Advertisement

Neurotoxicity Research

, Volume 33, Issue 4, pp 702–715 | Cite as

Alteration of the PAC1 Receptor Expression in the Basal Ganglia of MPTP-Induced Parkinsonian Macaque Monkeys

  • M. Feher
  • B. Gaszner
  • A. Tamas
  • A. L. Gil-Martinez
  • E. Fernandez-Villalba
  • M. T. Herrero
  • D. ReglodiEmail author
ORIGINAL ARTICLE

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson’s disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson’s disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson’s disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson’s disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP-treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with l-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease.

Keywords

Parkinson’s disease PACAP Caudate Putamen Pallidum Cortex 

Notes

Acknowledgments

Hungarian Brain Research Program—KTIA_13_NAP-A-III/5, 2017-1.2.1-NKP-2017-00002, GINOP-2.3.2-15-2016-00050 “PEPSYS,” Spanish Ministry of Science and Innovation (FIS PI13 01293; ISCIII Plan Estatal de I+D+I 2013-2016), Fundacion Seneca (FS/19540/PI/14), and IMIB (Biomedical Research Institute of Murcia, MTH). The National Research, Development and Innovation Fund K119759 and NKFIH-124188, PTE AOK Research Grant No. KA-2017-01, AOK KA Research Grants, TAMOP 4.2.4.A/2-11-1-2012-0001 “National Excellence Program,” UNKP-16-4-IV New National Excellence Program of the Ministry of Human Capacities, and Centre for Neuroscience, University of Pecs. EFOP-3.6.1.-16-2016-00004, Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pecs, MTA-TKI 14016, Bolyai Scholarship. The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pecs, Hungary. Authors are thankful to Miss Aniko Kiss for her excellent tachnical contribution to immunolabelings.

Compliance with Ethical Standards

All studies were approved by the Ethical Committee of the University of Murcia and carried out in accordance with the guidelines of the European Convention for the protection of Vertebrate Animals used for Experimental and other scientific purposes of the Council of Europe (no. 123, June 15th, 2006) and the European Communities Council Directive 2010/63/ECC.

