CELLULAR & MOLECULAR BIOLOGY LETTERS http://www.cmbl.org.pl Received: 16 September 2014 Final form accepted: 17 February 2015 Published online: 13 March 2015
Volume 20 (2015) pp 265-278 DOI: 10.1515/cmble-2015-0008 © 2014 by the University of Wrocław, Poland
Mini review THERAPEUTIC POTENTIAL OF PACAP FOR NEURODEGENERATIVE DISEASES RONGQIANG YANG1, XIN JIANG2, RUI JI1, LINGBIN MENG3, FULI LIU4, XIAOLEI CHEN5,* and YING XIN6,* 1 Department of Biochemistry and Molecular Biology, University of Louisville, School of Medicine, Louisville, KY 40202, USA, 2Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China, 3 Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA, 4Department of Physiology and Neurobiology, Geisel Medical School at Dartmouth, Lebanon, NH 03756, USA, 5Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA, 6Ying Xin, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China Abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the central and peripheral nervous system. PACAP can initiate multiple signaling pathways through binding with three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2. Previous studies have revealed numerous biological activities of PACAP in the nervous system. PACAP acts as a neurotransmitter, neuromodulator and neurotrophic factor. Recently, its neuroprotective potential has been demonstrated in numerous in vitro and in vivo studies. Furthermore, evidence suggests that PACAP might move across the blood-brain barrier in amounts sufficient to affect the brain functions. Therefore, PACAP has been examined as a potential therapeutic method for neurodegenerative diseases. The present review summarizes the recent findings with special focus on the models of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Based on these observations, the administered PACAP inhibits pathological processes in models of AD and PD, and alleviates clinical symptoms. It thus offers a novel therapeutic approach for the treatment of AD and PD. * Authors for correspondence. Email: [email protected]; [email protected] Abbreviations used: AD – Alzheimer’s disease; Bcl-2 – B-cell lymphoma 2; BDNF – brain-derived neurotrophic factor; Caspase – cysteinyl aspartate-specific protease; cAMP – cyclic adenosine monophosphate; DA – dopamine; PACAP – pituitary adenylate cyclase activating polypeptide; PD – Parkinson’s disease; PAC1-R – PACAP-specific receptor
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Keywords: Pituitary adenylate cyclase activating polypeptide, Neurodegenerative diseases, Neuroprotective, Neurotrophic, Alzheimer’s disease, Parkinson’s disease PACAP AND ITS RECEPTORS Pituitary adenylate cyclase-activating polypeptide (PACAP) was first isolated from ovine hypothalamic extracts by Dr. Arimura and colleagues in 1989 [1]. PACAP belongs to a superfamily of structurally related peptide hormones, which includes PACAP, vasoactive intestinal peptide (VIP), glucagon, glucagon-like peptide-1 (GLP1), glucagon-like peptide-2 (GLP2), glucose-dependent insulinotropic polypeptide (GIP), growth hormone-releasing hormone (GHRH) and peptide histidine isoleucine (PHI) (Table 1) [2]. Table 1. Primary structure of the different members of PACAP-VIP-secretin-GHRH superfamily in humans. PACAP38 PACAP27 VIP GLP1 GLP2 GIP GHRH Secretin Glucagon PHI
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVL- NH2 HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2 HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 HADGSFSDEMNTILDNLAARDFINWLIQTKITD -NH2 YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-NH2 YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2 HSDGTFTSELSRLREGARLLQGLV-NH2 HSQGTFTSDYSKYLDSRRAQFVQWLMNT-NH2 HADGVFTSDYSRLLGQISAKKYLESLI-NH2
PACAP was shown to have 38 amino acids, but was also present in a shorter biologically active form with 27 amino acids of the N-terminal. PACAP is one of the most conservative peptides in the vertebrate lineage (Table 2) [3-6], which suggests that it must have important biological functions [7]. Characterization of the PACAP binding sites led to cloning of three PACAP receptors, PAC1, VPAC1 and VPAC2. VPAC1 and VPAC2 were shared with VIP, whereas PAC1 showed a specific affinity with PACAP [8]. VPAC1, VPAC2 and PAC1 all belong to class B, G protein coupled receptor families (GPCRs), which have a larger N-terminal extracellular domain for ligand recognition. Recently, PACAP27 was found to bind with another receptor, FPR2. FPR2 is widely expressed in the brain and belongs to the GPCR family as well [9-11]. The PAC1 gene expresses numerous splicing variants, including the presence or absence of the HOP and HIP cassette in the third intracellular loop [12]. The variants of PAC1 show differences in signal transduction pathways. Binding with these receptors, PACAP can increase intracellular concentrations of cAMP by increasing the activity of adenylate cyclase through a Gs protein. PACAP can also initiate intracellular signaling through PKC/MAPK pathways [13].
