兼具抗paf活性的新型ache抑制剂pms777神经药理学活性研究-药理学专业论文.docxVIP

上海交通大学博士研究生毕业论文(2006) 上海交通大学博士研究生毕业论文(2006) 中文摘要 抗PAF受体，明显减轻PAF(10／aM)对SH．SY5Y人神经母细胞瘤细胞 的毒性，其分子生物学机制涉及bcl．2／bax和COX一2基因的表达调控及 caspase．3相关性机制；在相同的浓度范围内，PMS777也能够通过调控 凋亡或炎症相关基因的表达，抑制AD关键致病分子A13(本研究中应用 Ap25-35 20肛M)的神经毒性。 本研究在国内外首次提出AChE和PAF双靶点干预AD的设想，并 通过体内外实验证明，PMS777是一种兼有PAF受体拮抗和AChE抑制 活性的新型双靶点化合物，在分子水平通过调控凋亡或炎症相关基因的 表达抑制PAF和AB的神经毒性，在整体水平能够明显改善脑内胆碱能 功能减退和慢性炎症反应导致的学习记忆功能障碍，有望成为具有开发 价值的治疗AD的先导化合物。 关键词阿尔茨海默病，PAF受体拮抗剂，AChE抑制剂，PMS777，他 克林 上海交通大学博士研究生毕业论文(2006) 上海交通大学博士研究生毕业论文(2006) 英文摘要 NEURoPHARMACoLoGICAL PRoFILE oF PM$777，A NEW AChE INHIBIToR WITH ANTI．PAF ACTIVITY ABSTRACT The key pathophysiological mechanisms in Ahheimer’s disease involve the selective loss of cholinergic neurons and proinflammatory mediator-related chronic inflammatory responses in brain，so interventions of these processes are crucial to the treatment of this disease．In the present study,the neuropharmacological profile of PMS777，a new acetylcholinesterase(AChE)inhibitor with anti—platelet—activating factor(PAF)activity, has been evaluated in vitro and in rive．Our results demonstrated that PMS777(1-100州) dose·-dependently inhibited PAF·-induced rabbit platelet aggregation by competing with [3H]-PAF for its receptor on platelet，and markedly inhibited brain AChE activity in mice with modest selectivity for AChE(AChE：IC50=2．48±0．12州；butyrylcholinesterase： IC50=4．47±O．1 5州)．Ex vivo，PMS777(5，10，20 or 40 mg／kg，i．p．)reduced brain AChE activity in a dose—dependent manner．／n vivo studies revealed that PMS777 fO．25—5 mg／kg，i．p．)could reverse scopolamine(ip)一induced memory retrieval deficits in mice，and attenuate lipopolysaccharide(LPS，icy)一induced cerebral inflammatory responses and dementia，and displayed typical bell—shaped dose—response relationship．Besides， PMS777(10—100 uM)protected human neuroblastoma cell line SH—SY5Y against PAJF or A{3：5．35一induced neurotoxicity,via bax／bcl一2 ratio increase and caspase