Neuroprotective roles of pituitary adenylate cyclase-activating polypeptide in neurodegenerative diseases
Neuroprotective roles of pituitary adenylate cyclase-activating polypeptide in neurodegenerative diseases
BMB Reports. 2014. Jul, 47(7): 369-375
Copyright © 2014, Korean Society for Biochemistry and Molecular Biology
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Received : April 18, 2014
  • Published : July 30, 2014
Export by style
Cited by
About the Authors
Eun Hye Lee
Su Ryeon Seo

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic bioactive peptide that was first isolated from an ovine hypothalamus in 1989. PACAP belongs to the secretin/glucagon/vasoactive intestinal polypeptide (VIP) superfamily. PACAP is widely distributed in the central and peripheral nervous systems and acts as a neurotransmitter, neuromodulator, and neurotrophic factor via three major receptors (PAC1, VPAC1, and VPAC2). Recent studies have shown a neuroprotective role of PACAP using in vitro and in vivo models. In this review, we briefly summarize the current findings on the neurotrophic and neuroprotective effects of PACAP in different brain injury models, such as cerebral ischemia, Parkinson’s disease (PD), and Alzheimer’s disease (AD). This review will provide information for the future development of therapeutic strategies in treatment of these neurodegenerative diseases. [BMB Reports 2014; 47(7): 369-375]
PACAP is a protein encoded by the ADCYAP1 gene in humans. PACAP was isolated from ovine hypothalamus and named after its ability to stimulate cAMP formation in rat anterior pituitary cells (1) . PACAP exists in a 27- and a 38-amino acid form (PACAP27 and PACAP38, respectively) processed from a prohormone precursor (2) . Based on its amino acid composition, PACAP belongs to secretin/glucagon/vasoactive intestinal polypeptide (VIP) superfamily. The sequence homology of PACAP from protochordates to mammals suggests the conservation of important biological functions during evolution. Three G protein coupled seven transmembrane receptors (GPCR), PAC1, VPAC1, and VPAC2, have been cloned and identified as major PACAP receptors. PAC1 receptor acts as a PACAP-selective receptor, whereas VPAC1 and VPAC2 receptors have equal affinities for PACAP and VIP. Several PAC1 receptor isoforms are generated from alternative splicing of the N-terminal extracellular domain and the C-terminal cytoplasmic intracellular loop (ic3) (3 - 5) . Cell-type specific expression of PACAP receptors determines relative ligand-binding potency and distinct patterns of intracellular signaling pathways (6) . All PACAP receptors are coupled to adenylate cyclases (ACs) and increase intracellular concentrations of 3',5'cyclic adenosine monophosphate (cAMP). The PAC1 receptor isoform can also be coupled to phospholipase Cβ (PLCβ) and produce inositol phosphate by activating IP3 receptor-mediated Ca 2+ mobilization (7) .
PACAP is expressed throughout the central nervous system (CNS), such as in the hypothalamus, hippocampus, cerebellum, and substantia nigra (8 , 9) . In the peripheral nervous system (PNS), PACAP is expressed in sensory neurons, sympathetic preganglionic neurons, and parasympathetic ganglionic neurons (10) . The widespread distribution of PACAP indicates that the peptide has pleiotropic functions in the nervous system. PACAP has been shown to function as a neurohormone, a neurotransmitter, and a neurotrophic factor. In the developing CNS, PACAP acts as a neurotrophic factor, promoting cell survival and differentiation in various cells, including cerebellar granule cells, dorsal root ganglion cells, and cortical neuroblast (11 - 13) . The neurotrophic effects of PACAP can be modulated according to splice variants of the PAC1 receptor expressed in development. In mature brain, PACAP also inhibits apoptotic cell death and promotes survival and regeneration under various pathological conditions. In cultured cells, PACAP is known to promote the survival of rat cortical neurons against glutamate-induced toxicity (14) . PACAP increases the survival of dopaminergic neurons against 6-hydroxydopamine-induced neurotoxicity (15) . In differentiated PC12 cells and primary sympathetic neurons, PACAP also prevents serum and NGF withdrawal-induced cell death (16 - 19) . The neurotrophic and neuroprotective effects of PACAP are mediated by direct or indirect mechanisms (20) . In most studies, the neurotrophic and neuroprotective actions of PACAP occur through the activation of the cAMP-protein kinase A (PKA) pathway (16 , 21) . Additionally, PACAP can influence the mitogen activated protein kinase (MAPK) pathway (22 , 23) . A direct protective effect of PACAP on neurons is often accompanied by the inhibition of caspase-3, a key apoptotic enzyme (24) . Induction of transcriptional target gene expression, such as BDNF, mediates the neuroprotective action of PACAP in rat cortical neurons (25) . In some cases, PACAP inhibits the expression of proapoptotic factors, such as Bcl-2-associated X protein (Bax), and activates the phosphatidylinositol 3'-OH kinase (PI3K) pathway (26 , 27) ( Fig. 1 ). Indirectly, PACAP mediates neuroprotective actions by modulating glial cells to provide neurotrophic support and control of inflammatory responses (28) . PACAP induces astroglial cells, which have large numbers of PACAP receptors, to release interleukin-6 (IL-6) in ischemia in vivo to protect neurons (29 , 30) .
