抗艾滋性认知功能障碍的中、西药NMDA拮抗剂效果差异的比较、筛选及临床前研究

艾滋性认知功能障碍(HAND)是重要艾滋病并发症。我们的前期研究发现:以NR2BR为主的NMDAR在HAND发生过程中起重要作用,有望成为药物治疗新靶点;还发现三七总皂苷PNS可阻断NMDAR介导的钙内流和兴奋性突触后电流,并能改善认知功能。因西药NMDAR拮抗剂临床应用的局限性,使高效低毒的中药日益受到重视渐成为国内外研究热点。我们认为PNS改善认知功能的机制和靶点符合现代医学对HAND发病机理的认识, 具有开发潜力,因此,拟在前期研究基础上,运用膜片钳、基因转录及蛋白表达、[Ca2+]i动态扫描、RT-PCR等技术,继续研究并筛选PNS及其主要单体成分改善认知功能作用是否通过阻断NMDAR尤其是突触外NR2BR介导,同时以拮抗NMDAR的西药抗痴呆药ifenprodil和美金刚为阳性药,比较它们的差异以确定中药的作用效果,从而更深层次认识HAND发生机制,为治疗HAND提供更多选择。

HIV-1-associated neurocognitive disorders(HAND) is an important AIDS complication.Our previous studies found that: NR2B subtype of NMDA receptor plays a key role in the pathogenesis of HAND. NR2BR is expected to become a new target for drug therapy. And we found that the total saponins of panax notoginseng (PNS) can improve cognitive function from the synaptic level, PNS can also block the NMDAR mediated Ca2+ influx. Because the severe side effects limit the clinical application of modern NMDAR antagonists, traditional Chinese medicine with high efficiency and low toxicity has been paid more and more attention and become the international research hotspot. We think the target of PNS to improve cognitive function is in accordance with the recent studies for mechanism of HAND, and has development as a potential medicine for HAND. Based on our previous observations we intend to further characterize the role that extrasynaptic NR2BR might play in MCP-1 induced HAND and the effects of PNS on NMDAR, especially on NR2BR in Xenopus oocytes, rat hippocampal brain slices, and cultured hippocampal neurons. In our research work the patch clamp, gene transcription, protein expression, [Ca2+]i dynamic scanning, RealTime-PCR, and other technology may be used to uncover whether the improving effect of PNS on cognitive function is related to its blocking effect on NMDAR, especially on extrasynaptic NR2BR. At the same time, we intend to use the recognized modern NMDAR antagonist ifenprodil and memantine as the positive medicine to compare the differences between PNS and Hesperian medicine, and identify whether PNS has obvious superiority compared with Hesperian medicine.