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Table 2. Comparison of the primary structure of PACAP from a protochordate to various vertebrate species. Bold letters indicate different amino acids compared to human PACAP. Human Mouse Chicken Frog Salmon Catfish Sturgeon Stingray Tunicate1 Tunicate2
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HIDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRIKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYRQRYRNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGRRYRQRFRNK-NH2 HSDGIFTDSYSRYREQMAVKKYLAAVLGKRYRQRIRNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKPKIRNSGRRVFY-NH2 HSDGIFTDSYSRYRNQMAVKKYLAAVL-NH2 HSDGIFTDSYSRYRNQMAVKKYINALL-NH2
After the isolation of PACAP, Dr. Arimura and his colleagues investigated the distribution of the peptide by immunoassay and PCR [14]. In the central nervous system (CNS), PACAP is expressed in both cell bodies and fibers in various brain regions, such as the hypothalamus, cerebral cortex, amygdala and hippocampus. PACAP can be detected in the brain as early as embryonic day 14. PACAP is not co-localized with VIP in most of the brain regions. PACAP receptors were found in many brain structures as well [2]. Over the last couple of decades, many studies have investigated physiological functions of PACAP in the CNS because of the high concentrations of the peptide and its receptors in the brain. Previous data provide clear evidence that PACAP and its receptors mediated neuron proliferation, plasticity and release of neurotrophic factors. Furthermore, PACAP plays a key role in behavioral and neuropsychiatric disorders, such as post-traumatic stress disorder [15-17]. Therefore, PACAP has been widely studied in different neurodegenerative disease models. NEURODEGENERATIVE DISEASES Neurodegenerative diseases, which are caused by progressive loss of neurological function, are one of the rising global problems for the aged. Common types of neurodegenerative diseases include Alzheimer’s, Parkinson’s and Huntington’s diseases and amyotrophic lateral sclerosis (ALS). The mechanisms of development of the disease are still unclear in spite of many years’ studies. Currently, we have no effective diagnostic method to identify the patients unless they are in advanced stages of the neurodegenerative diseases. We also lack effective therapies for stopping and/or healing the neurodegenerative diseases. The design of drugs for the treatment of these diseases is also a major challenge for health professionals, because of the existence of the blood-brain barrier (BBB). Previous studies have demonstrated that some peptides can cross the BBB, including insulin, TNF- and IL-1 [18-22]. The problems with the use
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of peptides as therapeutics are rapid degradation in blood and low bioavailability. However, recent studies have shown that intranasal administration could bypass the BBB and produce lower levels in blood [23,24]. PACAP, which can be transported across the BBB to some extent like some other peptides, has the potential to treat neurodegenerative diseases [25-28]. Our review will focus on the effects of PACAP for Alzheimer’s and Parkinson’s diseases, which are more common than the other neurodegenerative diseases. PACAP AND ALZHEIMER’S DISEASE Alzheimer’s disease was named after the German neurologist Alois Alzheimer, who first described the clinical and pathological features of this unusual brain disease in 1906 [29]. After one hundred years, Alzheimer’s disease has become the most common form of age-related neurodegenerative disease in the world. In 2006, about 26.6 million people suffered from AD. It has been estimated that the number will have quadrupled by 2050 [30,31]. Alzheimer’s disease is not only a physiological but also a social problem due to the increasing time, funds and labor required to deal with these patients. The common symptoms of AD include short- and long-term memory loss, confusion, irritability, aggression, mood swings and trouble with language. To confirm AD, a brain scan and examination of brain tissue are required [32]. In terms of the pathological hallmarks, AD is associated with amyloid plaques and neurofibrillary tangles [33]. Although AD has been investigated for more than one hundred years, the exact mechanism of AD development is still unclear. Recently most researchers have agreed that AD arises from a combination of various factors including genetic, behavioral, dietary and environmental. Several competing hypotheses have been proposed to explain the cause of Alzheimer’s disease. PACAP and its receptors are highly expressed in the brain regions affected most by Alzheimer’s disease. Evidence indicates that PACAP may be involved at multiple levels in the pathology of AD. The cholinergic hypothesis, which proposes that AD is caused by reduced levels of the neurotransmitter acetylcholine (Ach), is the oldest hypothesis of Alzheimer’s disease [34]. It is based on the presynaptic deficits found in the brains of patients and studies of the role of Ach in animal and human behavior. Previous studies revealed that PACAP cooperating with nerve growth factor (NGF) maintained cholinergic function through increasing choline acetyltransferase (ChAT) activity [35-37]. However, this hypothesis is not widely supported because the drugs based on it have not been very effective. In 1991, a new hypothesis proposed that AD is caused by deposits of extracellular -amyloid (A) [38,39]. The amyloid hypothesis has dominated research on AD for the past 20 years. The hypothesis has received various supporting evidence, including from a genetic mouse model and Down syndrome patients, who exhibit AD by 40 years old [40]. A is generated from the amyloid precursor protein (APP) through cleavage by -secretase. Apart from the toxic