References

  1. Banki E, Sosnowska D, Tucsek Z, Gautam T, Toth P, Tarantini S, Tamas A, Helyes Z, Reglodi D, Sonntag WE, Csiszar A, Ungvari Z (2015) Age-related decline of autocrine pituitary adenylate cyclase-activating polypeptide impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 70(6):665–674.  https://doi.org/10.1093/gerona/glu116 CrossRefPubMedGoogle Scholar
  2. Barcia C, de Pablos V, Bautista-Hernández V, Sánchez-Bahillo A, Bernal I, Fernández-Villalba E, Martín J, Bañón R, Fernández-Barreiro A, Herrero MT (2005) Increased plasma levels of TNF-alpha but not of IL1-beta in MPTP-treated monkeys one year after the MPTP administration. Parkinsonism Relat Disord 11(7):435–439.  https://doi.org/10.1016/j.parkreldis.2005.05.006 CrossRefPubMedGoogle Scholar
  3. Barcia C, Ros CM, Ros-Bernal F, Gomez A, Annese V, Carrillo-de Sauvage MA, Yuste JE, Campuzano CM, de Pablos V, Fernández-Villalba E, Herrero MT (2013) Persistent phagocytic characteristics of microglia in the substantia nigra of long-term parkinsonian macaques. J Neuroimmunol 261(1-2):60–66.  https://doi.org/10.1016/j.jneuroim.2013.05.001 CrossRefPubMedGoogle Scholar
  4. Bortolanza M, Bariotto-Dos-Santos KD, Dos-Santos-Pereira M, da Silva CA, Del-Bel E (2016) Antidyskinetic effect of 7-nitroindazole and sodium nitroprusside associated with amantadine in a rat model of Parkinson’s disease. Neurotox Res 30(1):88–100.  https://doi.org/10.1007/s12640-016-9618-4 CrossRefPubMedGoogle Scholar
  5. 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(3):600–607.  https://doi.org/10.1007/s12031-013-0015-7 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brown D, Tamas A, Reglodi D, Tizabi Y (2014) PACAP protects against inflammatory-mediated toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson’s disease. Neurotox Res 26(3):230–239.  https://doi.org/10.1007/s12640-014-9468-x CrossRefPubMedGoogle Scholar
  7. Chung YC, Seo H, Sonntag KC, 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(13):1709–1725.  https://doi.org/10.1093/hmg/ddi178 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Deguil J, Jailloux D, Page G, Fauconneau B, Houeto JL, Philippe M, Muller JM, 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(9):2017–2025.  https://doi.org/10.1002/jnr.21318 CrossRefPubMedGoogle Scholar
  9. Deguil J, Chavant F, Lafay-Chebassier C, Pérault-Pochat MC, Fauconneau B, Pain S (2010) Neuroprotective effect of PACAP on translational control alteration and cognitive decline in MPTP parkinsonian mice. Neurotox Res 17(2):142–155.  https://doi.org/10.1007/s12640-009-9091-4 CrossRefPubMedGoogle Scholar
  10. Doan ND, Chatenet D, Létourneau M, Vaudry H, Vaudry D, Fournier A (2012) Receptor-independent cellular uptake of pituitary adenylate cyclase-activating polypeptide. Biochim Biophys Acta 1823(4):940–949.  https://doi.org/10.1016/j.bbamcr.2012.02.001 CrossRefPubMedGoogle Scholar
  11. Falluel-Morel A, Tascau LI, Sokolowksi K, Braet P, DiCicco-Bloom E (2008) Granule cell survival is deficient in PAC1−/− mutant cerebellum. J Mol Neurosci 36(1-3):38–44.  https://doi.org/10.1007/s12031-008-9066-6 CrossRefPubMedGoogle Scholar
  12. Faucheux BA, Herrero MT, Villares J, Levy R, Javoy-Agid F, Obeso JA, Hauw JJ, Agid Y, Hirsch EC (1995) Autoradiographic localization and density of [125I]ferrotransferrin binding sites in the basal ganglia of control subjects, patients with Parkinson's disease and MPTP-lesioned monkeys. Brain Res 691(1-2):115–124.  https://doi.org/10.1016/0006-8993(95)00629-5 CrossRefPubMedGoogle Scholar
  13. Gaszner B, Van Wijk DC, Korosi A, Jozsa R, Roubos EW, Kozicz T (2009) Diurnal expression of period 2 and urocortin 1 in neurones of the non-preganglionic Edinger-Westphal nucleus in the rat. Stress 12(2):115–124.  https://doi.org/10.1080/10253890802057221 CrossRefPubMedGoogle Scholar
  14. Gillardon F, Hata R, Hossmann KA (1998) Delayed up-regulation of Zac1 and PACAP type I receptor after transient focal cerebral ischemia in mice. Mol Brain Res 61(1-2):207–210.  https://doi.org/10.1016/S0169-328X(98)00202-2 CrossRefPubMedGoogle Scholar
  15. Giunta S, Castorina A, Bucolo C, Magro G, Drago F, D’Agata V (2012) Early changes in pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide and related receptors expression in retina of streptozotocin-induced diabetic rats. Peptides 37(1):32–39.  https://doi.org/10.1016/j.peptides.2012.06.004 CrossRefPubMedGoogle Scholar
  16. Gołembiowska K, Dziubina A, Kowalska M, Kamińska K (2009) Effect of adenosine A(2A) receptor antagonists on L-DOPA-induced hydroxyl radical formation in rat striatum. Neurotox Res 15(2):155–166.  https://doi.org/10.1007/s12640-009-9016-2 CrossRefPubMedGoogle Scholar
