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）是一种多效神经肽，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，是一种神经调节剂、神经递质、神经营养因子或神经保护因子。另一方面，maxadilan是一种从长掌沙蝇唾液腺中分离出来的有效血管扩张肽，是一种特异性的PACAP I型受体（PAC1-R）激动剂。由于尚不清楚PACAP或maxadilan是否具有神经保护作用，我们研究了PACAP或maxadilan在大鼠脑短暂性全脑缺血和缺氧时的作用。神经元的文化。PACAP和Maxadilan剂量依赖性保护神经元细胞培养抗缺氧和葡萄糖剥夺。这种作用似乎是通过PAC1-R介导的，因为它被一种选择性的、竞争性的PAC1-R拮抗剂max.d.4阻断。我们还观察到，在脑缺血前10 mm至缺血后72小时内，给予马沙地兰（10 pmol/h）灌胃，马沙地兰对全脑缺血的神经保护作用。此外，给予maxadilan后，培养神经元的CREB发生短暂磷酸化。CREB是一种重要的转录调节因子，目前被认为在包括缺血在内的各种病理条件下的神经保护中起着至关重要的作用。总体数据表明，maxadilan通过PAC1-R诱导的cAMP/PKA/CREB通路的激活可能有助于对缺氧的神经保护。这些结果表明，麦沙迪兰可以用于治疗中风和其他形式的脑缺血。

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.