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A, the APP also produces a neurotrophic and neuroprotective factor, soluble N-terminal APP fragments (sAPP), through -secretase [41,42]. The cerebrospinal fluid (CSF) of AD patients exhibits a decreased sAPP level [43,44]. In addition, exogenous sAPP also improves the memory performance [45,46]. Numerous studies have shown that PACAP also has relevance in the amyloid hypothesis. In cell culture studies, PACAP protected against -amyloid toxicity in PC-12 and astrocyte cells [47]. In cultured neuroblastoma cells, PACAP strongly increases the -secretase activity to release more sAPP [48]. Many animal AD models have been developed based on the amyloid hypothesis. The human APP transgenic models are the most widely used models. In a gene expression screen of three mouse models of AD, PACAP, together with BDNF and ILGF 1 receptor, was one of the 3 genes that were down-regulated [49]. In a recent study using human AD samples, PACAP expression was reduced in these patients [50]. PACAP protected against -amyloid toxicity in cultured mouse cortical neurons. PACAP activates the AMPK pathway to enhance sirt3, which is relevant in AD [50]. PACAP stimulates nonamyloidogenic processing of APP by enhancing -secretase to increase sAPP production and to reduce sAPP secretion. Intranasal administration was used for applying PACAP into the brain of APP-transgenic mice. In the novel object recognition test, PACAPtreated APP transgenic mice spent about 30% more time with the novel object than control APP transgenic mice. Intranasal PACAP was effective in improving memory in the aged SAMP8 mouse, which is a natural mutation with learning and memory defects. Long-term PACAP treatment of APP [V717I]-transgenic mice increased secretion of the neuroprotective sAPP and positively influenced expression levels of AD-relevant genes and proteins, such as BDNF, Bcl-2, and RAGE [51]. PACAP also indirectly regulated A in the brain by up-regulating somatostatin and neprilysin. Besides the amyloid hypothesis, oxidative stress has been reported to enhance AD processing [52]. PACAP could protect cells from apoptosis caused by oxidative stress. For example, co-incubation of the cerebellar granule cells with hydrogen peroxide and PACAP enabled the cells to survive and maintain the morphological characters of the neuron [53]. Neuro-inflammation was also investigated in Alzheimer’s disease. AD patients lose most of the endogenous anti-inflammatory agent norepinephrine in the microenvironment of the neocortex and hippocampus [54]. At the same time, PACAP is a neuropeptide with anti-inflammatory activity. This may be the other way PACAP could affect the development of AD. PACAP AND PARKINSON’S DISEASE Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Most PD patients are older than 60. In 1817, the English physician James Parkinson first described the clinical features of the disease [55]. Unlike
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AD patients, PD patients mainly exhibit movement disorder and other related issues such as a balance problem. The classical motor symptoms of PD are defined as tremor, bradykinesia (difficulty in initiating and executing movements) and muscle rigidity [56]. These symptoms are caused by the reduction in the release of neurotransmitters such as dopamine because of the lesion in the brain region substantia nigra pars compacta (SNpc) [57]. Lewy bodies, which are composed mainly of -synuclein, are also a key pathological feature of PD [58]. The causes of Parkinson’s disease have not been specified yet. Only a small proportion of PD cases are a result of known genetic factors. Many other factors may increase the risk of PD, but no common causes of the disease have been proven. Pesticide and heavy metal exposure has been proposed to cause a risk of developing PD [59-61]. As with other neurodegenerative diseases, PD is closely related to oxidative stress as well [62,63]. The mouse models of PD are obtained by the use of two neurotoxins: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH) [64]. MPTP seems to cause death of dopaminergic neurons in the SNpc, while METH inhibits oxidative phosphorylation in dopaminergic neurons [63,65]. In addition, a rat model of PD, which is induced by neurotoxin 6-hydroxydopamine (6-OHDA), is also used in many studies [66]. PACAP began to be used in the studies of PD since it is demonstrated to protect neurons from apoptosis. Incubation of the cerebellar granule cells with PACAP prevented toxin-induced apoptotic cell death. The toxic factors include 4-hydroxynonenal, ethanol, H2O2 and ceramides [53,67-70]. In in vitro studies of PD, PACAP protected PC12 cells against rotenone neurotoxicity. Rotenone is a mitochondrial complex inhibitor and is associated with PD. Chronic exposure of PC12 cells to rotenone resulted in dose-dependent cell apoptosis. PACAP reduced the death of PC12 cells through the PAC1-mediated PKA and MAPK pathway [71]. PACAP also resisted inflammatory-mediated toxicity induced by salsolinol in SH-SY5Y dopaminergic cells [72]. The protective effect of PACAP has been investigated in experimental PD models as well. In a rat model of PD, in which 6-OHDA induced the lesion of the substantia nigra, PACAP treatment rescued the dopaminergic neurons and improved behavioral symptoms [73,74]. In MPTP-induced PD mice, the treatment of PACAP slowed down the memory impairment in the spatial reference version of the water maze. The effects of PACAP may be involved in the modulation of K (ATP) subunits and D2 receptors in the striatum [75]. More and more evidence from patient and animal studies has proved the importance of inflammation in the pathogenesis of PD [76,77]. The microglia are the immune cells of the CNS and play a key role in brain inflammation [78-80]. The risk factors of PD such as pesticides and heavy metals could trigger microglia to produce reactive oxygen species (ROS) and/or proinflammatory factors, which harm DA neurons more than other cell types [81]. Thus, inhibition of microglial activation may help the treatment of PD by reducing the toxic factors for the
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DA neuron. PACAP could inhibit ROS production induced by LPS through blocking NADPH oxidase in primary rat mesencephalic neuron-glia cultures [82]. This study revealed another way that PACAP could protect DA neurons in the development of PD. CONCLUSIONS In sum, PACAP displays a significant neuroprotective and neurotrophic potential through both direct and indirect ways in a number of in vitro and in vivo neurodegenerative models. PACAP could inhibit apoptosis gene activities, ROS production and brain inflammation to help neuron survival. Above, we mentioned a PACAP27-specific receptor, FPR2. It has not been well studied in the neurodegenerative diseases yet. In the neutrophil cells, PACAP27 stimulates intracellular calcium mobilization, CD11b surface up-regulation, chemotactic migration and ERK, Akt and MAPK phosphorylation through FPR2 [9,11]. It is possible that it is a new direction to investigate PACAP27 in neurodegenerative diseases (Fig. 1). Therefore, the endogenous PACAP is supposed to be an
Fig. 1. Schematic representation of the intracellular mechanisms that are likely to be involved in the neuroprotective and neurotrophic potential of PACAP.
