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

PACAP可预防海马区缺血性迟发性神经细胞死亡(凋亡性炎症)。PACAP抑制MAP激酶家族的活性，特别是JNK/SAPK和p38的活性，从而保护细胞的死亡。脑缺血再灌注后，锥体细胞和星形胶质细胞的PACAP受体(PAC1-Rs)表达均增加。锥体细胞变性，反应性星形胶质细胞增加其PAC1-R的表达。PACAP不仅直接抑制细胞凋亡，而且通过PAC1-Rs作用于星形胶质细胞。白介素6(IL-6)是由星形胶质细胞产生的，在预防脑缺血和创伤、刺激神经元生长方面具有多种作用。PACAP对脑脊液中IL-6的分泌有极强的刺激作用，提示PACAP可刺激星形胶质细胞分泌IL-6。我们研究了PACAP对脑缺血后野生型和IL-6KO小鼠的影响。在野生型动物中，PACAP显著抑制细胞死亡，而在IL-6 KO动物中，PACAP没有明显的细胞保护作用。这些结果表明，PACAP部分通过IL-6抑制细胞凋亡。据认为，PACAP本身和IL-6在PACAP刺激分泌的同时，都协同抑制JNK/SAPK和p38信号通路，从而保护神经细胞死亡。(1677字)

Ischemic delayed neuronal cell death (apoptotis) 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 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 PAC 1-R. PACAP does not only inhibit apoptotic cell death directly, but also affects on astrocytes through PAC1-Rs. Interleukin-6 (IL-6), produced in astrocytes, has several effects on prevention of brain ischemia and trauma and stimulating neuronal growth. IL-6 secretion into the CSF was stimulated extremely 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 neuronal cell death. (1677 Words)