PPT Slide
Lager Image
Schematic representation summarizing the mechanism concerning neuroprotective actions of PACAP in neurodegenerative diseases. PACAP binding with PAC1 receptors activates adenylate cyclase (AC)-linked signal transduction pathway. PACAP triggers the anti-apoptotic transcriptional target gene expression. PACAP also inhibits apoptotic signaling responses, including ROS generation, mitochondrial Bax and cytochrome C release, and subsequence caspase-3 activation.
- Cerebral ischemia
Decreased blood flow to the brain causes decreases in oxygen and glucose, resulting in cerebral ischemia or stroke. Total loss of blood flow to the brain causes global ischemia while local interruption due to cerebral artery occlusion causes focal cerebral ischemia (31) . PACAP has significant neurotrophic and neuroprotective effects after stroke. PACAP can cross the blood-brain barrier (BBB) and injection of PACAP prevent ischemic neuronal damage in transient global and focal cerebral ischemia (32) . Application of PACAP intracerebroventricularly or intravenously in a model of transient global ischemia prevented the ischemic death of rat CA1 neurons, even if administration was delayed until 1 day after the ischemic event (33) . Systemic administration of PACAP also effectively decreased infarct volume in a rat model of focal ischemia and ameliorated neurological defects when administration began 4 h after middle cerebral artery occlusion (MCAO), a mouse model of stroke (34) . Additionally, PACAP-deficient mice show more vulnerability following MCAO (15) . The infarct volumes and neurological deficits were greater in PACAP-deficient mice than in the wild-type mice. Studies comparing transcriptome alterations during ischemic insult in wild type and PACAP deficient mice suggest the possible involvement of Ier3, met enkephalin, substance P, and neurotensin expression in its neuroprotective effects (15) . PACAP-deficient mice exhibit higher cytoplasmic cytochrome c levels and lower Bcl-2 expression than wild-type mice, indicating that the PACAP acts on the mitochondrial apoptotic pathway to inhibit caspase-9 and subsequent caspase-3 activation (30) . PACAP also activates the DNA repair function of apurinic/apyrimidinic endonuclease 1 (APE1) (35) . Stroke is categorized as acute, subacute, and chronic depending on the period. During the acute period (variable from a few minutes to hours), impaired adenosine triphosphate (ATP) production, loss of Na + -K + pump activity, glutamate bursts, and increases in intracellular Ca 2+ concentration occur, leading to excitotoxicity in neurons. In the subacute periods (a few hours to a few days), neurons and microglial cells are activated and produce reactive oxygen species (ROS) and inflammatory cytokines. In the chronic period (a few days after), neurons die apoptotically and mitochondria are the structures in this process. PACAP may act on several of these processes for neuroprotection. For example, PACAP can protect against glutamate-induced cytotoxicity and excitotoxic concentrations of glutamate stimulate PACAP expression (14 , 36) . PACAP inhibits ROS-induced cell death in several cell types (37 , 38) . Furthermore, PACAP decreases the neuroinflammatory response and attenuates microglial activation (39 , 40) .
- Traumatic brain injury
Traumatic brain injury (TBI), physical damage to the brain, is a major factor leading to death and chronic disability in individuals under the age of 45 years worldwide (41 , 42) . Pathological evidence suggest that TBI involves a complex neurodegenerative process, which includes many pathways (43) . Studies have shown neuroprotective effects of PACAP in different models of TBI. Moderate TBI in rat brain induces changes in the mRNA expression of PACAP and the PAC1 receptor in the cortex and hippocampus (44) . The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in the neuronal regeneration (45) . In a rat model of TBI induced by central fluid percussion, PACAP treatment significantly reduced the diffusion of axonal injury and protected the cortocospinal tract (46) . PACAP promotes neural restoration through enhanced neurogenesis, angiogenesis, and neuroprotective effects in TBI (47) . In a weight-drop model of TBI, microinjection cerebroventricularly before TBI significantly improved motor and cognitive dysfunction, attenuated apoptosis, and decreased brain edema (48) .
The inflammatory response is a common pathological reaction to brain trauma like other neuronal diseases (49) . The cerebral inflammatory response to TBI activates macrophages/microglia, neurons, and astrocytes, and increases the release of inflammatory mediators, such as interleukin-1β (IL1β) and tumor necrosis factor-α (TNF-α) (50) . PACAP has immunomodulatory properties and can inhibit production of TNF-α from microglia activated by lipopolysaccharide (LPS) in vitro (51 , 52) . Exogenous administration of PACAP alleviates TBI in rats through a mechanism involving the TLR4/MyD88/NF-κB pathway (48) . Thus, PACAP exerts a neuroprotective effect by inhibiting a secondary inflammatory response in microglia and neurons (48) . TBI induces T cell-mediated immune suppression in both animal and clinical studies (53) . PACAP inhibits the expression of IL-12, thereby suppressing T cell proliferation (53) . Although cerebral ischemia and TBI have differing pathogenesis, they may also share some common pathways, including excitotoxicity, ROS generation, nitric oxide production, elevated Ca 2+ levels, and apoptosis (54 , 55) .