element of the natural defense system. Furthermore, exogenous PACAP shows some potential to cross the blood-brain barrier. The next challenges include determining the safety dose, improving ways of delivery and stabilizing the peptide in fluids. The proper dose of administered PACAP as well as the specific
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region of delivery is important to reduce the side effects. Reducing the degradation of PACAP will lengthen the duration of the effect in the target region. Based on previous findings, and according to the view of the present authors, PACAP may become one of the great potential therapeutic agents in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. REFERENCES 1. Miyata, A., Arimura, A., Dahl, R.R., Minamino, N., Uehara, A., Jiang, L., Culler, M.D. and Coy, D.H. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem. Biophys. Res. Commun. 164 (1989) 567-574. 2. Vaudry, D., Falluel-Morel, A., Bourgault, S., Basille, M., Burel, D., Wurtz, O., Fournier, A., Chow, B.K., Hashimoto, H., Galas, L. and Vaudry, H. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev. 61 (2009) 283-357. 3. Arimura, A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn. J. Physiol. 48 (1998) 301-331. 4. Nowak, J.Z. and Zawilska, J.B. PACAP in avians: origin, occurrence, and receptors--pharmacological and functional considerations. Curr. Pharm. Des. 9 (2003) 467-481. 5. Rawlings, S.R. and Hezareh, M. Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP/vasoactive intestinal polypeptide receptors: actions on the anterior pituitary gland. Endocr. Rev. 17 (1996) 4-29. 6. Sherwood, N.M., Krueckl, S.L. and McRory, J.E. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr. Rev. 21 (2000) 619-670. 7. Miyata, A., Jiang, L., Dahl, R.D., Kitada, C., Kubo, K., Fujino, M., Minamino, N. and Arimura, A. 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 (1990) 643-648. 8. Harmar, A.J., Fahrenkrug, J., Gozes, I., Laburthe, M., May, V., Pisegna, J.R., Vaudry, D., Vaudry, H., Waschek, J.A. and Said, S.I. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br. J. Pharmacol. 166 (2012) 4-17. 9. El Zein, N., Badran, B. and Sariban, E. The neuropeptide pituitary adenylate cyclase activating polypeptide modulates Ca2+ and pro-inflammatory functions in human monocytes through the G protein-coupled receptors VPAC-1 and formyl peptide receptor-like 1. Cell Calcium 43 (2008) 270-284.
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10. Cattaneo, F., Parisi, M. and Ammendola, R. Distinct signaling cascades elicited by different formyl peptide receptor 2 (FPR2) agonists. Int. J. Mol. Sci. 14 (2013) 7193-7230. 11. Kim, Y., Lee, B.D., Kim, O., Bae, Y.S., Lee, T., Suh, P.G. and Ryu, S.H. Pituitary adenylate cyclase-activating polypeptide 27 is a functional ligand for formyl peptide receptor-like 1. J. Immunol. 176 (2006) 2969-2975. 12. Spengler, D., Waeber, C., Pantaloni, C., Holsboer, F., Bockaert, J., Seeburg, P.H. and Journot, L. Differential signal transduction by five splice variants of the PACAP receptor. Nature 365 (1993) 170-175. 13. Zhou, C.J., Shioda, S., Yada, T., Inagaki, N., Pleasure, S.J. and Kikuyama, S. PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signaling pathways. Curr. Protein Pept. Sci. 3 (2002) 423-439. 14. Arimura, A., Somogyvari-Vigh, A., Miyata, A., Mizuno, K., Coy, D.H. and Kitada, C. Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology 129 (1991) 2787-2789. 15. Ressler, K.J., Mercer, K.B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S.D., Kilaru, V., Smith, A.K., Myers, A.J., Ramirez, M., Engel, A., Hammack, S.E., Toufexis, D., Braas, K.M., Binder, E.B. and May, V. Posttraumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470 (2011) 492-497. 16. Shen, S., Gehlert, D.R. and Collier, D.A. PACAP and PAC1 receptor in brain development and behavior. Neuropeptides 47 (2013) 421-430. 17. Almli, L.M., Mercer, K.B., Kerley, K., Feng, H., Bradley, B., Conneely, K.N. and Ressler, K.J. ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 162B (2013) 262-272. 18. Banks, W.A., Moinuddin, A. and Morley, J.E. Regional transport of TNFalpha across the blood-brain barrier in young ICR and young and aged SAMP8 mice. Neurobiol. Aging 22 (2001) 671-676. 19. Banks, W.A., Farr, S.A. and Morley, J.E. Permeability of the blood-brain barrier to albumin and insulin in the young and aged SAMP8 mouse. J. Gerontol. A Biol Sci. Med. Sci. 55 (2000) B601-606. 20. Moinuddin, A., Morley, J.E. and Banks, W.A. Regional variations in the transport of interleukin-1alpha across the blood-brain barrier in ICR and aging SAMP8 mice. Neuroimmunomodulation 8 (2000) 165-170. 21. Ji, R., Tian, S., Lu, H.J., Lu, Q., Zheng, Y., Wang, X., Ding, J., Li, Q. and Lu, Q. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation. J. Immunology 191 (2013) 6165-6177. 22. Banks, W.A. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr. Pharm. Des. 11 (2005) 973-984. 23. Born, J., Lange, T., Kern, W., McGregor, G.P., Bickel, U. and Fehm, H.L. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 5 (2002) 514-516.
