title: VPAC2 receptors mediate vasoactive intestinal peptide-induced neuroprotection against neonatal excitotoxic brain lesions in mice.
abstract: 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: VPAC(1) and VPAC(2). 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 VPAC(2) agonists and PHI but not by VPAC(1) agonists, PACAP 27, or PACAP 38. VIP neuroprotective effects were lost in mice lacking VPAC(2) receptor. In situ hybridization confirmed the presence of VPAC(2) 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 VPAC(2) receptors. The pharmacology of this VPAC(2) 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.
authors.affiliation: INSERM U 676, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France.
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Rangon
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Goursaud
authors.forename: Fadia
authors.initials: F
authors.lastname: Medja
authors.forename: Vincent
authors.initials: V
authors.lastname: Lelièvre
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mounien
authors.forename: Isabelle
authors.initials: I
authors.lastname: Husson
authors.forename: Philippe
authors.initials: P
authors.lastname: Brabet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jégou
authors.forename: Thierry
authors.initials: T
authors.lastname: Janet
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects; D005260:Female; D007051:Ibotenic Acid / Q000494:pharmacology; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010451:Peptide PHI / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011247:Pregnancy; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000187:drug effects; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide / Q000187:drug effects*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
chemical_list: C495402:Adcyap1 protein, mouse; D009414:Nerve Growth Factors; D009479:Neuropeptides; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D010451:Peptide PHI; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; C495510:Vipr2 protein, mouse; D007051:Ibotenic Acid; D014660:Vasoactive Intestinal Peptide