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

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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.