- Parkinson’s disease
Parkinson’s disease (PD) is characterized by motor movement disorders due to damage to or destruction of dopaminergic neurons in the substantia nigra (SN) (56) . In addition to the motor impairment, cognitive and behavioral disturbances may also arise in the disease. Several animal models have been developed to study the pathogenesis of PD. In particular, 1methyl-4-phenyl-1,2,3,6-etrahydropyridine (MPTP) is a widely used neurotoxin to produce experimental models of PD. MPTP inhibits the mitochondrial respiratory chain, causing energy depletion and dopaminergic neuronal loss in the SN (57 , 58) . In this model, the pretreatment of MPTP-intoxicated mice with PACAP improved memory impairment in the test session of the spatial reference version of the water maze (59) .
Unilateral lesion of the dopaminergic cells with the 6-hydroxydopamine (6-OHDA) is also commonly used for the generation of PD rodent models (60) . Injection of PACAP into 6OHDA-induced lesions in the SN can effectively reduce dopaminergic neurodegeration in the SN and ventral tegmental area and improve behavioral symptoms (61 , 62) . PACAP effectively protects dopaminergic nigrostriatal neurons from apoptosis (61) . Moreover, PACAP-treated animals show less severe acute neurological symptoms and a more rapid amelioration of behavioral deficits than wild-type animals (61) . PACAP also protects PC12 cells from apoptosis induced by rotenone, which is thought to provoke PD by interrupting mitochondrial complex I activity (63) . PACAP protects dopaminergic neurons against rotenone-, 6-OHDA-, and MPP + -induced toxicity in cell culture (64 , 65) . PACAP protects SH-SY5Y dopaminergic cells in salsolinol (SALS)-induced PD models (66) .
Recent advances in PD pathology suggest that diverse cellular and molecular events, including oxidative stress, microglia-mediated inflammation, as well as apoptotic mechanisms, are likely to be involved in the neurodegenerative process (67) . The neuroprotective effect of PACAP is mediated by inhibition of ROS production by microglial cells (68) . In mesencephalic cultures, pretreatment with PACAP protects dopaminergic neurons against 6-OHDA-induced neurotoxicity (64) . Moreover, PACAP increases the number of tyrosine hydroxylase (TH) immunoreactive neurons, and enhances dopamine uptake. Because PACAP also acts as a neuromodulator, regulating synaptic transmission, the neuroprotective actions of PACAP in PD may occur through the regulation of dopamine release. Consistent with this, PACAP induces catecholamine release from adrenal chromaffin cells, sympathetic neurons, and neurosecretory cells by elevating intracellular Ca 2+ concentrations (69 - 71) . Neuroprotective effects of PACAP in MPTP-induced PD mouse models involve the modulation of K(ATP) subunits and D2 receptors in the striatum (72) . The neuroprotective effects of PACAP affect not only dopaminergic neurotransmission but also cholinergic neurotransmission, balancing the dopamine-acetylcholine systems in the basal ganglia neuronal pathway (72) . PACAP can also act on the MPTP-altered expression of proteins, such as the mTOR anti-apoptotic and RNA-dependent protein kinase (PKR) apoptotic pathways of translational control (TC) (73 , 74) .
- Alzheimer’s disease
Deposition of amyloid β peptide (Aβ) is a central process leading to the development of Alzheimer’s disease (AD) (75) . Aβ is produced by the proteolytic cleavage of the amyloid precursor protein (APP) with sequential cleavages by a group of enzymes termed α-, β-, and γ-secretases. ADAM family (a disintegrinand metalloproteinase-family enzyme) acts an α-secretase and β-site APP-cleaving enzyme 1 (BACE1) acts as a β-secretase. The γ-secretase is a complex of enzymes, composed of presenilin 1 or 2 (PS1 or PS2), nicastrin, and anterior pharynx defective and presenilin enhancer 2 (76) . Proteolytic cleavage of APP by α-secretase precludes formation of amyloidogenic peptides and leads to the release of soluble N-terminal APP fragments (sAPPα) with neurotrophic and neuroprotective properties. Several reports suggest the neuroprotective action of PACAP is mediated by stimulating α-secretase activity (77) . In the brain of the APP[V717I] AD transgenic mouse model, PACAP treatment results in an enhancement of the non-amyloidogenic pathway of APP processing and in improved cognitive function (78) . Treatment of SK-N-MC neuroblastoma cells, which express endogenous PAC1 receptors, with PACAP shows enhanced secretion of sAPPα versus untreated cells (77) . The activation of the α-secretase activity in cells endogenously expressing PAC1 receptor indicates that physiological receptor levels are sufficient to mediate this response (77) . Moreover, stably overexpressing functional PAC1 receptors in HEK cells strongly stimulates α-secretase cleavage of APP (77) . A comparative analysis of cortical gene expression profiles showed that PACAP was significantly downregulated in several AD mice models and in the human AD temporal cortex, supporting the physiological relevance of PACAP in AD (79) . PACAP is neuroprotective, but brain uptake is limited by an efflux component, such as peptide transport system-6 (PTS-6) (80) . In the SAMP8 AD mouse model, PACAP with antisense-PTS shows improved cognition by inhibiting the peptide efflux pump (80) . There is increasing evidence for the involvement of a key lipid carrier, apolipoprotein (ApoE) in AD (81) . A mouse deficient in ApoE serves as a useful in vivo model to study development and degeneration (82) . VIP, a PACAP family member, shows protection from developmental retardation and memory deficits in ApoE-deficient mice (83) . In rat PC12 cell cultures, PACAP also shows a potent neuroprotective effect over a long period at a very low concentration from Aβ-induced cytotoxicity (84) . The enzyme caspase-3 is involved in the signaling pathways for this neurotrophic effect of PACAP.
