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

PACAP可预防海马中的缺血性迟发性神经元细胞死亡（Ischemic delayed neuronal cell death，EAE）。PACAP抑制MAP激酶家族的活性增加，尤其是JNK/SAPK和p38，从而保护凋亡性细胞死亡。缺血再灌注后，锥体细胞和星形胶质细胞的PACAP受体（PAC 1-Rs）表达增加。锥体细胞变性，反应性星形胶质细胞PAC 1-R表达增加. PACAP不仅能直接抑制凋亡细胞的死亡，而且还能通过PAC 1-Rs作用于星形胶质细胞。星形胶质细胞产生的白细胞介素-6（IL-6）对预防脑缺血和创伤以及刺激神经元生长具有多种作用。在PACAP输注后，IL-6分泌到CSF中被极大地刺激，表明PACAP刺激星形胶质细胞分泌IL-6。我们研究了PACAP对野生型和IL-6基因敲除小鼠脑缺血后的影响。在野生型动物中，PACAP显著抑制细胞死亡，但在IL-6 KO动物中未观察到PACAP的细胞保护作用。这些结果表明，PACAP抑制凋亡细胞死亡部分通过IL-6。认为PACAP本身和由PACAP刺激分泌的IL-6两者协同抑制JNK/SAPK和p38信号传导途径，从而保护神经元细胞死亡。(1677话）

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)