Functional significance of PACAP in inhibiting neuronal cell death by using gene targeting method

我们已经证明，无论是脑室内或静脉注射垂体腺苷酸环化酶激活多肽（PACAP）的缺血诱导的神经元凋亡的大鼠海马CA 1区的预防。然而，PACAP抗凋亡作用的分子机制仍有待确定。在缺血后3-6 h内，海马中丝裂原活化蛋白（MAP）激酶家族成员，包括细胞外信号调节激酶（ERK）、Jun N-末端激酶（JNK）/应激活化蛋白激酶（SAPK）和p38的活性增加。缺血应激对MAP激酶家族有明显影响，尤其是JNK/SAPK。PACAP可抑制缺血应激后JNK/SAPK的激活。这表明PACAP可抑制JNK/SAPK信号通路，从而保护神经元免于凋亡。我们最近成功地制备了PACAP受体转基因小鼠，因此我们现在试图阐明PACAP通过其特异性受体抑制神经细胞死亡的直接作用。

We have demonstrated that the ischemia-induced apoptosis of neurons in the CA1 region of the rat hippocampus was prevented by either intracerebroventricular or intravenous infusion of pituitary adenylate cyclase-activating polypeptide (PACAP). However, the molecular mechanisms underlying the anti-apoptotic effect of PACAP remain to be determined. Within 3-6 h after ischemia, the activities of members of the mitogen-activated protein (MAP) kinase family, including extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), and p38 were increased in the hippocampus. The ischemic stress had a potent influence on the MAP kinase family, especially on JNK/SAPK. PACAP inhibited the activation of JNK/SAPK after ischemic stress. These suggest that PACAP acts to inhibit the JNK/SAPK signaling pathway, thereby protecting neurons against apoptosis. We have recently succeeded to make PACAP receptor transgenic mice, therefore we are now trying to clarify direct effect of PACAP on inhibiting neuronal cell death via its specific receptors.