PACAP shows significant neuroprotective potential resulting from its neurotrophic and anti-apoptotic effect in various in vivo and in vitro models. In vivo , PACAP is a peptide and is metabolized mainly by dipeptidyl peptidase IV (DPP IV), a ubiquitous amino-terminal dipeptidase (85) . Thus, metabolically stable PACAP analogs or derivatives may represent promising drug candidates. In support of this, a metabolically stable PACAP derivative, acetyl-[Ala 15 , Ala 20 ]PACAP38-propylamide, which behaves as a super-agonist of the PAC1 receptor, is being developed (86) . To avoid side effect such as migraine, it will be necessary to determine the lowest dose of PACAP needed in animal models. Moreover, strategies to target the delivery of the PACAP to the tissues of interest may also need to be developed (87) . Based on published data, PACAP may become useful a therapeutic agent in many neurological disorders characterized by neurodegeneration, such as cerebral ischemia, TBI, PD, and AD.
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0065231 and 2010-0023815). This work was also supported by 2013 Research Grant from Kangwon National University (No.120131439).
Miyata A. , Arimura A. , Dahl R. R. , Minamino N. , Uehara A. , Jiang L. , Culler M. D. , Coy D. H. (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem. Biophys. Res. Commun. 164 567 - 574    DOI : 10.1016/0006-291X(89)91757-9
Läuffer J. M. , Modlin I. M. , Tang L. H. (1999) Biological relevance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the gastrointestinal tract. Regul. Pepti. 84 1 - 12    DOI : 10.1016/S0167-0115(99)00024-5
Journot L. , Spengler D. , Pantaloni C. , Dumuis A. , Sebben M. , Bockaert J. (1994) The PACAP receptor: Generation by alternative splicing of functional diversity among G protein-coupled receptors in nerve cells. Semin. Cell Dev. Biol. 5 263 - 272    DOI : 10.1006/scel.1994.1032
Pantaloni C. , Brabet P. , Bilanges B. , Dumuis A. , Houssami S. , Spengler D. , Bockaert J. , Journot L. (1996) Alternative splicing in the N-terminal extracellular domain of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor modulates receptor selectivity and relative potencies of PACAP-27 and PACAP-38 in phospholipase C activation. J. Biol. Chem. 271 22146 - 22151    DOI : 10.1074/jbc.271.36.22146
Hosoya M. , Onda H. , Ogi K. , Masuda Y. , Miyamoto Y. , Ohtaki T. , Okazaki H. , Arimura A. , Fujino M. (1993) Molecular cloning and functional expression of rat cDNAs encoding the receptor for pituitary adenylate cyclase activating polypeptide (PACAP). Biochem. Biophys. Res. Commun. 194 133 - 143    DOI : 10.1006/bbrc.1993.1795
Spengler D. , Waeber C. , Pantaloni C. , Holsboer F. , Bockaert J. , Seeburg P. H. , Journot L. (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365 170 - 175    DOI : 10.1038/365170a0
Harmar A. J. (2001) Family-B G-protein-coupled receptors. Genome Biol. 2 REVIEWS393.1 - 3013.10.    DOI : 10.1186/gb-2001-2-12-reviews3013
Arimura A. , Somogyvari-Vigh A. , Weill C. , Fiore R. C. , Tatsuno I. , Bay V. , Brenneman D. E. (1994) PACAP functions as a neurotrophic factor. Ann. N. Y. Acad. Sci. 739 228 - 243    DOI : 10.1111/j.1749-6632.1994.tb19825.x
Hannibal J. (2002) Pituitary adenylate cyclase-activating peptide in the rat central nervous system: an immunohistochemical and in situ hybridization study. J. Comp. Neurol. 453 389 - 417    DOI : 10.1002/cne.10418
Sundler F. , Ekblad E. , Hannibal J. , Moller K. , Zhang Y. Z. , Mulder H. , Elsas T. , Grunditz T. , Danielsen N. , Fahrenkrug J. , Uddman R. (1996) Pituitary adenylate cyclase-activating peptide in sensory and autonomic ganglia: localization and regulation. Ann. N. Y. Acad. Sci. 805 427 - 428
Gonzalez B. J. , Basille M. , Vaudry D. , Fournier A. , Vaudry H. (1997) Pituitary adenylate cyclase-activating polypeptide promotes cell survival and neurite outgrowth in rat cerebellar neuroblasts. Neuroscience 78 419 - 430    DOI : 10.1016/S0306-4522(96)00617-3
Vaudry D. , Gonzalez B. J. , Basille M. , Yon L. , Fournier A. , Vaudry H. (2000) Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol. Rev. 52 269 - 324
Lioudyno M. , Skoglosa Y. , Takei N. , Lindholm D. (1998) Pituitary adenylate cyclase-activating polypeptide (PACAP) protects dorsal root ganglion neurons from death and induces calcitonin gene-related peptide (CGRP) immunoreactivity in vitro. J. Neurosci. Res. 51 243 - 256    DOI : 10.1002/(SICI)1097-4547(19980115)51:2<243::AID-JNR13>3.0.CO;2-9
