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

本研究采用mdr 1a基因敲除（ko）小鼠，观察了mdr 1a基因编码的P-gp对大脑中动脉闭塞（MCAO）所致局灶性脑缺血的功能影响。通过测量和比较mdrla ko小鼠和野生小鼠的梗死体积来评价缺血性损伤。mdrla ko小鼠组的脑梗死体积明显小于野生小鼠组。两组之间的血压和心率没有差异。PaO_2、PaCO_2、B.E.缺血前及再灌注30 min时血红蛋白含量。Willis环脑血管解剖的印度墨水染色表明，脑循环的血管模式没有大体解剖差异。提示P-gp在脑缺血时可导致脑梗死加重。接下来，我们研究了IK 312548和Ac-PACAP，它们是血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽（PACAP）的新型衍生物，对由双血管闭塞（2-VO）和MCAO诱导的小鼠脑缺血的影响。IK 312548和Ac-PACAP处理抑制2-VO和MCAO引起的神经元死亡。同时，我们研究了ac-PACAP对谷氨酸（Glu）诱导的脑神经元死亡的神经保护作用。ac-PACAP对Glu诱导的神经元/胶质细胞共培养细胞死亡有明显的抑制作用。这些结果表明，两者都显示出神经保护作用。

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.