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

PACAP预防神经细胞迟发性死亡及其分子机制

• 批准号: 14380354
• 负责人: SHIODA Seiji
• 金额: $ 9.47万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14380354/
• 关键词: PACAP; IL-6; Neuronal cell death; Hippocamnus; Rat; Mouse

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)

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）

项目成果

Effects of lipopolysaccaride on leptin transport across the blood-brain barrier.

脂多糖对瘦素跨血脑屏障转运的影响。

• 发表时间: 2004
• 期刊: Brain Res. 1016
• 作者: Chiyonobu T;Sasaki J;Nagai Y;Takeda S;Funakoshi H;Nakamura T;Sugimoto T;Toda T;Nonaka N.
• 通讯作者: Nonaka N.

Ohtaki, H.: "Evaluation of neuronal cell death after a new global ischemia model in infant mice."Acta Neurochir. 86(Suppl). 97-100 (2003)

Ohtaki, H.：“对婴儿小鼠新的全局缺血模型后神经元细胞死亡的评估。”Acta Neurochir。

Ohtaki, H.: "Suppression of oxidative stress after transient focal ischemia in interleukin-1 knock out mice."Acta Neurochir. 86(Suppl). 191-194 (2003)

Ohtaki, H.：“白介素 1 敲除小鼠短暂局灶性缺血后氧化应激的抑制。”Acta Neurochir。

Zhou, CJ.: "Pleiotropic effects of PACAP and multiple signaling pathways under its receptors in nervous system"Curr Protein & Peptide Sci. 3. 423-439 (2002)

Zhou, CJ.：“PACAP 的多效性及其受体在神经系统中的多种信号通路”Curr 蛋白

Mizushima, H.: "Reduced postischemic hippocampal apoptosis in mice deficient interleukin-1"J Comp Neurol. 448. 203-216 (2002)

Mizushima, H.：“白细胞介素 1 缺陷小鼠缺血后海马细胞凋亡减少”J Comp Neurol。