Neuroprotective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide
Rui Ji1, Lingbin Meng2 and Rongqiang Yang1*
1Department of Biochemistry and Molecular biology, University of Louisville, School of Medicine, Louisville, KY 40202, USA
2Department of Anatomical Sciences and Neurobiology, University of Louisville, School of Medicine, Louisville, KY 40202, USA
- *Corresponding Author:
- Dr. Rongqiang Yang
University of Louisville, School of Medicine
319 Abraham Flexner Way, Louisville, KY 40202, USA
E-mail: [email protected]
Received date: June 15, 2014; Accepted date: June 24, 2014; Published date: June 27, 2014
Citation: Rui J, Lingbin M, Rongqiang Y (2014) Neuroprotective Effects of Pituitary Adenylate Cyclase-Activating Polypeptide. Int J Adv Innovat Thoughts Ideas 3:156. doi:10.4172/2277-1891.1000156
Copyright: © 2014 Rui Ji, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at International Journal of Advance Innovations, Thoughts & Ideas
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the secretin/glucagon/vasoactive intestinal peptide (VIP) super family. PACAP was first isolated from an ovine hypothalamus and named because it stimulated cAMP production in the rat pituitary cell culture. PACAP is widely expressed in the central and peripheral nervous systems. PACAP plays the roles of neurotransmitter, neuromodulator and neurotrophic factors via three Gprotein binding receptors, PAC1, VAPC1 and VPAC2. A number of recent studies have discovered the neuroprotective functions of PACAP in both in vitro and in vivo models. PACAP protects the neurons from death through both direct and indirect ways. PACAP inhibits caspase-3 through cAMP-PKA or MAP kinase-signaling pathways. Moreover, PACAP can stimulate astrocytes to release neuroprotective factors, such as interleukin-6 (IL-6). The present review will briefly summarize the recent studies and provide information for the future use in the clinic.
Pituitary adenylate cyclase-activating polypeptide; Neuroprotection; Neurodegeneration; Alzheimer’s disease; Parkinson’s disease
Pituitary adenylate cyclase-activating polypeptide (PACAP) was first isolated from an ovine hypothalamus by Dr. Arimura and his colleagues in 1989 and demonstrated to be one of most conserved peptide through the different species . PACAP belongs to the secretin/glucagon/vasoactive intestinal peptide family and exists in a full form (PACAP-38) and a shorter form (PACAP-27) [2,3]. PACAP and its three different receptors, PAC1, VPAC1 and VPAC2, have been demonstrated in the central and peripheral nervous system [4-8]. Furthermore, previous studies have proved that PACAP has pleiotropic functions, such as the regulation of neurodevelopment and protection against neuron apoptosis. The peptide exerts its physiological effects via PAC1, VPAC1 and VPAC2 receptors, which all belong to the class B, family of G protein-coupled receptors (GPCRs) [8-10]. The primary signaling pathways of PACAP receptors are cAMP mediated both PKA and MAPK pathways. The phospholipase D (PLD) and calcium signaling pathways can be activated by PACAP receptors as well [11-16].