  17. Guillot TS, Richardson JR, Wang MZ, Li YJ, Taylor TN, Ciliax BJ, Zachrisson O, Mercer A, Miller GW (2008) PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity. Neuropeptides 42(4):423–434.  https://doi.org/10.1016/j.npep.2008.04.003 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Guo X, Yu R, Xu Y, Lian R, Yu Y, Cui Z, Ji Q, Chen J, Li Z, Liu H, Chen J (2016) PAC1R agonist maxadilan enhances hADSC viability and neural differentiation potential. J Cell Mol Med 20(5):874–890.  https://doi.org/10.1111/jcmm.12772 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hagino N (2008) Performance of PAC1-R heterozygous mice in memory tasks-II. J Mol Neurosci 36(1-3):208–219.  https://doi.org/10.1007/s12031-008-9101-7 CrossRefPubMedGoogle Scholar
  20. Halene TB, Kozlenkov A, Jiang Y, Mitchell AC, Javidfar B, Dincer A, Park R, Wiseman J, Croxson PL, Giannaris EL, Hof PR, Roussos P, Dracheva S, Hemby SE, Akbarian S (2016) NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure. Schizophr Res 170(2-3):235–244.  https://doi.org/10.1016/j.schres.2015.12.016 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Han P, Liang W, Baxter LC, Yin J, Tang Z, Beach TG, Caselli RJ, Reiman EM, Shi J (2014) Pituitary adenylate cyclase-activating polypeptide is reduced in Alzheimer disease. Neurology 82(19):1724–1728.  https://doi.org/10.1212/WNL.0000000000000417 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Han P, Caselli RJ, Baxter L, Serrano G, Yin J, Beach TG, Reiman EM, Shi J (2015) Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease. JAMA Neurol 72(3):333–339.  https://doi.org/10.1001/jamaneurol.2014.3625 CrossRefPubMedGoogle Scholar
  23. Han P, Nielsen M, Song M, Yin J, Permenter MR, Vogt JA, Engle JR, Dugger BN, Beach TG, Barnes CA, Shi J (2017) The impact of aging on brain pituitary adenylate cyclase activating polypeptide, pathology and cognition in mice and rhesus macaques. Front Aging Neurosci 9:180.  https://doi.org/10.3389/fnagi.2017.00180 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hannibal J, Georg B, Fahrenkrug J (2016) Altered circadian food anticipatory activity rhythms in PACAP receptor 1 (PAC1) deficient mice. PLoS One 11(1):e0146981.  https://doi.org/10.1371/journal.pone.0146981 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Herrero MT, Perez-Otano I, Oset C, Kastner A, Hirsch EC, Agid Y, Luquin MR, Obeso JA, Del Rio J (1993) GM-1 ganglioside promotes the recovery of surviving mid-brain dopaminergic neurons in MPTP-treated monkeys. Neuroscience 56(4):965–972.  https://doi.org/10.1016/0306-4522(93)90142-3 CrossRefPubMedGoogle Scholar
  26. Herrero MT, Augood SJ, Hirsch EC, Javoy-Agid F, Luquin MR, Agid Y, Obeso JA, Emson PC (1995) Effects of L-DOPA on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum. Neuroscience 68(4):1189–1198.  https://doi.org/10.1016/0306-4522(95)00120-8 CrossRefPubMedGoogle Scholar
  27. Herrero MT, Levy R, Ruberg M, Luquin MR, Villares J, Guillen J, Faucheux B, Javoy-Agid F, Guridi J, Agid Y, Obeso JA, Hirsch EC (1996a) Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum. Neurology 47(1):219–224.  https://doi.org/10.1212/WNL.47.1.219 CrossRefPubMedGoogle Scholar
  28. Herrero MT, Augood SJ, Asensi H, Hirsch EC, Agid Y, Obeso JA, Emson PC (1996b) Effects of L-DOPA-therapy on dopamine D2 receptor mRNA expression in the striatum of MPTP-intoxicated parkinsonian monkeys. Brain Res Mol Brain Res 42(1):149–155.  https://doi.org/10.1016/S0169-328X(96)00157-X CrossRefPubMedGoogle Scholar
  29. 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(2):148–152.  https://doi.org/10.1016/j.neulet.2010.08.039 CrossRefPubMedGoogle Scholar
  30. Jamen F, Laden JC, Bouschet T, Rodriguez-Henche N, Bockaert J, Brabet P (2000) Nerve growth factor upregulates the PA1 promoter by activating the MAP kinase pathway in rat PC12 cells. Ann N Y Acad Sci 921:390–394CrossRefPubMedGoogle Scholar
  31. Jamen F, Bouschet T, Laden JC, Bockaert J, Brabet P (2002) Up-regulation of the PACAP type-1 receptor (PAC1) promoter by neurotrophins in rat PC12 cells and mouse cerebellar granule cells via the Ras/mitogen-activated protein kinase cascade. J Neurochem 82(5):1199–1207CrossRefPubMedGoogle Scholar
  32. Jolivel V, Basille M, Aubert N, de Jouffrey S, Ancian P, Le Bigot JF, Noack P, Massonneau M, Fournier A, Vaudry H, Gonzalez BJ, Vaudry D (2009) Distribution and functional characterization of pituitary adenylate cyclase-activating polypeptide receptors in the brain of non-human primates. Neuroscience 160(2):434–451.  https://doi.org/10.1016/j.neuroscience.2009.02.028 CrossRefPubMedGoogle Scholar