Morio H. , Tatsuno I. , Hirai A. , Tamura Y. , Saito Y. (1996) Pituitary adenylate cyclase-activating polypeptide protects rat-cultured cortical neurons from glutamate-induced cytotoxicity. Brain Res. 741 82 - 88    DOI : 10.1016/S0006-8993(96)00920-1
Chen Y. , Samal B. , Hamelink C. R. , Xiang C. C. , Chen M. , Vaudry D. , Brownstein M. J. , Hallenbeck J. M. , Eiden L. E. (2006) Neuroprotection by endogenous and exogenous PACAP following stroke. Regul. Pept. 137 4 - 19    DOI : 10.1016/j.regpep.2006.06.016
Tanaka J. , Koshimura K. , Murakami Y. , Sohmiya M. , Yanaihara N. , Kato Y. (1997) Neuronal protection from apoptosis by pituitary adenylate cyclase-activating polypeptide. Regul. Pept. 72 1 - 8    DOI : 10.1016/S0167-0115(97)01038-0
Waschek J. A. (2002) Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Dev. Neurosci. 24 14 - 23    DOI : 10.1159/000064942
Waschek J. A. (2013) VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair. Br. J. Pharmacol. 169 512 - 523    DOI : 10.1111/bph.12181
May V. , Lutz E. , MacKenzie C. , Schutz K. C. , Dozark K. , Braas K. M. (2010) Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J. Biol. Chem. 285 9749 - 9761    DOI : 10.1074/jbc.M109.043117
Dejda A. , Sokolowska P. , Nowak J. Z. (2005) Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. Pharmacol. Rep. 57 307 - 320
Shoge K. , Mishima H. K. , Saitoh T. , Ishihara K. , Tamura Y. , Shiomi H. , Sasa M. (1999) Attenuation by PACAP of glutamate-induced neurotoxicity in cultured retinal neurons. Brain Res. 839 66 - 73    DOI : 10.1016/S0006-8993(99)01690-X
Pugh P. C. , Margiotta J. F. (2006) PACAP support of neuronal survival requires MAPK- and activity-generated signals. Mol. Cell. Neurosci. 31 586 - 595    DOI : 10.1016/j.mcn.2005.11.012
Villalba M. , Bockaert J. , Journot L. (1997) Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway. J. Neurosci. 17 83 - 90
Vaudry D. , Gonzalez B. J. , Basille M. , Pamantung T. F. , Fontaine M. , Fournier A. , Vaudry H. (2000) The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32. Proc. Natl. Acad. Sci. U. S. A. 97 13390 - 13395    DOI : 10.1073/pnas.97.24.13390
Frechilla D. , Garcia-Osta A. , Palacios S. , Cenarruzabeitia E. , Del Rio J. (2001) BDNF mediates the neuroprotective effect of PACAP-38 on rat cortical neurons. Neuroreport 12 919 - 923    DOI : 10.1097/00001756-200104170-00011
Falluel-Morel A. , Aubert N. , Vaudry D. , Basille M. , Fontaine M. , Fournier A. , Vaudry H. , Gonzalez B. J. (2004) Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells. J. Neurochem. 91 1231 - 1243    DOI : 10.1111/j.1471-4159.2004.02810.x
Bhave S. V. , Hoffman P. L. (2004) Phosphatidylinositol 3'-OH kinase and protein kinase A pathways mediate the anti-apoptotic effect of pituitary adenylyl cyclase-activating polypeptide in cultured cerebellar granule neurons: modulation by ethanol. J. Neurochem. 88 359 - 369    DOI : 10.1046/j.1471-4159.2003.02167.x
Delgado M. , Ganea D. (2003) Vasoactive intestinal peptide prevents activated microglia-induced neurodegeneration under inflammatory conditions: potential therapeutic role in brain trauma. FASEB J. 17 1922 - 1924
Gottschall P. E. , Tatsuno I. , Arimura A. (1994) Regulation of interleukin-6 (IL-6) secretion in primary cultured rat astrocytes: synergism of interleukin-1 (IL-1) and pituitary adenylate cyclase activating polypeptide (PACAP). Brain Res. 637 197 - 203    DOI : 10.1016/0006-8993(94)91233-5
Ohtaki H. , Nakamachi T. , Dohi K. , Aizawa Y. , Takaki A. , Hodoyama K. , Yofu S. , Hashimoto H. , Shintani N. , Baba A. , Kopf M. , Iwwakura Y. , Matsuda K. , Arimura A. , Shioda S. (2006) Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc. Natl. Acad. Sci. U. S. A. 103 7488 - 7493    DOI : 10.1073/pnas.0600375103
Dejda A. , Seaborn T. , Bourgault S. , Touzani O. , Fournier A. , Vaudry H. , Vaudry D. (2011) PACAP and a novel stable analog protect rat brain from ischemia: Insight into the mechanisms of action. Peptides. 32 1207 - 1216    DOI : 10.1016/j.peptides.2011.04.003
Banks W. A. , Uchida D. , Arimura A. , Somogyvari-Vigh A. , Shioda S. (1996) Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons. Ann. N. Y. Acad. Sci. discussion 277-279. 805 277 - 279
