PACAP as a neuronal cell death in hibiting function

PACAP 作为抑制功能的神经元细胞死亡

• 批准号: 08458249
• 负责人: SHIODA Seiji
• 金额: $ 4.29万
• 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: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08458249/
• 关键词: PACAP; brain ischemia; Apoptosis; signal transdustion; immunohistochemistry; in situ hybridization; rat; 免疫細胞化学; 海馬

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.

我们发现，在脑室和股静脉中输注极低浓度的 PACAP（垂体腺苷酸环化酶激活多肽）可以防止大鼠海马 CA1 区域的延迟性神经元细胞死亡（细胞凋亡）。然而，PACAP 抗凋亡作用的分子机制仍有待确定。本研究的目的是阐明 PACAP 在预防大鼠海马神经元细胞死亡中的功能意义。我们证明，丝裂原激活蛋白 (MAP) 激酶家族成员的活性在海马中增加，包括细胞外信号调节激酶 (ERK)、Jun N 末端激酶 (JNK)/应激激活蛋白激酶 (SAPK) 和 p38。缺血应激对MAP激酶家族尤其是JNK/SAPK有很强的影响。PACAP抑制缺血应激后JNK/SAPK的激活。 PACAP 输注后，白细胞介素 6 (IL-6) 分泌到脑脊液中受到强烈刺激。 IL-6抑制JNK/SAPK的激活，同时激活ERK。这些观察结果强烈表明PACAP和IL-6可以抑制JNK/SAPK信号通路，从而保护神经元免于凋亡。目前的研究表明，通过全身施用低剂量的肽，可以达到大脑中低浓度的 PACAP，从而防止 CA1 区域的缺血性死亡。该结果与其他神经保护化合物的结果相反，在临床上应该非常重要。

项目成果

Shioda S,Yada T,Nakajo S,Nakaya K,Nakai Y,Arimura A.: "Pituitay adenylate cyclase-activating polypeptide (PACAP) : a novel regulator of vasopressin-containig neurons." Brain Research. 765. 81-90 (1997)

Shioda S，Yada T，Nakajo S，Nakaya K，Nakai Y，Arimura A.：“Pituitay 腺苷酸环化酶激活多肽（PACAP）：含有加压素神经元的新型调节剂。”

Shioda,S.: "PACAP and its type I receptors in the rat hypothalamus : Neuroendocrine interaction." Ann NY Acad Sci. 805. 670-676 (1996)

Shioda,S.：“大鼠下丘脑中的 PACAP 及其 I 型受体：神经内分泌相互作用。”

Shioda,S.: "Pituitary adenylate cyclase-activating polypeptide : a key player in male reproduction?" Amalus of Endocrinology. 57. 57 (1996)

Shioda,S.：“垂体腺苷酸环化酶激活多肽：男性生殖的关键角色？”

Shioda S,Nakai Y,Nakajo S,Nakaya K,Arimura A.: "PACAP and its type I receptors in the rat hypothalamus : neuroendocrine in teraction." Ann NY Acad Sci. 805. 670-676 (1996)

Shioda S、Nakai Y、Nakajo S、Nakaya K、Arimura A.：“大鼠下丘脑中的 PACAP 及其 I 型受体：神经内分泌的相互作用。”

Li M,Shioda S,Somogyvari-Vigh, Onda H,Arimura A.: "Specific antibody recognition of rat pituitary abenylate cyclase activating polypeptide receptors." Endocrine. 7. 183-190 (1997)

Li M、Shioda S、Somogyvari-Vigh、Onda H、Arimura A.：“大鼠垂体苯甲酸环化酶激活多肽受体的特异性抗体识别。”