PACAP as a neuronal cell death in hibiting function

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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.