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51. Rat, D., Schmitt, U., Tippmann, F., Dewachter, I., Theunis, C., Wieczerzak, E., Postina, R., van Leuven, F., Fahrenholz, F. and Kojro, E. Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice. FASEB J. 25 (2011) 3208-3218. 52. Pohanka, M. Alzheimer s disease and oxidative stress: a review. Curr. Med. Chem. 21 (2013) 356-364. 53. Vaudry, D., Pamantung, T.F., Basille, M., Rousselle, C., Fournier, A., Vaudry, H., Beauvillain, J.C. and Gonzalez, B.J. PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. Eur. J. Neurosci. 15 (2002) 1451-1460. 54. Heneka, M.T., Nadrigny, F., Regen, T., Martinez-Hernandez, A., Dumitrescu-Ozimek, L., Terwel, D., Jardanhazi-Kurutz, D., Walter, J., Kirchhoff, F., Hanisch, U.K. and Kummer, M.P. Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc. Natl. Acad. Sci. U.S.A. 107 (2010) 6058-6063. 55. De Lau, L.M. and Breteler, M.M. Epidemiology of Parkinson's disease. Lancet Neurol. 5 (2006) 525-535. 56. Gelb, D.J., Oliver, E. and Gilman, S. Diagnostic criteria for Parkinson disease. Arch. Neurol. 56 (1999) 33-39. 57. Jankovic, J. Parkinson's disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79 (2008) 368-376. 58. McKeith, I.G., Dickson, D.W., Lowe, J., Emre, M., O'Brien, J.T., Feldman, H., Cummings, J., Duda, J.E., Lippa, C., Perry, E.K., Aarsland, D., Arai, H., Ballard, C.G., Boeve, B., Burn, D.J., Costa, D., Del Ser, T., Dubois, B., Galasko, D., Gauthier, S., Goetz, C.G., Gomez-Tortosa, E., Halliday, G., Hansen, L.A., Hardy, J., Iwatsubo, T., Kalaria, R.N., Kaufer, D., Kenny, R.A., Korczyn, A., Kosaka, K., Lee, V.M., Lees, A., Litvan, I., Londos, E., Lopez, O.L., Minoshima, S., Mizuno, Y., Molina, J.A., Mukaetova-Ladinska, E.B., Pasquier, F., Perry, R.H., Schulz, J.B., Trojanowski, J.Q., Yamada, M. and Consortium on, D.L.B. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65 (2005) 1863-1872. 59. Forte, G., Bocca, B., Senofonte, O., Petrucci, F., Brusa, L., Stanzione, P., Zannino, S., Violante, N., Alimonti, A. and Sancesario, G. Trace and major elements in whole blood, serum, cerebrospinal fluid and urine of patients with Parkinson's disease. J. Neural. Transm. 111 (2004) 1031-1040. 60. Witholt, R., Gwiazda, R.H. and Smith, D.R. The neurobehavioral effects of subchronic manganese exposure in the presence and absence of preparkinsonism. Neurotoxicol. Teratol. 22 (2000) 851-861. 61. Matusch, A., Depboylu, C., Palm, C., Wu, B., Hoglinger, G.U., Schafer, M.K. and Becker, J.S. Cerebral bioimaging of Cu, Fe, Zn, and Mn in the MPTP mouse model of Parkinson's disease using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). J. Am. Soc. Mass Spectrom. 21 (2010) 161-171.
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62. Goldman, S.M. Environmental toxins and Parkinson's disease. Annu. Rev. Pharmacol. Toxicol. 54 (2014) 141-164. 63. Chin, M.H., Qian, W.J., Wang, H., Petyuk, V.A., Bloom, J.S., Sforza, D.M., Lacan, G., Liu, D., Khan, A.H., Cantor, R.M., Bigelow, D.J., Melega, W.P., Camp, D.G., 2nd, Smith, R.D. and Smith, D.J. Mitochondrial dysfunction, oxidative stress, and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson's disease. J. Proteome Res. 7 (2008) 666-677. 64. Gerlach, M. and Riederer, P. Animal models of Parkinson's disease: an empirical comparison with the phenomenology of the disease in man. J. Neural Transm. 103 (1996) 987-1041. 65. Lotharius, J. and Brundin, P. Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. Nat. Rev. Neurosci. 3 (2002) 932-942. 66. Deumens, R., Blokland, A. and Prickaerts, J. Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp. Neurol. 175 (2002) 303-317. 67. Ito, Y., Arakawa, M., Ishige, K. and Fukuda, H. Comparative study of survival signal withdrawal- and 4-hydroxynonenal-induced cell death in cerebellar granule cells. Neurosci. Res. 35 (1999) 321-327. 68. Vaudry, D., Rousselle, C., Basille, M., Falluel-Morel, A., Pamantung, T.F., Fontaine, M., Fournier, A., Vaudry, H. and Gonzalez, B.J. Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death. Proc. Natl. Acad. Sci. U.S.A. 99 (2002) 6398-6403. 69. Falluel-Morel, A., Vaudry, D., Aubert, N., Galas, L., Benard, M., Basille, M., Fontaine, M., Fournier, A., Vaudry, H. and Gonzalez, B.J. Pituitary adenylate cyclase-activating polypeptide prevents the effects of ceramides on migration, neurite outgrowth, and cytoskeleton remodeling. Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 2637-2642. 70. Meng, L., Chen, X., Yang, R. and Ji, R. Role of BDNF in the taste system. Front. Biol. 9 (2014) 481-488. 71. Wang, G., Qi, C., Fan, G.H., Zhou, H.Y. and Chen, S.D. PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone. FEBS Lett. 579 (2005) 40054011. 72. Brown, D., Tamas, A., Reglodi, D. and Tizabi, Y. PACAP protects against salsolinol-induced toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson's disease. J. Mol. Neurosci. 50 (2013) 600-607. 73. Reglodi, D., Tamas, A., Lubics, A., Szalontay, L. and Lengvari, I. Morphological and functional effects of PACAP in 6-hydroxydopamineinduced lesion of the substantia nigra in rats. Regul. Pept. 123 (2004) 85-94. 74. Reglodi, D., Lubics, A., Tamas, A., Szalontay, L. and Lengvari, I. Pituitary adenylate cyclase activating polypeptide protects dopaminergic neurons and
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Volume 20 (2015) pp 265-278 DOI: 10.1515/cmble-2015-0008 © 2014 by the University of Wrocław, Poland
Mini review THERAPEUTIC POTENTIAL OF PACAP FOR NEURODEGENERATIVE DISEASES RONGQIANG YANG1, XIN JIANG2, RUI JI1, LINGBIN MENG3, FULI LIU4, XIAOLEI CHEN5,* and YING XIN6,* 1 Department of Biochemistry and Molecular Biology, University of Louisville, School of Medicine, Louisville, KY 40202, USA, 2Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, 130021, China, 3 Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA, 4Department of Physiology and Neurobiology, Geisel Medical School at Dartmouth, Lebanon, NH 03756, USA, 5Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA, 6Ying Xin, Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China Abstract: Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the central and peripheral nervous system. PACAP can initiate multiple signaling pathways through binding with three class B G-protein coupled receptors, PAC1, VPAC1 and VPAC2. Previous studies have revealed numerous biological activities of PACAP in the nervous system. PACAP acts as a neurotransmitter, neuromodulator and neurotrophic