能有效改善认知障碍，但它是否对精神分裂症的认知障碍有影响尚不清楚。在这项研究中，我们评估了多奈哌齐对苯环利定（PCP）诱导的精神分裂症样认知功能障碍的作用及其机制。通过给小鼠注射 PCP 建立精神分裂症认知功能障碍模型，利培酮作为一种非典型抗精神病药物作为阳性对照药物。采用新物体识别（NOR）试验、Morris 水迷宫（MWM）和被动回避（PA）试验三种行为学试验评估多奈哌齐对 PCP 诱导的认知功能障碍的影响。进一步采用 ELISA 法检测小鼠海马和皮质中脑源性神经营养因子（BDNF）和神经生长因子（NGF）的含量，Western blot 法检测海马和皮质中 p-GSK-3β/GSK-3β、p-Akt/Akt、Bcl-2/Bax 和 Caspase-3 的表达。结果表明，多奈哌齐对 PCP 诱导的认知功能障碍具有保护作用。此外，多奈哌齐还可以通过抑制神经元凋亡和调节突触可塑性来改善 PCP 诱导的精神分裂症样认知功能障碍，其机制可能与上调 p-Akt、p-GSK-3β、Bcl-2 和下调 Bax、Caspase-3 有关。这些结果表明，多奈哌齐可能对治疗精神分裂症认知功能障碍有有益作用。
