抗疟药甲氟喹对神经病理性疼痛发生的预防作用及机制研究

发布时间：2018-05-03 05:14

本文选题：神经病理性疼痛 + 电突触　；参考：《华东师范大学》2014年硕士论文

【摘要】：神经病理性疼痛是由神经受损而引发的慢性疼痛。该疾病的一个关键机制为前扣带皮层(The anterior cingulate cortex, ACC)神经元之间的突触联系过度强化。研究表明,在神经受损初期通过药物(如NMDA受体、cAMP阻断剂)阻止ACC可塑性的诱导能有效防止该疾病的发生。但这些药物毒副作用较大、而不能应用于临床。因此,寻求毒副作用小、且能有效阻断与该疾病形成过程中可塑性变化意义重大。我们注意到临床抗疟疾药物甲氟喹的一个作用靶点为神经元的电突触连接蛋白36 (Connexin 36, Cx36),且能跨血脑屏障。由于电突触偶联是神经可塑性所依赖的神经网络同步化及兴奋度的神经基础之一,因此,在神经受损初期,给予甲氟喹可能可以通过阻断Cx36的活动而阻断ACC可塑性的诱导,进而预防神经病理性疼痛的发生。我们发现,在大鼠上系统应用电突触阻断剂甲氟喹或者缝隙连接的广谱阻断剂生胃酮均能有效预防神经病理性疼痛发生：在坐骨神经慢性结扎(The chronic constriction injury of the sciatic nerve, CCI)以及坐骨神经分支损伤(The spared nerve injury, SNI)动物模型建立的早期腹腔注射或ACC局部埋管导入该两种药物之一,均能显著提升动物机械痛及热痛的阈值,且该效果可长期(1月以上)维持；通过RNA干扰使ACC区域Cx36表达下调也可产生同样的预防效果。我们研究发现临床药物甲氟喹可有效预防神经病理性疼痛的发生,且作用机制与阻断电突触活动密切相关。研究结果为该疾病发生的临床预防手段,以及其潜在作用靶点的神经机制研究提供了新的启发。
[Abstract]:Neuropathic pain is a chronic pain caused by nerve damage. One of the key mechanisms of the disease is the overexpression of synaptic connections between the anterior cingulate cortexes (ACCs) neurons in the anterior cingulate cortical cortex. It has been shown that blocking ACC plasticity by drugs such as NMDA receptor camp blocker in the early stage of nerve injury can effectively prevent the occurrence of the disease. However, these drugs have more side effects and can not be used in clinical practice. Therefore, it is of great significance to seek for less toxic side effects and to effectively block the plasticity changes during the formation of the disease. We note that one of the targets of the clinical antimalarial drug mefloquine is electronsynaptic junction protein 36 Connexin 36, Cx36, and can cross the blood-brain barrier. As electrical synaptic coupling is one of the neural bases for neural network synchronization and excitability, mefloquine may block the induction of ACC plasticity by blocking the activity of Cx36 in the early stage of nerve injury. And then prevent the occurrence of neuropathic pain. We found that, The systemic use of mefloquine, an electrical synaptic blocker, or gastric ketone, a broad-spectrum blocker of gap junctions, can effectively prevent neuropathic pain in rats: the chronic constriction injury of the sciatic nerve, CCI) and the ischium in the chronic ligation of the sciatic nerve The spared nerve injurys (SNI) model was established by early intraperitoneal injection or local embedding of ACC into one of the two drugs. The threshold of mechanical pain and heat pain could be significantly increased, and the effect could be maintained for a long time (more than one month), and the down-regulation of Cx36 expression in ACC region by RNA interference could also produce the same preventive effect. We found that mefloquine can effectively prevent neuropathic pain and its mechanism is closely related to blocking electrical synaptic activity. The results provide new inspiration for the clinical prevention of the disease and the neural mechanism of its potential target.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R741

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