factor. Recently, its neuroprotective potential has been demonstrated in numerous in vitro and in vivo studies. Furthermore, evidence suggests that PACAP might move across the blood-brain barrier in amounts sufficient to affect the brain functions. Therefore, PACAP has been examined as a potential therapeutic method for neurodegenerative diseases. The present review summarizes the recent findings with special focus on the models of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Based on these observations, the administered PACAP inhibits pathological processes in models of AD and PD, and alleviates clinical symptoms. It thus offers a novel therapeutic approach for the treatment of AD and PD. * Authors for correspondence. Email: [email protected]; [email protected] Abbreviations used: AD – Alzheimer’s disease; Bcl-2 – B-cell lymphoma 2; BDNF – brain-derived neurotrophic factor; Caspase – cysteinyl aspartate-specific protease; cAMP – cyclic adenosine monophosphate; DA – dopamine; PACAP – pituitary adenylate cyclase activating polypeptide; PD – Parkinson’s disease; PAC1-R – PACAP-specific receptor
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Keywords: Pituitary adenylate cyclase activating polypeptide, Neurodegenerative diseases, Neuroprotective, Neurotrophic, Alzheimer’s disease, Parkinson’s disease PACAP AND ITS RECEPTORS Pituitary adenylate cyclase-activating polypeptide (PACAP) was first isolated from ovine hypothalamic extracts by Dr. Arimura and colleagues in 1989 [1]. PACAP belongs to a superfamily of structurally related peptide hormones, which includes PACAP, vasoactive intestinal peptide (VIP), glucagon, glucagon-like peptide-1 (GLP1), glucagon-like peptide-2 (GLP2), glucose-dependent insulinotropic polypeptide (GIP), growth hormone-releasing hormone (GHRH) and peptide histidine isoleucine (PHI) (Table 1) [2]. Table 1. Primary structure of the different members of PACAP-VIP-secretin-GHRH superfamily in humans. PACAP38 PACAP27 VIP GLP1 GLP2 GIP GHRH Secretin Glucagon PHI
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVL- NH2 HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2 HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 HADGSFSDEMNTILDNLAARDFINWLIQTKITD -NH2 YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-NH2 YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2 HSDGTFTSELSRLREGARLLQGLV-NH2 HSQGTFTSDYSKYLDSRRAQFVQWLMNT-NH2 HADGVFTSDYSRLLGQISAKKYLESLI-NH2
PACAP was shown to have 38 amino acids, but was also present in a shorter biologically active form with 27 amino acids of the N-terminal. PACAP is one of the most conservative peptides in the vertebrate lineage (Table 2) [3-6], which suggests that it must have important biological functions [7]. Characterization of the PACAP binding sites led to cloning of three PACAP receptors, PAC1, VPAC1 and VPAC2. VPAC1 and VPAC2 were shared with VIP, whereas PAC1 showed a specific affinity with PACAP [8]. VPAC1, VPAC2 and PAC1 all belong to class B, G protein coupled receptor families (GPCRs), which have a larger N-terminal extracellular domain for ligand recognition. Recently, PACAP27 was found to bind with another receptor, FPR2. FPR2 is widely expressed in the brain and belongs to the GPCR family as well [9-11]. The PAC1 gene expresses numerous splicing variants, including the presence or absence of the HOP and HIP cassette in the third intracellular loop [12]. The variants of PAC1 show differences in signal transduction pathways. Binding with these receptors, PACAP can increase intracellular concentrations of cAMP by increasing the activity of adenylate cyclase through a Gs protein. PACAP can also initiate intracellular signaling through PKC/MAPK pathways [13].
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Table 2. Comparison of the primary structure of PACAP from a protochordate to various vertebrate species. Bold letters indicate different amino acids compared to human PACAP. Human Mouse Chicken Frog Salmon Catfish Sturgeon Stingray Tunicate1 Tunicate2
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HIDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRIKNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYRQRYRNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGRRYRQRFRNK-NH2 HSDGIFTDSYSRYREQMAVKKYLAAVLGKRYRQRIRNK-NH2 HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKPKIRNSGRRVFY-NH2 HSDGIFTDSYSRYRNQMAVKKYLAAVL-NH2 HSDGIFTDSYSRYRNQMAVKKYINALL-NH2
After the isolation of PACAP, Dr. Arimura and his colleagues investigated the distribution of the peptide by immunoassay and PCR [14]. In the central nervous system (CNS), PACAP is expressed in both cell bodies and fibers in various brain regions, such as the hypothalamus, cerebral cortex, amygdala and hippocampus. PACAP can be detected in the brain as early as embryonic day 14. PACAP is not co-localized with VIP in most of the brain regions. PACAP receptors were found in many brain structures as well [2]. Over the last couple of decades, many studies have investigated physiological functions of PACAP in the CNS because of the high concentrations of the peptide and its receptors in the brain. Previous data provide clear evidence that PACAP and its receptors mediated neuron proliferation, plasticity and release of neurotrophic factors. Furthermore, PACAP plays a key role in behavioral and neuropsychiatric disorders, such as post-traumatic stress disorder [15-17]. Therefore, PACAP has been widely studied in different neurodegenerative disease models. NEURODEGENERATIVE DISEASES Neurodegenerative diseases, which are caused by progressive loss of neurological function, are one of the rising global problems for the aged. Common types of neurodegenerative diseases include Alzheimer’s, Parkinson’s and Huntington’s diseases and amyotrophic lateral sclerosis (ALS). The mechanisms of development of the disease are still unclear in spite of many years’ studies. Currently, we have no effective diagnostic method to identify the patients unless they are in advanced stages of the neurodegenerative diseases. We also lack effective therapies for stopping and/or healing the neurodegenerative diseases. The design of drugs for the treatment of these diseases is also a major challenge for health professionals, because of the existence of the blood-brain barrier (BBB). Previous studies have demonstrated that some peptides can cross the BBB, including insulin, TNF- and IL-1 [18-22]. The problems with the use
