Neuroimmunologic research of endogenous and exogenous protection on brain, taking account of the meaning of the BBB's existence

采用大脑中动脉闭塞(MCAO)模型，用基因敲除小鼠(KO)观察mdr1a编码的P-gp基因对局灶性脑缺血的作用。通过测量和比较mdrla Ko小鼠和野生鼠的脑梗塞体积来评价脑缺血损伤。Mdrla Ko小鼠模型组的脑梗塞体积明显小于野生鼠模型组。血压和心率在不同组之间没有差异。动脉血氧分压(PaO2)、二氧化碳分压(PaCO2)、二氧化碳分压(B.E.)、血红蛋白(Hb)在缺血前和再灌流后30min无显著差异。脑血管Willis环的印度墨汁染色显示，脑循环的血管图型没有大体解剖差异。这些结果表明，P-gp可加重脑缺血时的脑梗塞。接下来，我们研究了血管活性肠肽(VIP)和垂体腺苷环化酶激活肽(PACAP)的新衍生物IK312548和Ac-PACAP对双血管阻断(2-VO)和大脑中动脉阻塞(MCAO)所致小鼠脑缺血的影响。IK312548和Ac-PACAP可抑制2-VO和MCAO所致的神经元死亡。同时，我们观察了Ac-PACAP对谷氨酸(Glu)诱导的脑神经元死亡的神经保护作用。在神经元/胶质细胞共培养细胞中，Ac-PACAP对Glu诱导的细胞死亡有明显抑制作用。这些结果表明，两者都具有神经保护作用。

We investigated the functional effects of mdrla encoded P-gp on focal cerebral ischemia, which is prepared by the middle cerebral artery occlusion(MCAO) model, using mdrl a knockout (ko) mice. The ischemic damages were evaluated with measuring and comparing the infarct volumes of mdrla ko mice and wild mice. Infarction volume of mdrla ko mice group was significantly smaller than that seen in wild mice group. The blood pressure and heart rate did not differ between groups. There are no significant differences in PaO_2, PaCO_2, B.E. and hemoglobin before ischemia and 30 min after reperfusion. India ink staining of cerebrovascular anatomy of the circle of Willis demonstrated that there were no gross anatomic differences in the vascular pattern of the cerebral circulation. These results indicate that P-gp leads to exacerbate cerebral infarction in brain ischemia. Next, We examined the effects of IK312548 and Ac-PACAP, which are novel derivatives of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide(PACAP), on brain ischemia induced by two-vessel occlusion(2-VO) and MCAO in mice. IK312548 and Ac-PACAP treatment inhibited neuronal death by 2-VO and MCAO. Concurrently, we examined the neuroprotective effects of ac-PACAP on brain neuronal death induced by glutamate (Glu). The significant inhibitions of ac-PACAP on the cell death unduced by Glu were seen in the neuron/glia cocultured cells. These results indicate that both of them showed the neuroprotection.