Uchida D. , Arimura A. , Somogyvári-Vigh A , Shioda S. , Banks W. A. (1996) Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide. Brain Res. 736 280 - 286    DOI : 10.1016/0006-8993(96)00716-0
Reglodi D. , Somogyvari-Vigh A. , Vigh S. , Kozicz T. , Arimura A. (2000) Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat. Stroke 31 1411 - 1417    DOI : 10.1161/01.STR.31.6.1411
Stetler R. A. , Gao Y. , Zukin R. S. , Vosler P. S. , Zhang L. , Zhang F. , Cao G. , Bennett M. V. , Chen J. (2010) Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia. Proc. Natl. Acad. Sci. U. S. A. 107 3204 - 3209    DOI : 10.1073/pnas.1000030107
Shintani N. , Suetake S. , Hashimoto H. , Koga K. , Kasai A. , Kawaguchi C. , Morita Y. , Hirose M. , Sakai Y. , Tomimoto S. , Matsuda T. , Bada A. (2005) Neuroprotective action of endogenous PACAP in cultured rat cortical neurons. Regul. Pept. 126 123 - 128    DOI : 10.1016/j.regpep.2004.08.014
Vaudry D. , Pamantung T. F. , Basille M. , Rousselle C. , Fournier A. , Vaudry H. , Beauvillain J. C. , Gonzalez B. J. (2002) PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. Eur. J. Neurosci. 15 1451 - 1460    DOI : 10.1046/j.1460-9568.2002.01981.x
Horvath G. , Reglodi D. , Opper B. , Brubel R. , Tamas A. , Kiss P. , Toth G. , Csernus V. , Matkovits A. , Racz B. (2010) Effects of PACAP on the oxidative stress-induced cell death in chicken pinealocytes is influenced by the phase of the circadian clock. Neurosci. Lett. 484 148 - 152    DOI : 10.1016/j.neulet.2010.08.039
Armstrong B. D. , Abad C. , Chhith S. , Cheung-Lau G. , Hajji O. E. , Nobuta H. , Waschek J. A. (2008) Impaired nerve regeneration and enhanced neuroinflammatory response in mice lacking pituitary adenylyl cyclase activating peptide. Neuroscience 151 63 - 73    DOI : 10.1016/j.neuroscience.2007.09.084
Suk K. , Park J. H. , Lee W. H. (2004) Neuropeptide PACAP inhibits hypoxic activation of brain microglia: a protective mechanism against microglial neurotoxicity in ischemia. Brain Res. 1026 151 - 156    DOI : 10.1016/j.brainres.2004.08.017
Bruns J. , Hauser W. A. (2003) The epidemiology of traumatic brain injury: a review. Epilepsia 44 (Suppl 10) 2 - 10    DOI : 10.1046/j.1528-1157.44.s10.3.x
Werner C. , Engelhard K. (2007) Pathophysiology of traumatic brain injury. Br. J. Anaesth 99 4 - 9    DOI : 10.1093/bja/aem131
Raghupathi R. (2004) Cell death mechanisms following traumatic brain injury. Brain Pathol. 14 215 - 222    DOI : 10.1111/j.1750-3639.2004.tb00056.x
Skoglosa Y. , Lewen A. , Takei N. , Hillered L. , Lindholm D. (1999) Regulation of pituitary adenylate cyclase activating polypeptide and its receptor type 1 after traumatic brain injury: comparison with brain-derived neurotrophic factor and the induction of neuronal cell death. Neuroscience 90 235 - 247    DOI : 10.1016/S0306-4522(98)00414-X
Tamas A. , Reglodi D. , Farkas O. , Kovesdi E. , Pal J. , Povlishock J.T. , Schwarcz A. , Czeiter E. , Szanto Z. , Doczi T. , Buki A. , Bukovics P. (2012) Effect of PACAP in central and peripheral nerve injuries. Int. J. Mol. Sci. 13 8430 - 8448    DOI : 10.3390/ijms13078430
Kovesdi E. , Tamas A. , Reglodi D. , Farkas O. , Pal J. , Toth G. , Bukovics P. , Doczi T. , Buki A. (2008) Posttraumatic administration of pituitary adenylate cyclase activating polypeptide in central fluid percussion injury in rats. Neurotox. Res. 13 71 - 78    DOI : 10.1007/BF03033558
Johanson C. , Stopa E. , Baird A. , Sharma H. (2011) Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus-CSF nexus. J. Neural. Transm. 118 115 - 133    DOI : 10.1007/s00702-010-0498-0
Mao S. S. , Hua R. , Zhao X. P. , Qin X. , Sun Z. Q. , Zhang Y. , Wu Y. Q. , Jia M. X. , Cao J. L. , Zhang Y. M. (2012) Exogenous administration of PACAP alleviates traumatic brain injury in rats through a mechanism involving the TLR4/MyD88/NF-κB pathway. J. Neurotrauma 29 1941 - 1959    DOI : 10.1089/neu.2011.2244
Ziebell J. M. , Morganti-Kossmann M. C. (2010) Involvement of Pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics. 7 22 - 30    DOI : 10.1016/j.nurt.2009.10.016
Marklund N. , Bakshi A. , Castelbuono D. J. , Conte V. , McIntosh T. K. (2006) Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr. Pharm. Des. 12 1645 - 1680    DOI : 10.2174/138161206776843340