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of peptides as therapeutics are rapid degradation in blood and low bioavailability. However, recent studies have shown that intranasal administration could bypass the BBB and produce lower levels in blood [23,24]. PACAP, which can be transported across the BBB to some extent like some other peptides, has the potential to treat neurodegenerative diseases [25-28]. Our review will focus on the effects of PACAP for Alzheimer’s and Parkinson’s diseases, which are more common than the other neurodegenerative diseases. PACAP AND ALZHEIMER’S DISEASE Alzheimer’s disease was named after the German neurologist Alois Alzheimer, who first described the clinical and pathological features of this unusual brain disease in 1906 [29]. After one hundred years, Alzheimer’s disease has become the most common form of age-related neurodegenerative disease in the world. In 2006, about 26.6 million people suffered from AD. It has been estimated that the number will have quadrupled by 2050 [30,31]. Alzheimer’s disease is not only a physiological but also a social problem due to the increasing time, funds and labor required to deal with these patients. The common symptoms of AD include short- and long-term memory loss, confusion, irritability, aggression, mood swings and trouble with language. To confirm AD, a brain scan and examination of brain tissue are required [32]. In terms of the pathological hallmarks, AD is associated with amyloid plaques and neurofibrillary tangles [33]. Although AD has been investigated for more than one hundred years, the exact mechanism of AD development is still unclear. Recently most researchers have agreed that AD arises from a combination of various factors including genetic, behavioral, dietary and environmental. Several competing hypotheses have been proposed to explain the cause of Alzheimer’s disease. PACAP and its receptors are highly expressed in the brain regions affected most by Alzheimer’s disease. Evidence indicates that PACAP may be involved at multiple levels in the pathology of AD. The cholinergic hypothesis, which proposes that AD is caused by reduced levels of the neurotransmitter acetylcholine (Ach), is the oldest hypothesis of Alzheimer’s disease [34]. It is based on the presynaptic deficits found in the brains of patients and studies of the role of Ach in animal and human behavior. Previous studies revealed that PACAP cooperating with nerve growth factor (NGF) maintained cholinergic function through increasing choline acetyltransferase (ChAT) activity [35-37]. However, this hypothesis is not widely supported because the drugs based on it have not been very effective. In 1991, a new hypothesis proposed that AD is caused by deposits of extracellular -amyloid (A) [38,39]. The amyloid hypothesis has dominated research on AD for the past 20 years. The hypothesis has received various supporting evidence, including from a genetic mouse model and Down syndrome patients, who exhibit AD by 40 years old [40]. A is generated from the amyloid precursor protein (APP) through cleavage by -secretase. Apart from the toxic
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A, the APP also produces a neurotrophic and neuroprotective factor, soluble N-terminal APP fragments (sAPP), through -secretase [41,42]. The cerebrospinal fluid (CSF) of AD patients exhibits a decreased sAPP level [43,44]. In addition, exogenous sAPP also improves the memory performance [45,46]. Numerous studies have shown that PACAP also has relevance in the amyloid hypothesis. In cell culture studies, PACAP protected against -amyloid toxicity in PC-12 and astrocyte cells [47]. In cultured neuroblastoma cells, PACAP strongly increases the -secretase activity to release more sAPP [48]. Many animal AD models have been developed based on the amyloid hypothesis. The human APP transgenic models are the most widely used models. In a gene expression screen of three mouse models of AD, PACAP, together with BDNF and ILGF 1 receptor, was one of the 3 genes that were down-regulated [49]. In a recent study using human AD samples, PACAP expression was reduced in these patients [50]. PACAP protected against -amyloid toxicity in cultured mouse cortical neurons. PACAP activates the AMPK pathway to enhance sirt3, which is relevant in AD [50]. PACAP stimulates nonamyloidogenic processing of APP by enhancing -secretase to increase sAPP production and to reduce sAPP secretion. Intranasal administration was used for applying PACAP into the brain of APP-transgenic mice. In the novel object recognition test, PACAPtreated APP transgenic mice spent about 30% more time with the novel object than control APP transgenic mice. Intranasal PACAP was effective in improving memory in the aged SAMP8 mouse, which is a natural mutation with learning and memory defects. Long-term PACAP treatment of APP [V717I]-transgenic mice increased secretion of the neuroprotective sAPP and positively influenced expression levels of AD-relevant genes and proteins, such as BDNF, Bcl-2, and RAGE [51]. PACAP also indirectly regulated A in the brain by up-regulating somatostatin and neprilysin. Besides the amyloid hypothesis, oxidative stress has been reported to enhance AD processing [52]. PACAP could protect cells from apoptosis caused by oxidative stress. For example, co-incubation of the cerebellar granule cells with hydrogen peroxide and PACAP enabled the cells to survive and maintain the morphological characters of the neuron [53]. Neuro-inflammation was also investigated in Alzheimer’s disease. AD patients lose most of the endogenous anti-inflammatory agent norepinephrine in the microenvironment of the neocortex and hippocampus [54]. At the same time, PACAP is a neuropeptide with anti-inflammatory activity. This may be the other way PACAP could affect the development of AD. PACAP AND PARKINSON’S DISEASE Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Most PD patients are older than 60. In 1817, the English physician James Parkinson first described the clinical features of the disease [55]. Unlike
