Neuroprotective effects of a pituitary adenylate cyclase activating polypeptide(PACAP)in global cerebral ischemia and in hypoxic neuronal cultures

垂体腺苷酸环化酶激活多肽（PACAP）在全脑缺血和缺氧神经元培养中的神经保护作用

• 批准号: 14571322
• 负责人: NAGAYAMA Tetsuya
• 金额: $ 1.92万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571322/
• 关键词: PACAP; maxadilan; ischemia; apoptosis; Max.d.4; brain

Pituitary adenylate cyclase activating polypeptide(PACAP), a pleiotropic neuropeptide, was originally isolated from ovine hypothalamic tissues.PACAP is widely distributed in the brain, and act as a neuromodulatar, neurotransmitter, neurotrophic or neuroprotective factor.On the other hand, maxadilan, a potent vasodilator peptideisolated from salivary glands of the sand fly Lutzomyia longipalpis, is a specific agonist for the PACAP type I receptor(PAC1-R).Since it is not known whether PACAP or maxadilan exerts a neuroprotective effect, we have investigated the effect of PACAP or maxadilan in rat brain in transient global cerebral ischemia and in hypoxic. neuronal cultures.PACAP and Maxadilan dose-dependently protect neuronal cell culture against hypoxia and glucose deprivation.This effect appears to be mediated through PAC1-R, because it is blocked by a selective, competitive PAC 1 -R antagonist, max.d.4.We also observed neuroprotection by maxadilan in global cerebral ischemia with maxadilan administered i.c.v(10 pmol/h)from 10 mm before to 72 hr after schemia. In addition, transient CREB phosphorylation occurred after administration of maxadilan in cultured neuron.CREB is an important transcriptional regulatory factor, and is now thought to play a crucial role in neuroprotection in various pathological conditions, including ischemia.The overall data demonstrate that maxadilan-induced activation of the several pathways such as cAMP/PKA/CREB pathway through the PAC1-R may contribute to neuroprotection against hypoxia.These results suggest thot maxadilan could be usefull in the treatment of stroke and other forms of cerebral ischemia.

垂体腺苷酸环化酶激活多肽（PACAP）是一种多效性神经肽，最初是从绵羊下丘脑组织中分离出来的。PACAP广泛分布于大脑中，作为神经调节剂、神经递质、神经营养或神经保护因子。另一方面，马卡迪兰是一种有效的血管扩张剂。 从白蛉的唾液腺中分离出的肽，是 PACAP I 型受体 (PAC1-R) 的特异性激动剂。由于尚不清楚 PACAP 或 maxadilan 是否发挥神经保护作用，因此我们研究了 PACAP 或 maxadilan 在短暂性全脑缺血和缺氧的大鼠脑中的作用。神经元培养物。PACAP 和 Maxadilan 剂量依赖性地保护神经细胞培养物免受缺氧和葡萄糖剥夺的影响。这种作用似乎是通过 PAC1-R 介导的，因为它被选择性、竞争性 PAC 1 -R 拮抗剂 max.d.4 阻断。我们还观察到 maxadilan 在全脑缺血中 i.c.v 给予 maxadilan 的神经保护作用（10 pmol/h）从缺血前 10 毫米到缺血后 72 小时。此外，在培养的神经元中给予 maxadilan 后，会发生短暂的 CREB ​​磷酸化。CREB ​​是一种重要的转录调节因子，现在被认为在包括缺血在内的各种病理条件下的神经保护中发挥着至关重要的作用。总体数据表明，maxadilan 通过 PAC1-R 诱导的 cAMP/PKA/CREB ​​通路等多种途径的激活可能有助于 这些结果表明 maxadilan 可用于治疗中风和其他形式的脑缺血。

项目成果

Miyata A: "The neuron specific regulation of pituitary adenylate cyclase activating polypeptide (PACAP) gene expression."Acta Physiol.Hung. 89. 264 (2002)

Miyata A：“垂体腺苷酸环化酶激活多肽（PACAP）基因表达的神经元特异性调节。”Acta Physiol.Hung。

Jin K, Nagayama T, Mao X, Kawaguchi K, Hickey RW, Greenberg DA, Simon RP, Graham SH.: "Two caspase-2 transcripts are expressed in rat hippocampus after global cerebral ischemia."J Neurochem.. 81. 25-35 (2002)

Jin K, Nagayama T, Mao X, Kawaguchi K, Hickey RW, Greenberg DA, Simon RP, Graham SH.：“全脑缺血后大鼠海马中表达了两种 caspase-2 转录本。”J Neurochem.. 81. 25-

Cao G, Luo Y, Nagayama T, Pei W, Stetler RA, Graham SH, Chen J.: "Cloning and characterization of rat caspase-9:implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia."J Cereb Blood Flow Meta

Cao G、Luo Y、Nagayama T、Pei W、Stetler RA、Graham SH、Chen J.：“大鼠 caspase-9 的克隆和表征：对介导短暂性脑缺血后 caspase-3 激活和海马细胞死亡的作用的影响

Miyata A, Kangawa K: "Structure and functions of pituitary adenylate cyclase activating polypeptide (PACAP) as a neurotrophic factor. Strategic Medical Science against Brain Attack (H.Kikuchi ed.)"Springer-Verlag Tokyo. 57-77 (2002)

Miyata A、Kangawa K：“垂体腺苷酸环化酶激活多肽（PACAP）作为神经营养因子的结构和功能。针对脑攻击的战略医学科学（H.Kikuchi 编辑）”Springer-Verlag 东京。

Miyata A.: "The neuron specific regulation of pituitary adenylate cyclase activating polypeptide(PACAP)gene expression."Acta Physlol.Hung.. 89. 264 (2002)

Miyata A.：“垂体腺苷酸环化酶激活多肽（PACAP）基因表达的神经元特异性调节。”Acta Physlol.Hung.. 89. 264 (2002)