Fang K. M. , Chen J. K. , Hung S. C. , Chen M. C. , Wu Y. T. , Wu T. J. , Lin H. I. , Chen C. H. , Cheng H. , Yang C. S. , Tzeng S. F. (2010) Effects of combinatorial treatment with pituitary adenylate cyclase activating peptide and human mesenchymal stem cells on spinal cord tissue repair. PLoS One 5 e15299 -    DOI : 10.1371/journal.pone.0015299
Kim D. H. , Ko I. G. , Kim B. K. , Kim T. W. , Kim S. E. , Shin M. S. , Kim C. J. , Kim H. , Kim K. M. , Baek S. S. (2010) Treadmill exercise inhibits traumatic brain injury-induced hippocampal apoptosis. Physiol. Behav. 101 660 - 665    DOI : 10.1016/j.physbeh.2010.09.021
Reglodi D. , Kiss P. , Lubics A. , Tamas A. (2011) Review on the protective effects of PACAP in models of neurodegenerative diseases In Vitro and In Vivo. Curr. Pharm. Des. 17 962 - 972    DOI : 10.2174/138161211795589355
Leker R. R. , Shohami E. (2002) Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res. Brain Res. Rev. 39 55 - 73    DOI : 10.1016/S0165-0173(02)00157-1
Buki A. , Okonkwo D. O. , Wang K. K. , Povlishock J. T. (2000) Cytochrome c release and caspase activation in traumatic axonal injury. J. Neurosci. 20 2825 - 2834
Jankovic J. (2008) Parkinson's disease: Clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79 368 - 376    DOI : 10.1136/jnnp.2007.131045
Gerlach M. , Riederer P. (1996) Animal models of Parkinson's disease: an empirical comparison with the phenomenology of the disease in man. J. Neural. Transm. 103 987 - 1041    DOI : 10.1007/BF01291788
Kostrzewa R. M. , Segura-Aguilar J. (2002) Neurotoxicological and neuroprotective elements in Parkinson's disease. Neurotox. Res. 4 83 - 86    DOI : 10.1080/10298420290015890
Masuo Y. , Matsumoto Y. , Tokito F. , Tsuda M. , Fujino M. (1993) Effects of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) on the spontaneous release of acetylcholine from the rat hippocampus by brain microdialysis. Brain Res. 611 207 - 215    DOI : 10.1016/0006-8993(93)90504-G
Deumens R. , Blokland A. , Prickaerts J. (2002) Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp. Neurol. 175 303 - 317    DOI : 10.1006/exnr.2002.7891
Reglodi D. , Lubics A. , Tamas A. , Szalontay L. , Lengvari I. (2004) Pituitary adenylate cyclase activating polypeptide protects dopaminergic neurons and improves behavioral deficits in a rat model of Parkinson's disease. Behav. Brain Res. 151 303 - 312    DOI : 10.1016/j.bbr.2003.09.007
Reglodi D. , Tamas A. , Lubics A. , Szalontay L. , Lengvari I. (2004) Morphological and functional effects of PACAP in 6-hydroxydopamine-induced lesion of the substantia nigra in rats. Regul. Pept. 123 85 - 94    DOI : 10.1016/j.regpep.2004.05.016
Wang G. , Qi C. , Fan G. H. , Zhou H. Y. , Chen S. D. (2005) PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone. FEBS Lett. 579 4005 - 4011    DOI : 10.1016/j.febslet.2005.06.013
Takei N. , Skoglösa Y. , Lindholm D. (1998) Neurotrophic and neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on mesencephalic dopaminergic neurons. J. Neurosci. Res. 54 698 - 706    DOI : 10.1002/(SICI)1097-4547(19981201)54:5<698::AID-JNR15>3.0.CO;2-5
Chung C. Y. , Seo H. , Sonntag K. C. , Brooks A. , Lin L. , Isacson O. (2005) Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum. Mol. Genet. 14 1709 - 1725    DOI : 10.1093/hmg/ddi178
Brown D. , Tamas A. , Reglodi D. , Tizabi Y. (2013) PACAP protects against salsolinol-induced toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson's disease. J. Mol. Neurosci. 50 600 - 607    DOI : 10.1007/s12031-013-0015-7
von Bohlen und Halbach O. , Schober A. , Krieglstein K. (2004) Genes, proteins, and neurotoxins involved in Parkinson's disease. Prog. Neurobiol. 73 151 - 177    DOI : 10.1016/j.pneurobio.2004.05.002
Yang S. , Yang J. , Yang Z. , Chen P. , Fraser A. , Zhang W. , Pang H. , Gao X. , Wilson B. , Hong J. S. , Block M. L. (2006) Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and PACAP4-6 are neuroprotective through inhibition of NADPH oxidase: potent regulators of microglia-mediated oxidative stress. J. Pharmacol. Exp. Ther. 319 595 - 603    DOI : 10.1124/jpet.106.102236
Przywara D. A. , Guo X. , Angelilli M. L. , Wakade T. D. , Wakade A. R. (1996) A non-cholinergic transmitter, pituitary adenylate cyclase-activating polypeptide, utilizes a novel mechanism to evoke catecholamine secretion in rat adrenal chromaffin cells. J. Biol. Chem. 271 10545 - 10550    DOI : 10.1074/jbc.271.18.10545