Evidences from numbers of in vitro and in vivo experiments suggest that PACAP may enhance neuronal survival and neuronal regeneration in the nervous system [17-19]. The cultured cerebellar granule cell, a model of programmed cell death, is widely used for investigation of the neuroprotective factors. PACAP was demonstrated to prevent programmed cell death of cerebellar granule cell during cerebellar development [20-22]. PACAP has been reported to protect cerebellar granule cells against apoptosis induced by different neurotoxins including ethanol, hydrogen peroxide and ceramides. Incubating cultured granule cells with PACAP and the neurotoxins increased the number of living cells, decreased DNA fragmentation and resorted mitochondrial activity [23-25]. PACAP also showed its neuroprotective function in the other model systems. For example, PACAP protected neuron-like PC12 cells against cytotoxicity of b-amyloid, which is a key player in Alzheimer’s disease . PACAP has been reported to maintain the PC12 cell living under exposure of rotenone, which may cause Parkinson’s disease . The neuroprotective effects of PACAP are also observed in some in vivo models, especially in some neurodegenerative and neuron injury diseases models. PACAP has significant neurotrophic and neuroprotective effects after the cerebral ischemia or stroke, which is caused by decrease in oxygen and glucose in the brain [28-30]. For example, the injection of PACAP prevented the ischemic death of rat CA1 neurons in a model of transient global ischemia. In a mouse model of stroke, PACAP ameliorates neurological defects when administration begins 4 hours after middle cerebral artery occlusion . As well PACAP appeared to be a neuroprotective factor in some animal models of Parkinson’s diseases (PD) and Alzhihermer’s diseases (AD). Reglodi and colleagues discovered that PACAP prevented the substantia nigra (SN) dopaminergic neurons from apoptosis and improved behavioral symptoms in a rat model of PD induced by the 6-hydroxydopamine (6-OHDA) . In another PD model produced by the 1-methy1-4-phenyl-1, 2, 3, 6-etrahydropyridine (MPTP), several groups have showed that injection of PACAP improved memory impairment in the water maze test . PACAP is one of three genes that are down regulated in both AD patients and AD rodent models . Several reports suggest that PACAP stimulates the α-secretase activity, which can lead to the release of soluble N-terminal APP fragments with neurotrophic and neuroprotective properties [33-36].
The mechanisms of the neuroproticetive action of PACAP can be summarized to direct and indirect ways based on published manuscripts. The direct mechanism is that PACAP protects neurons via its receptors on neuronal cells to activate cAMP-PKA/MAPK pathways [23,25,26,37]. Through the pathways, PACAP can deactivate caspase-3, an apoptotic key enzyme, and induce expression of neurotrophin such as Brain-derived neurotrophic factor (BDNF) to keep the neurons survival [21,38]. Indirectly, PACAP protects the neurons by modulating glial cells to improve the microenvironments around the neurons. For instance, the astrocytes express a lot of PACAP receptors. PACAP can induce the high secretion of interleukin-6 (IL-6) to protect CA1 neurons against apoptosis in the ischemic hippocampus .
In conclusion, a numbers of previous studies have showed that PACAP has a significant neuroprotective potential because of its neurotrophic and anti-apoptosis effect through direct and indirect mechanisms. Furthermore, PACAP has the ability to cross the blood brain barrier . Therefore, PACAP may become a useful therapeutic agent in many brain injury and neurodegenerative diseases. In order to utilizing PACAP in clinic, researchers still need to pay more attention to delivery of PACAP into the specific region and blockade of PACAP degradation
- Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, et al. (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164: 567-574.
- Miyata A, Jiang L, Dahl RD, Kitada C, Kubo K, et al. (1990) Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38). Biochem Biophys Res Commun 170: 643-648.
- Sherwood NM, Krueckl SL, McRory JE (2000) The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21: 619-670.
- Arimura A, Somogyvari-Vigh A, Miyata A, Mizuno K, Coy DH, et al. (1991) Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology 129: 2787-2789.
- M, Murai Z, Arimura A, Koves K (1999) Distribution of pituitary adenylate cyclase activating polypeptide (PACAP) immunoreactive elements in the brain stem of rats studied by immunohistochemistry. Neurobiology (Bp) 7: 19-31.
- Hosoya M, Onda H, Ogi K, Masuda Y, Miyamoto Y, et al. (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.
- 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.
- Pantaloni C, Brabet P, Bilanges B, Dumuis A, Houssami S, et al. (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.
- Journot L, Spengler D, Pantaloni C, Dumuis A, Sebben M, et al. (1994) The PACAP receptor: generation by alternative splicing of functional diversity among G protein-coupled receptors in nerve cells. Semin Cell Biol 5: 263-272.
- Harmar AJ (2001) Family-B G-protein-coupled receptors. Genome Biol 2: REVIEWS3013.
- Hezareh M, Schlegel W, Rawlings SR (1996) PACAP and VIP stimulate Ca2+ oscillations in rat gonadotrophs through the PACAP/VIP type 1 receptor (PVR1) linked to a pertussis toxin-insensitive G-protein and the activation of phospholipase C-beta. J Neuroendocrinol 8: 367-374.
