神经干细胞是一类具有自我更新和分化潜能的细胞，它能在特定的情况下分化为神经元、星形胶质细胞和少突胶质细胞等中枢神经系统所需的细胞，给由于神经元损伤或丢失导致的中枢神经系统的退行性疾病的治疗提供了一条全新的潜在治疗途径。小分子化合物作为现代临床使用药物的主要来源，由于其成分单一、分子量小等特点克服了大分子不能透过血脑屏障、中药成分复杂等缺点成为研究的热点。Stemazole是通过化合物高通量筛选的方法选出的能体外促进神经干细胞增殖的一个杂环类小分子化合物，对于成体和胚胎神经干细胞均有促增殖作用。本论文在此研究基础上，进一步研究Stemazole在体内的药理学作用以及其促神经干细胞增殖的可能通路。本论文采用放射性示踪的方法用[3H]-Stemazole对Stemazole在小鼠体内的分布、富集情况进行追踪，重点考察其是否能进入脑部发挥生理作用；并进一步应用脑内注射缠结的Aβ1-40 的AD大鼠模型来评价Stemazole的药效作用，用水迷宫评价Stemazole是否能改善AD大鼠的空间学习记忆能力，同时用PET/CT和ELISA方法对脑中所含有的Aβ1-40含量进行检测；最后用Western的方法检测PI3K、ERK通路的几个关键蛋白，考察Stemazole是否对其表达有影响，推测Stemazole促神经干细胞增殖可能的调控机制。实验结果表明：Stemazole能够穿过血脑屏障进入小鼠脑内，并能较长时间的存在于脑中，1 d内处于相对饱和的状态，1 d后随着血药浓度的下降而下降。其在体内肝肾组织中分布较多，且能在小鼠体内存在较长时间，5 d时都有少量存在，有利于其更好的发挥其生理作用；体内动物实验结果表明，腹腔注射不同浓度（3、10、30 mg/kg）的Stemazole 14 d能明显改善AD大鼠的学习记忆能力，且有量效关系，10、30 mg/kg组在垮台次数的变化量和站台象限停留时间上与模型组均有显著性差异；进一步PET研究发现，给药组大鼠脑中存在的Aβ1-40含量随着Stemazole给药剂量的增加有所减少，这一结论同时也由ELISA方法得到了证实；通过检测PI3K、Akt、ERK1/2、p-ERK1/2蛋白我们发现，与PI3K通路相关的PI3K、Akt蛋白含量有所增加，而与MAPK通路相关的ERK1/2总蛋白含量不变的情况下，p-ERK1/2蛋白含量有所下降，猜测其可能的作用通路是通过激活PI3K通路起作用。通过以上实验结果，我们发现小分子Stemazole能够穿过血脑屏障，并在脑部发挥其生理作用，改善AD大鼠的学习记忆能力，这一作用可能与减少AD模型脑中的Aβ1-40含量直接相关。另一方面，Stemazole促神经干细胞增殖可能与MAPK、PI3K通路密切相关，但具体的作用机制还有待进一步研究。

Neural stem cells are a kind of cells which can self-renewal and have differentiation potential, it can differentiate into cells needed by central nervous system，such as neurons, astrocytes，oligodendrocytes in certain circumstances. Neural stem cells are needed to therapy degenerative diseases in central nervous system caused by neural stem cells damage or loss, provide a new potential approach to therapy Alzheimer's Disease. Small molecule compounds are major source of clinic drug, these compounds can go through the blood-brain barrier because their small molecular weight, and can overcome the shortcoming of biological macromolecule, become a hot research now. Stemazole (a heterocyclic small molecule compounds) is founded through high-throughput screening method, can promote neural stem cell proliferation in vitro, not only for adult but also embryonic neural stem cells.In this thesis, we use [3H]-Stemazole as a radioactive tracer to track the distribution of Stemazole in vivo, examine whether it can across the blood-brain barrier, in order that play physiological activity; and further use intracerebral injection aggrecated Aβ1-40 AD rat model to evaluate the pharmacological effects of Stemazole, water maze task is used to evaluate whether Stemazole improve learning and memory in AD rats or not, PET/CT and ELISA method examine the contained Aβ1-40 in hippocampus; Finally, Western is used to detect several key proteins in PI3K, ERK pathway to examine whether its expression changed, searching possible pathway which Stemazole promote neural stem cell proliferation.The results show that: Stemazole can access blood-brain barrier easily, mainly distribute in liver and kidney, can exist in each organizations of mouse for a long time. In brain, it is saturated in day 1, and decline with the decline of blood-drug concentration after 1 day. On day 5, it remain has little in each organizations. So it is possible for stemazole play better physiological activity. AD animal experiment showed that, drug administration of Stemazole (3,10,30 mg/kg) for 14 d (intraperitoneal injection) can improve learning and memory ability of AD rats, these still have dose-effect relationship, the change of times acrossing the platform position and times stay at the target quadrantin of 10,30 mg/kg group have significantly difference compared with model group; PET study found that the Aβ1-40 concetration in the treatment group rat's brain reduced with Stemazole dose rise, this conclusion also been confirmed by the ELISA method; Detecting PI3K, Akt, ERK1/2, p-ERK1/2 protein, we found that the content of PI3K, Akt protein increased associated with p-ERK1/2 protein level declined, speculating MAPK pathways may be the possible regulate pathway to regulation the proliferation of neuron stem cell promote by stemazole.According the above results, we found that small molecules Stemazole can cross the blood-brain barrier and play its physiological role in the brain, improving learning and memory abilities of AD rats, this effection may be related to the reduction of Aβ1-40 concetration in AD model rat's brain. On the other hand, Stemazole promote neural stem cells proliferation may be closely related to MAPK, PI3K pathway, but the specific mechanism of action remains to be further studied.