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AD patients, PD patients mainly exhibit movement disorder and other related issues such as a balance problem. The classical motor symptoms of PD are defined as tremor, bradykinesia (difficulty in initiating and executing movements) and muscle rigidity [56]. These symptoms are caused by the reduction in the release of neurotransmitters such as dopamine because of the lesion in the brain region substantia nigra pars compacta (SNpc) [57]. Lewy bodies, which are composed mainly of -synuclein, are also a key pathological feature of PD [58]. The causes of Parkinson’s disease have not been specified yet. Only a small proportion of PD cases are a result of known genetic factors. Many other factors may increase the risk of PD, but no common causes of the disease have been proven. Pesticide and heavy metal exposure has been proposed to cause a risk of developing PD [59-61]. As with other neurodegenerative diseases, PD is closely related to oxidative stress as well [62,63]. The mouse models of PD are obtained by the use of two neurotoxins: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH) [64]. MPTP seems to cause death of dopaminergic neurons in the SNpc, while METH inhibits oxidative phosphorylation in dopaminergic neurons [63,65]. In addition, a rat model of PD, which is induced by neurotoxin 6-hydroxydopamine (6-OHDA), is also used in many studies [66]. PACAP began to be used in the studies of PD since it is demonstrated to protect neurons from apoptosis. Incubation of the cerebellar granule cells with PACAP prevented toxin-induced apoptotic cell death. The toxic factors include 4-hydroxynonenal, ethanol, H2O2 and ceramides [53,67-70]. In in vitro studies of PD, PACAP protected PC12 cells against rotenone neurotoxicity. Rotenone is a mitochondrial complex inhibitor and is associated with PD. Chronic exposure of PC12 cells to rotenone resulted in dose-dependent cell apoptosis. PACAP reduced the death of PC12 cells through the PAC1-mediated PKA and MAPK pathway [71]. PACAP also resisted inflammatory-mediated toxicity induced by salsolinol in SH-SY5Y dopaminergic cells [72]. The protective effect of PACAP has been investigated in experimental PD models as well. In a rat model of PD, in which 6-OHDA induced the lesion of the substantia nigra, PACAP treatment rescued the dopaminergic neurons and improved behavioral symptoms [73,74]. In MPTP-induced PD mice, the treatment of PACAP slowed down the memory impairment in the spatial reference version of the water maze. The effects of PACAP may be involved in the modulation of K (ATP) subunits and D2 receptors in the striatum [75]. More and more evidence from patient and animal studies has proved the importance of inflammation in the pathogenesis of PD [76,77]. The microglia are the immune cells of the CNS and play a key role in brain inflammation [78-80]. The risk factors of PD such as pesticides and heavy metals could trigger microglia to produce reactive oxygen species (ROS) and/or proinflammatory factors, which harm DA neurons more than other cell types [81]. Thus, inhibition of microglial activation may help the treatment of PD by reducing the toxic factors for the
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DA neuron. PACAP could inhibit ROS production induced by LPS through blocking NADPH oxidase in primary rat mesencephalic neuron-glia cultures [82]. This study revealed another way that PACAP could protect DA neurons in the development of PD. CONCLUSIONS In sum, PACAP displays a significant neuroprotective and neurotrophic potential through both direct and indirect ways in a number of in vitro and in vivo neurodegenerative models. PACAP could inhibit apoptosis gene activities, ROS production and brain inflammation to help neuron survival. Above, we mentioned a PACAP27-specific receptor, FPR2. It has not been well studied in the neurodegenerative diseases yet. In the neutrophil cells, PACAP27 stimulates intracellular calcium mobilization, CD11b surface up-regulation, chemotactic migration and ERK, Akt and MAPK phosphorylation through FPR2 [9,11]. It is possible that it is a new direction to investigate PACAP27 in neurodegenerative diseases (Fig. 1). Therefore, the endogenous PACAP is supposed to be an
Fig. 1. Schematic representation of the intracellular mechanisms that are likely to be involved in the neuroprotective and neurotrophic potential of PACAP.
element of the natural defense system. Furthermore, exogenous PACAP shows some potential to cross the blood-brain barrier. The next challenges include determining the safety dose, improving ways of delivery and stabilizing the peptide in fluids. The proper dose of administered PACAP as well as the specific
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region of delivery is important to reduce the side effects. Reducing the degradation of PACAP will lengthen the duration of the effect in the target region. Based on previous findings, and according to the view of the present authors, PACAP may become one of the great potential therapeutic agents in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. REFERENCES 1. Miyata, A., Arimura, A., Dahl, R.R., Minamino, N., Uehara, A., Jiang, L., Culler, M.D. and Coy, D.H. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem. Biophys. Res. Commun. 164 (1989) 567-574. 2. Vaudry, D., Falluel-Morel, A., Bourgault, S., Basille, M., Burel, D., Wurtz, O., Fournier, A., Chow, B.K., Hashimoto, H., Galas, L. and Vaudry, H. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev. 61 (2009) 283-357. 3. Arimura, A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn. J. Physiol. 48 (1998) 301-331. 4. Nowak, J.Z. and Zawilska, J.B. PACAP in avians: origin, occurrence, and receptors--pharmacological and functional considerations. Curr. Pharm. Des. 9 (2003) 467-481. 5. Rawlings, S.R. and Hezareh, M. Pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP/vasoactive intestinal polypeptide receptors: actions on the anterior pituitary gland. Endocr. Rev. 17 (1996) 4-29. 6. Sherwood, N.M., Krueckl, S.L. and McRory, J.E. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr. Rev. 21 (2000) 619-670. 7. Miyata, A., Jiang, L., Dahl, R.D., Kitada, C., Kubo, K., Fujino, M., Minamino, N. and Arimura, A. 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 (1990) 643-648. 8. Harmar, A.J., Fahrenkrug, J., Gozes, I., Laburthe, M., May, V., Pisegna, J.R., Vaudry, D., Vaudry, H., Waschek, J.A. and Said, S.I. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br. J. Pharmacol. 166 (2012) 4-17. 9. El Zein, N., Badran, B. and Sariban, E. The neuropeptide pituitary adenylate cyclase activating polypeptide modulates Ca2+ and pro-inflammatory functions in human monocytes through the G protein-coupled receptors VPAC-1 and formyl peptide receptor-like 1. Cell Calcium 43 (2008) 270-284.
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