[Prevention of delayed neuronal cell death by PACAP and its molecular mechanism]

Ischemic delayed neuronal cell death (apoptosis) in the hippocampus is prevented by PACAP. PACAP inhibits the increasing activity of the MAP kinase family, especially on JNK/SAPK and p38, thereby protecting against apoptotic cell death. After the ischemia-reperfusion, both pyramidal cells and astrocytes increased their expression of PACAP receptors (PAC1-Rs). The pyramidal cells degenerated but reactive astrocytes increased their expression of PAC1-R. PACAP does not only inhibit apoptotic cell death directly, but also affects astrocytes through PAC1-Rs. Interleukin-6 (IL-6), produced in astrocytes, has several effects on the prevention of brain ischemia and trauma and stimulating neuronal growth. IL-6 secretion into the CSF was markedly stimulated after PACAP infusion, suggesting that PACAP stimulates IL-6 secretion from astrocytes. We studied the effects of PACAP on the wild type and IL-6 KO mice after brain ischemia. In wild-type animals, PACAP significantly inhibited cell death, but in IL-6 KO animals, no cytoprotective effect of PACAP was seen. These results suggest that PACAP inhibits apoptotic cell death partly through IL-6. It is considered that PACAP itself and IL-6, stimulated secretion by PACAP, both synergistically inhibit the JNK/SAPK and p38 signaling pathway, thereby protecting against neuronal cell death.