组胺H3受体减轻异氟醚发育神经毒性的作用及机制研究

Extensive researches have shown that the general anesthetic isoflurane can trigger extensive neuronal apoptosis in the developing brain, neural circuit dysfunction, and result in short- or long-term cognitive impairment. What the mechanism is and how to prevent or treat are important scientific issue and major clinical challenge. The central histaminergic system is known to play important regulatory roles in the function of neuronal circuits involved in cognition. As the presynaptic histamine receptor, H3 modulates the release of histamine, GABA and other neurotransmitters. Our preliminary study indicates that H3 agonist can reverse propofol-induced inhibition of LTP in rats’ CA1 region of the hippocampus by the GABA pathway and in addition prevent isoflurane-induced learning and memory injury in the neonatal rats. In the current project, we hypothesis that the H3 agonists could prevent isoflurane-induced developmental neurotoxicity by the pathway of hippocampal neural circuits function and calcium signal mediated apoptosis. Multiple experimental approaches including the brain slice electrophysiological, molecular biological and behavioral methods will be applied to confirm the hypothesis. The result form this project might provide novel insights in the prevention and therapy of anesthetic-induced developmental neurotoxicity.

异氟醚等全麻药可使发育中的神经元广泛凋亡，神经环路功能异常，导致短期甚至长期的认知功能损害。明确其发生机制，探索合理的干预途径是目前面临的重要科学和临床问题。中枢组胺能神经系统在情感认知相关神经环路发育和功能调节中发挥重要作用。作为突触前组胺受体的H3可调节组胺、γ-氨基丁酸等递质释放，影响神经环路和认知功能。我们的前期实验表明 H3 受体激动剂通过抑制γ-氨基丁酸介导的通路逆转异氟醚对成年大鼠海马CA1区LTP的抑制作用,并能减轻幼年大鼠异氟醚暴露后学习记忆功能的损害。本课题拟通过在体（动物）和离体（脑片和细胞）实验，应用动物行为学、脑片电生理和分子生物学等技术,研究H3受体激动剂对异氟醚引起的发育神经毒性的影响，并从海马神经环路功能，钙信号介导的神经元凋亡两个方面探索可能机制。研究成果可为干预全麻药发育神经毒性提供新的靶点。

全麻药暴露后神经发育毒性作用受到关注。本项目应用分子生物学、电生理学、动物行为学等实验技术观察了组胺H3受体激动剂alpha甲基组胺（RAMH）对幼年大鼠异氟醚暴露后的神经毒性的影响及机制。结果发现（1）RAMH可减轻幼年大鼠异氟醚暴露后海马区神经元凋亡及青年期空间记忆和恐惧能力的减退；（2）脑片电生理实验显示RAMH可减轻海马CA1区神经元sIPSC的频率而不影响其幅度；（3）幼年大鼠异氟醚暴露后海马区神经元发生钙内流以及凋亡，蛋白p53及Apaf-1表达上调，RAMH预处理可抑制蛋白p53及Apaf-1的上调。该结果表明RAMH可通过突触前抑制钙信号引起的海马区神经元凋亡，减轻异氟醚暴露后的神经发育毒性。提示中枢组胺H3受体是干预全麻药异氟醚暴露后神经发育毒性的潜在途径。