Neuroprotection by endogenous and exogenous PACAP following stroke

Abstract

We investigated the effects of PACAP treatment, and endogenous PACAP deficiency, on infarct volume, neurological function, and the cerebrocortical transcriptional response in a mouse model of stroke, middle cerebral artery occlusion (MCAO). PACAP-38 administered i.v. or i.c. v. 1 h after MCAO significantly reduced infarct volume, and ameliorated functional motor deficits measured 24 h later in wild-type mice. Infarct volumes and neurological deficits (walking faults) were both greater in PACAP-deficient than in wild-type mice, but treatment with PACAP reduced lesion volume and neurological deficits in PACAP-deficient mice to the same level of improvement as in wild-type mice.A 35,546-clone mouse cDNA microarray was used to investigate cortical transcriptional changes associated with cerebral ischemia in wild-type and PACAP-deficient mice, and with PACAP treatment after MCAO in wild-type mice. 229 known (named) transcripts were increased (228) or decreased (1) in abundance at least 50% following cerebral ischemia in wild-type mice. 49 transcripts were significantly up-regulated only at 1 h post-MCAO (acute response transcripts), 142 were up-regulated only at 24 h post-MCAO (delayed response transcripts) and 37 transcripts were up-regulated at both times (sustained response transcripts). More than half of these are transcripts not previously reported to be altered in ischemia.A larger percentage of genes up-regulated at 24 hr than at 1 hr required endogenous PACAP, suggesting a more prominent role for PACAP in later response to injury than in the initial response. This is consistent with a neuroprotective role for PACAP in late response to injury, i.e., even when administered 1 hr or more after MCAO. Putative injury effector transcripts regulated by PACAP include β-actin, midline 2, and metallothionein 1. Potential neuroprotective transcripts include several demonstrated to be PACAP-regulated in other contexts. Prominent among these ☆ Data deposition: The raw data from the expression profiling experiments reported in this paper have been deposited in the Gene Expression Omnibus database (accession no. GSE5902). The GSE5902 will be hyperlinked when it is released. were transcripts encoding the PACAP-regulated gene Ier3, and the neuropeptides enkephalin, substance P (tachykinin 1), and neurotensin.

Comparison of Intestinal Warm Ischemic Injury in PACAP Knockout and Wild-Type Mice

“…Numerous studies have shown that it plays a crucial role not only during secretion and motility but in immunity and inflammation processes (Azuma et al 2008;Arranz et al 2008;Gomariz et al 2006). Increasing evidence suggests that PACAP-38 has protective effects in I/R models, like in global and focal cerebral ischemia, retinal ischemia, kidney warm ischemia model, cultured cardiomyocytes, and in small bowel transplantation (Atlasz et al 2007;Chen et al 2006;Ohtaki et al 2008;Racz et al 2008;Riera et al 2001;Shioda et al 1998Shioda et al , 2006Reglodi et al 2004;Ferencz et al 2009a). However, there is no data on the effect of endogenous PACAP-38 against warm mesenteric ischemia.…”

A cAMP-Dependent, Protein Kinase A-Independent Signaling Pathway Mediating Neuritogenesis through Egr1 in PC12 Cells

“…A significant literature also implicates cAMP in a broad range of neuronal differentiation responses, including neuritogenesis, survival, regeneration, repair, and expression of genes encoding neuron-specific proteins, such as neurotransmitter biosynthetic enzymes, neuropeptides, receptors, and ion channels (Qiu et al, 2002), although the effects of first messengers that regulate cAMP generation in differentiating neurons have not been studied as extensively as receptor tyrosine kinase-stimulating neurotrophins such as NGF. The neuropeptide PACAP has garnered significant interest in this regard, because PACAP is neuritogenic upon exposure to PC12 cells (Deutsch and Sun, 1992), enhances neuronal survival of cerebellar granule cells (Kienlen Campard et al, 1997) and PC12 cells (Tanaka et al, 1996), and is neuroprotective after ischemic injury to the brain (Reglodi et al, 2000;Chen et al, 2006;Ohtaki et al, 2006). PACAP signaling in PC12 cells leading to neuritogenesis is distinct from that of NGF.…”

A new recombinant pituitary adenylate cyclase-activating peptide-derived peptide efficiently promotes glucose uptake and glucose-dependent insulin secretion

“…4(B)]. Whereas the IC50 for VIP(1 -7)/GRF (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), an established human VPAC1-specific agonist, at human VPAC2 was over 20 mM. These results showed that DBAYL could competitively displace […”

“…VPAC1 and VPAC2 receptors exhibit similar high affinity for PACAP38, PACAP27, and VIP [5]. PACAP is widely distributed in the brain and peripheral organs, notably in the endocrine pancreas, gonads, respiratory, and urogenital tracts, which has been shown to have effects on many pathological states including Parkinson's disease [6], diabetes [7,8], ischemia [9], traumatic injury [10], immunological disorders [11,12], myeloma kidney injury, and so on [13]. Most of these neuroprotective actions of PACAP are mediated through the selective PAC1 receptor whereas the effects on peripheral organs often involve VPAC1 or VPAC2 receptor.…”