Zhu Xinjian, Dong Jingde, Han Bing, Huang Rongrong, Zhang Aifeng, Xia Zhengrong, Chang Huanhuan, Chao Jie, Yao Honghong
Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
Department of Geriatric Neurology, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Front Behav Neurosci. 2017 Oct 18;11:203. doi: 10.3389/fnbeh.2017.00203. eCollection 2017.
Epilepsy is a chronic neurological disease which is usually associated with psychiatric comorbidities. Depsression and cognition impairment are considered to be the most common psychiatric comorbidities in epilepsy patients. However, the specific contribution of epilepsy made to these psychiatric comorbidities remains largely unknown. Here we use pentylenetetrazole (PTZ) kindling, a chronic epilepsy model, to identify neuronal nitric oxide synthase (nNOS) as a signaling molecule triggering PTZ kindling-induced cognitive impairment and depressive-like behavior. Furthermore, we identified that both hippocampal MAPK and PI3K/AKT signaling pathways were activated in response to PTZ kindling, and the increased MAPK and PI3K/AKT signaling activation was paralleled by increased level of reactive oxygen species (ROS) in the hippocampus. However, the PTZ kindling-induced MAPK, PI3K/AKT signaling activities and the ROS level were attenuated by nNOS gene deficiency, suggesting that nNOS may act through ROS-mediated MAPK and PI3K/AKT signaling pathways to trigger cognition deficit and depressive-like behavior in PTZ-kindled mice. Our findings thus define a specific mechanism for chronic epilepsy-induced cognitive impairment and depressive-like behavior, and identify a potential therapeutic target for psychiatric comorbidities in chronic epilepsy patients.
癫痫是一种慢性神经疾病，通常与精神疾病共病相关。抑郁和认知障碍被认为是癫痫患者中最常见的精神共病。然而，癫痫对这些精神共病的具体作用在很大程度上仍不清楚。在此，我们使用戊四氮（PTZ）点燃法，一种慢性癫痫模型，来确定神经元型一氧化氮合酶（nNOS）作为一种信号分子，触发PTZ点燃诱导的认知障碍和抑郁样行为。此外，我们发现海马中的丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3激酶/蛋白激酶B（PI3K/AKT）信号通路在PTZ点燃反应中被激活，并且MAPK和PI3K/AKT信号激活的增加与海马中活性氧（ROS）水平的增加平行。然而，nNOS基因缺陷减弱了PTZ点燃诱导的MAPK、PI3K/AKT信号活性和ROS水平，表明nNOS可能通过ROS介导的MAPK和PI3K/AKT信号通路触发PTZ点燃小鼠的认知缺陷和抑郁样行为。因此，我们的研究结果确定了慢性癫痫诱导的认知障碍和抑郁样行为的特定机制，并确定了慢性癫痫患者精神共病的潜在治疗靶点。