- Nowak JZ, Zawilska JB (2003) PACAP in avians: origin, occurrence, and receptors--pharmacological and functional considerations. Curr Pharm Des 9: 467-481.
- Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, et al. (2000) Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 52: 269-324.
- McCulloch DA, Lutz EM, Johnson MS, MacKenzie CJ, Mitchell R (2000) Differential activation of phospholipase D by VPAC and PAC1 receptors. Ann N Y Acad Sci 921: 175-185.
- Arimura A (1998) Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn J Physiol 48: 301-331.
- Balmer J, Ji R, Ray TA, Selber F, Gassmann M, et al. (2013) Presence of the Gpr179nob5 allele in a C3H-derived transgenic mouse. Molecular vision 19: 2615.
- Gonzalez BJ, 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.
- Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, et al. (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61: 283-357.
- Ji R (2012) Tyro-3, Axl, and Mertk (TAM) Receptors Maintain Adult Hippocampal Neurogenesis: University of Louisville.
- Vaudry D, Gonzalez BJ, Basille M, Fournier A, Vaudry H (1999) Neurotrophic activity of pituitary adenylate cyclase-activating polypeptide on rat cerebellar cortex during development. Proc Natl Acad Sci U S A 96: 9415-9420.
- Vaudry D, Gonzalez BJ, Basille M, Pamantung TF, Fontaine M, et al. (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.
- Ji R, Tian S, Lu HJ, Lu Q, Zheng Y, et al. (2013) TAM Receptors Affect Adult Brain Neurogenesis by Negative Regulation of Microglial Cell Activation. The Journal of Immunology 191: 6165-6177.
- Vaudry D, Pamantung TF, Basille M, Rousselle C, Fournier A, et al. (2002) PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. Eur J Neurosci 15: 1451-1460.
- Vaudry D, Rousselle C, Basille M, Falluel-Morel A, Pamantung TF, et al. (2002) Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death. Proc Natl Acad Sci U S A 99: 6398-6403.
- Vaudry D, Falluel-Morel A, Basille M, Pamantung TF, Fontaine M, et al. (2003) Pituitary adenylate cyclase-activating polypeptide prevents C2-ceramide-induced apoptosis of cerebellar granule cells. J Neurosci Res 72: 303-316.
- 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.
- Wang G, Qi C, Fan GH, Zhou HY, Chen SD (2005) PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone. FEBS Lett 579: 4005-4011.
- Reglodi D, Tamas A, Somogyvari-Vigh A, Szanto Z, Kertes E, et al. (2002) Effects of pretreatment with PACAP on the infarct size and functional outcome in rat permanent focal cerebral ischemia. Peptides 23: 2227-2234.
- Reglodi D, Somogyvari-Vigh A, Vigh S, Maderdrut JL, Arimura A (2000) Neuroprotective effects of PACAP38 in a rat model of transient focal ischemia under various experimental conditions. Ann N Y Acad Sci 921: 119-128.
- 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.
- 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.
- Wu ZL, Ciallella JR, Flood DG, O'Kane TM, Bozyczko-Coyne D, et al. (2006) Comparative analysis of cortical gene expression in mouse models of Alzheimer's disease. Neurobiol Aging 27: 377-386.
- LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 8: 499-509.
- Kojro E, Postina R, Buro C, Meiringer C, Gehrig-Burger K, et al. (2006) The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J 20: 512-514.
- Rat D, Schmitt U, Tippmann F, Dewachter I, Theunis C, et al. (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.
- Yan XB, Wang SS, Hou HL, Ji R, Zhou JN (2007) Lithium improves the behavioral disorder in rats subjected to transient global cerebral ischemia. Behav Brain Res 177: 282-289.
- 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.
- 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.
- Shioda S, Ozawa H, Dohi K, Mizushima H, Matsumoto K, et al. (1998) PACAP protects hippocampal neurons against apoptosis: involvement of JNK/SAPK signaling pathway. Ann N Y Acad Sci 865: 111-117.
- Banks WA, 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 805: 270-277; discussion 277-279.