Yu Wenjuan, Zhu Min, Fang Hongwei, Zhou Jie, Ye Le, Bian Wenyu, Wang Yuan, Zhu Hui, Xiao Jie, Zhu Hao, Li Huafang
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pharmacy, South Campus, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Behav Neurosci. 2019 Jul 23;13:163. doi: 10.3389/fnbeh.2019.00163. eCollection 2019.
MK-801, also known as dizocilpine, is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. Our previous study showed that brain-derived neurotrophic factor (BDNF) signaling was upregulated in cultured hippocampal astrocytes in response to MK-801. However, dysfunctional NMDA receptors are mainly expressed in neurons. The effects of MK-801 on neuron-derived BDNF expression and of risperidone on MK-801-induced cognitive impairment and changes in BDNF expression are unclear. To address this issue, we examined BDNF expression in the hippocampus of rats that received repeated injections of MK-801 (0.5 mg/kg body weight for 6 days) and in primary cultured hippocampal neurons incubated with 20 μM MK-801 for 24 h. BDNF expression and cognitive function were also evaluated in rats receiving intraperitoneal injections of risperidone (1 mg/kg body weight) once daily for 7 days and in hippocampal neurons incubated with 10 μM risperidone following MK801 treatment. MK-801 treatment decreased BDNF expression in the rat hippocampus as well as the expression and secretion of BDNF in hippocampal neurons . However, risperidone reversed the effects of MK801 on BDNF level and improved cognitive function in rats treated with MK801. These findings suggest that risperidone may alleviate cognitive impairment caused by MK801 upregulation of BNDF signaling in the hippocampus.
MK-801,也被称为地佐环平,是一种非竞争性N-甲基-D-天冬氨酸(NMDA)受体拮抗剂,可诱发精神分裂症样症状。我们之前的研究表明,在培养的海马星形胶质细胞中,脑源性神经营养因子(BDNF)信号通路会因MK-801而上调。然而,功能失调的NMDA受体主要在神经元中表达。MK-801对神经元源性BDNF表达的影响以及利培酮对MK-801诱导的认知障碍和BDNF表达变化的影响尚不清楚。为了解决这个问题,我们检测了反复注射MK-801(0.5毫克/千克体重,共6天)的大鼠海马体中BDNF的表达,以及用20微摩尔MK-801孵育24小时的原代培养海马神经元中BDNF的表达。我们还评估了每天腹腔注射利培酮(1毫克/千克体重,共7天)的大鼠以及在MK-801处理后用10微摩尔利培酮孵育的海马神经元中的BDNF表达和认知功能。MK-801处理降低了大鼠海马体中BDNF的表达以及海马神经元中BDNF的表达和分泌。然而,利培酮逆转了MK-801对BDNF水平的影响,并改善了MK-801处理大鼠的认知功能。这些发现表明,利培酮可能减轻MK-801引起的认知障碍,上调海马体中BDNF信号通路。