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NEUROPHARMACOLOGY

VPAC₂ Receptors Mediate Vasoactive Intestinal Peptide-Induced Neuroprotection against Neonatal Excitotoxic Brain Lesions in Mice

Institut National de la Santé et de la Recherche Médicale U 676 and Service de Neurologie Pédiatrique, Hôpital Robert Debré, Paris, France (C.-M.R., F.M., V.L., I.H., P.G.); Institut de Physiologie et Biologie Cellulaires Centre National de la Recherche Scientifique-Unité Mixte Recherche 6187 Pôle Biologie Santé, Poitiers, France (S.G., T.J.); Institut National de la Santé et de la Recherche Médicale U 413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP23), University of Rouen, Mont St. Aignan, France (L.M., S.J.); and Institut des Neurosciences de Montpellier-Institut National de la Santé et de la Recherche Médicale U583, Centre Hospitalier Universitaire Hôpital St. Eloi, Montpellier, France (P.B.)

Prepro-vasoactive intestinal peptide (VIP) mRNA codes for two neuropeptides: VIP and peptide histidine isoleucine (PHI). Two VIP receptors, shared with a similar affinity by pituitary adenylate cyclase-activating polypeptide (PACAP), have been cloned: VPAC₁ and VPAC₂. PHI binds to these receptors with a lower affinity. VPAC receptors are classically associated with a cAMP-dependent pathway, although other pathways, including calcium mobilization and protein kinase C activation have been described. We previously showed that intracerebral administration of the glutamate agonist ibotenate to postnatal day 5 mice induces white matter lesions mimicking human periventricular leukomalacia. In this model, coinjection of VIP protects against white matter lesions. This neuroprotection is independent from cAMP and is mediated by protein kinase C. Using this model, this study aimed to determine the receptor involved in VIP-induced neuroprotection. VIP effects were mimicked with a similar potency by VPAC₂ agonists and PHI but not by VPAC₁ agonists, PACAP 27, or PACAP 38. VIP neuroprotective effects were lost in mice lacking VPAC₂ receptor. In situ hybridization confirmed the presence of VPAC₂ mRNA in the postnatal day 5 white matter. When analyzed between embryonic life and adulthood, VIP-specific binding site density peaked at postnatal day 5. These data suggest that, in this model, VIP-induced neuroprotection is mediated by VPAC₂ receptors. The pharmacology of this VPAC₂ receptor seems unconventional because 1) PACAP does not mimic VIP effects, 2) PHI acts with a comparable potency, and 3) PACAP 27 modestly inhibited the VIP-specific binding, whereas for PHI or VIP, inhibition was complete.

Address correspondence to: Dr. Pierre Gressens, INSERM U 676, Hôpital Robert Debré, 48 Blvd Sérurier, 75019 Paris, France. E-mail: gressens{at}rdebre.inserm.fr