PACAP as a neuronal cell death in hibiting function

我们发现，脑室和股静脉内注入极低浓度的PACAP(垂体腺苷环化酶激活多肽)可延缓大鼠海马CA1区神经元细胞的死亡。然而，PACAP抗细胞凋亡作用的分子机制尚不清楚。本研究旨在阐明PACAP在预防大鼠海马神经细胞死亡中的功能意义。我们发现，在海马区，丝裂原活化蛋白(MAP)激酶家族的成员，包括细胞外Siganl调节激酶(ERK)、Jun氨基末端激酶(JNK)/应激激活蛋白激酶(SAPK)和p38的活性增加。化学应激对MAP激酶家族有显著影响，尤其是JNK/SAPK.PACAP可抑制缺血应激后JNK/SAPK的激活。PACAP注射后，脑脊液中IL-6的分泌被强烈刺激。IL-6抑制JNK/SAPK的激活，而激活ERK，提示PACAP和IL-6抑制JNK/SAPK信号通路，从而保护神经元免受细胞凋亡的影响。本研究表明，全身应用低剂量的PACAP可以达到低浓度的PACAP，从而防止CA1区的缺血性死亡。这一结果与其他神经保护化合物的结果相反，应该具有非常重要的临床意义。

We found that infusion of a very low concentration of PACAP (Pituitary Adenylate Cyclase Activating Polypeptide) in the cerebral ventrclle as well as in the femoral vein preventd delayd neyronal cell death (apoptosis) in rat hippocampal CA1 region. However, the molecular mechanisms underlying the anti-apoptotic effect of PACAP remain to be determined. The aim of this study was to clarify functional significance of PACAP in preventing neuronal cell death in rat hippocampus. We demonstra ted that the activities of members of the mitogen-activated protein (MAP) kinase family, including extracellular siganl-regulated kinase (ERK), Jun N-terminal kinase (JNK) /stress-activated protein kinase (SAPK), and p38 were increased in the hippocampus. The is chemic stress had a potent in fluence on the MAP kinase family, especially on JNK/SAPK.PACAP inhibited the activation of JNK/SAPK after ischemic stress. Secretion of interleukin-6 (IL-6) into the cerebrospinal fluid was intensly stimulated after PACAP infucion. IL-6 inhibited the activation of JNK/SAPK,while it activated ERK.These observations strongly suggest that PACAP and IL-6 act to inhibit the JNK/SAPK sigualing pathway, thereby protecting neurons against apoptosis. The present study suggest that a low concentration of PACAP in the brain which prevents the ischemic death of CA1 regions can be reached by the systemic administration of a low dose of the peptide. The results are in contrast to those with other neuroprotective compouds and should be clinically very important.