Ghzili H. , Grumolato L. , Thouennon E. , Tanguy Y. , Turquier V. , Vaudry H. , Anouar Y. (2008) Role of PACAP in the physiology and pathology of the sympathoadrenal system. Front Neuroendocrinol. 29 128 - 141    DOI : 10.1016/j.yfrne.2007.10.001
Mustafa T. , Walsh J. , Grimaldi M. , Eiden L. E. (2010) PAC1hop receptor activation facilitates catecholamine secretion selectively through 2-APB-sensitive Ca(2+) channels in PC12 cells. Cell Signal. 22 1420 - 1426    DOI : 10.1016/j.cellsig.2010.05.005
Wang G. , Pan J. , Tan Y. Y. , Sun X. K. , Zhang Y. F. , Zhou H. Y. , Ren R. J. , Wang X. J. , Chen S. D. (2008) Neuroprotective effects of PACAP27 in mice model of Parkinson's disease involved in the modulation of K(ATP) subunits and D2 receptors in the striatum. Neuropeptides 42 267 - 276    DOI : 10.1016/j.npep.2008.03.002
Deguil J. , Jailloux D. , Page G. , Fauconneau B. , Houeto J. L. , Philippe M. , Muller J. M. , Pain S. (2007) Neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in MPP+-induced alteration of translational control in Neuro-2a neuroblastoma cells. J. Neurosci. Res. 85 2017 - 2025    DOI : 10.1002/jnr.21318
Deguil J. , Chavant F. , Lafay-Chebassier C. , Perault-Pochat M. C. , Fauconneau B. , Pain S. (2010) Neuroprotective effect of PACAP on translational control alteration and cognitive decline in MPTP parkinsonian mice. Neurotox. Res. 17 142 - 155    DOI : 10.1007/s12640-009-9091-4
Hardy J. , Selkoe D. J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 353 - 356    DOI : 10.1126/science.1072994
LaFerla F. M. , Green K. N. , Oddo S. (2007) Intracellular amyloid-beta in Alzheimer's disease. Nat. Rev. Neurosci. 8 499 - 509    DOI : 10.1038/nrn2168
Kojro E. , Postina R. , Buro C. , Meiringer C. , Gehrig-Burger K. , Fahrenholz F. (2006) The neuropeptide PACAP promotes the α-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J. 20 512 - 514
Rat D. , Schmitt U. , Tippmann F. , Dewachter I. , Theunis C. , Wieczerzak E. , Postina R. , Van Leuven F. , Fahrenholz F. , Kojro E. (2011) Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice. FASEB J. 25 3208 - 3218    DOI : 10.1096/fj.10-180133
Wu Z. L. , Ciallella J. R. , Flood D. G. , O’Kane T. M. , Bozyczko-Coyne D. , Savage M. J. (2006) Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. Neurobiol. Aging 27 377 - 386    DOI : 10.1016/j.neurobiolaging.2005.02.010
Dogrukol-Ak D. , Kumar V. B. , Ryerse J. S. , Farr S. A. , Verma S. , Nonaka N. , Nakamachi T. , Ohtaki H. , Niehoff M. L. , Edwards J. C. , Shioda S. , Morley J. E. , Banks W. A. (2009) Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models. J. Cereb. Blood Flow Metab. 29 411 - 422    DOI : 10.1038/jcbfm.2008.131
Strittmatter W. J. , Roses A. D. (1995) Apolipoprotein E and Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 92 4725 - 4727    DOI : 10.1073/pnas.92.11.4725
Plump A. S. , Smith J. D. , Hayek T. , Aalto-Setala K. , Walsh A. , Verstuyft J. G. , Rubin E. M. , Breslow J. L. (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71 343 - 353    DOI : 10.1016/0092-8674(92)90362-G
Gozes I. , Bachar M. , Bardea A. , Davidson A. , Rubinraut S. , Fridkin M. , Giladi E. (1997) Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: implications for early treatment of Alzheimer's disease. J. Neurobiol. 33 329 - 342    DOI : 10.1002/(SICI)1097-4695(199709)33:3<329::AID-NEU10>3.0.CO;2-A
Onoue S. , Endo K. , Ohshima K. , Yajima T. , Kashimoto K. (2002) The neuropeptide PACAP attenuates beta-amyloid (1-42)-induced toxicity in PC12 cells. Peptides 23 1471 - 1478    DOI : 10.1016/S0196-9781(02)00085-2
Zhu L. , Tamvakopoulos C. , Xie D. , Dragovic J. , Shen X. , Fenyk-Melody J. E. , Schmidt K. , Bagchi A. , Griffin P. R. , Thornberry N. A. , Sinha Roy R. (2003) The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J. Biol. Chem. 278 22418 - 22423    DOI : 10.1074/jbc.M212355200
Bourgault S. , Vaudry D. , Botia B. , Couvineau A. , Laburthe M. , Vaudry H. , Fournier A. (2008) Novel stable PACAP analogs with potent activity towards the PAC1 receptor. Peptides 29 919 - 932    DOI : 10.1016/j.peptides.2008.01.022
Bourgault S. , Vaudry D. , Dejda A. , Doan N. D. , Vaudry H. , Fournier A. (2009) Pituitary adenylate cyclase-activating polypeptide: focus on structure-activity relationships of a neuroprotective Peptide. Curr. Med. Chem. 16 4462 - 4480    DOI : 10.2174/092986709789712899