VPAC₂Receptors 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.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Excitotoxic doses of glutamate also substantially increase PACAP mRNA expression, and the PACAP receptor antagonist PACAP(6 -38) exacerbates the deleterious effect of glutamate . Attenuation by PACAP of glutamate-induced neurotoxicity has also been reported in cultured retinal neurons (Shoge et al, 1999) and in neonatal brain lesions (Rangon et al, 2005;Favrais et al, 2007). Most of the actions of PACAP on cortical neurons are mediated through the cAMP pathway (Martin et al, 1995;Morio et al, 1996), although it has been reported that PACAP can directly modulate NMDA receptors independently of intracellular second messengers Madsen, 1997, 1998).…”

VIP-induced Neuroprotection of the Developing Brain

“…Surprisingly, VIP-induced neuroprotection was not mimicked by a large range of doses of PACAP 27 or PACAP 38 [27,31]. This atypical pharmacology of VIP-induced neuroprotection in P5 mice raised several hypotheses: i) activation of PAC 1 receptors could have a toxic effect on the excitotoxic lesions while activation of VPAC receptors could be neuroprotective, leading to a lack of detectable effect for PACAP.…”

“…VIP effects on white matter were mimicked with a similar potency by VPAC 2 agonists and PHI but not by VPAC 1 agonists [30,31]. Surprisingly, VIP-induced neuroprotection was not mimicked by a large range of doses of PACAP 27 or PACAP 38 [27,31].…”

“…The first stated hypothesis that activation of PAC 1 receptors could have a toxic effect on the excitotoxic lesions while activation of VPAC receptors could be neuroprotective, leading to a lack of detectable effect for PACAP38, can be ruled out by the lack of protective effects of PACAP 38 in PAC 1 -/-mice [31].…”

Identification and Characterization of a Small Molecule Antagonist of Human VPAC2 Receptor

“…Both VIP and PACAP, as well as their receptors, have a widespread distribution. A wide array of potential functions of VIP/ PACAP system has been demonstrated, including regulation of circadian rhythm (Harmar et al, 2002), neuronal survival (Rangon et al, 2005), tumor progression (Moody and Gozes, 2007;Valdehita et al, 2009), immune responses (Goetzl et al, 2001;Gonzalez-Rey et al, 2006), metabolic homeostasis (Tsutsumi et al, 2002), and megakaryocyte maturation (Freson et al, 2008). VPAC 2 knockout mice showed loss of electrical rhythmicity in suprachiasmatic neurons in the brain and a reduced behavioral circadian rhythm (Harmar et al, 2002).…”