  33. Joo KM, Chung YH, Kim MK, Nam RH, Lee BL, Lee KH, Cha CI (2004) Distribution of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC1, VPAC2, and PAC1 receptor) in the rat brain. J Comp Neurol 476(4):388–413.  https://doi.org/10.1002/cne.20231 CrossRefPubMedGoogle Scholar
  34. Kasica N, Podlasz P, Sundvik M, Tamas A, Reglodi D, Kaleczyc J (2016) Protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against oxidative stress in zebrafish hair cells. Neurotox Res 30(4):633–647.  https://doi.org/10.1007/s12640-016-9659-8 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kastner A, Herrero MT, Hirsch EC, Guillen J, Luquin MR, Javoy-Agid F, Obeso JA, Agid Y (1994) Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy. Ann Neurol 36(2):206–214.  https://doi.org/10.1002/ana.410360213 CrossRefPubMedGoogle Scholar
  36. Kormos V, Gaszner B (2013) Role of neuropeptides in anxiety, stress, and depression: from animals to humans. Neuropeptides 47(6):401–419.  https://doi.org/10.1016/j.npep.2013.10.014 CrossRefPubMedGoogle Scholar
  37. Kormos V, Gaspar L, Kovacs LA, Farkas J, Gaszner T, Csernus V, Balogh A, Hashimoto H, Reglodi D, Helyes Z, Gaszner B (2016) Reduced response to chronic mild stress in PACAP mutant mice is associated with blunted FosB expression in limbic forebrain and brainstem centers. Neuroscience 330:335–358.  https://doi.org/10.1016/j.neuroscience.2016.06.004 CrossRefPubMedGoogle Scholar
  38. Lam SY, Liu Y, Liong EC, Tipoe GL, Fung ML (2012) Upregulation of pituitary adenylate cyclase activating polypeptide and its receptor expression in the rat carotid body in chronic and intermittent hypoxia. Adv Exp Med Biol 758:301–306.  https://doi.org/10.1007/978-94-007-4584-1_41 CrossRefPubMedGoogle Scholar
  39. Lamine A, Letourneau M, Doan ND, Maucotel J, Couvineau A, Vaudry H, Chatenet D, Vaudry D, Fournier A (2016) Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model. Neuropharmacology 108:440–450.  https://doi.org/10.1016/j.neuropharm.2015.05.014 CrossRefPubMedGoogle Scholar
  40. Lee EH, Seo SR (2014) Neuroprotective roles of pituitary adenylate cyclase-activating polypeptide in neurodegenerative diseases. BMB Rep 47(7):369–375.  https://doi.org/10.5483/BMBRep.2014.47.7.086 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lee JC, Cho YJ, Kim J, Kim N, Kang BG, Cha CI, Joo KM (2010) Region-specific changes in the immunoreativity of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide reeptors VPAC2, and PAC1 receptor in the aged rats brains. Brain Res 1351:32–40.  https://doi.org/10.1016/j.brainres.2010.06.048 CrossRefPubMedGoogle Scholar
  42. Lin CH, Chiu L, Lee HT, Chiang CW, Liu SP, Hsu YH, Lin SZ, Hsu CY, Hsieh CH, Shyu WC (2015) PACAP38/PAC1 signaling induces bone marrow-derived cells homing to ishemic brain. Stem Cells 33(4):1153–1172.  https://doi.org/10.1002/stem.1915 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Maasz G, Zrinyi Z, Reglodi D, Petrovics D, Rivnyak A, Kiss T, Jungling A, Tamas A, Pirger Z (2017) Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective function in dopamine-based neurodegeneration developed in rat and snail parkinsonian models. Dis Model Mech 10(2):127–139.  https://doi.org/10.1242/dmm.027185 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Manavalan S, Getachew B, Manaye KF, Khundmiri SJ, Csoka AB, McKinley R, Tamas A, Reglodi D, Tizabi Y (2017) PACAP protects against ethanol and nicotine toxicity in SH-SY5Y cells: implications for drinking-smoking co-morbidity. Neurotox Res 32(1):8–13.  https://doi.org/10.1007/s12640-017-9727-8 CrossRefPubMedGoogle Scholar
  45. Marzagalli R, Leggio GM, Bucolo C, Pricoco E, Keay KA, Cardile V, Castorina S, Salomone S, Drago F, Castorina A (2016) Genetic blockade of the dopamine D3 receptor enhancces hippocampal expression of PACAP and receptors and alters their cortical distribution. Neuroscience 316:279–295.  https://doi.org/10.1016/j.neuroscience.2015.12.034 CrossRefPubMedGoogle Scholar
  46. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116(1):201–211PubMedGoogle Scholar
  47. Mustafa T, Jiang SZ, Eiden AM, Weihe E, Thislethwaite I, Eiden LE (2015) Impact of PACAP and PAC1 receptor deficiency on the neurochemical and ehavioral effects of acute and chronic restraint stress in male C57BL/6 mice. Stress 18(4):408–418.  https://doi.org/10.3109/10253890.2015.1025044 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Nakamachi T, Ohtaki H, Seki T, Yofu S, Kagami N, Hashimoto H, Shintani N, Baba A, Mark L, Lanekoff I, Kiss P, Farkas J, Reglodi D, Shioda S (2016) PACAP suppresses dry eye signs by stimulating tear secretion. Nat Commun 7:12034.  https://doi.org/10.1038/ncomms12034 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Ndlovu BC, Daniels WM, Mabandla MV (2016) Amelioration of L-dopa-associated dyskinesias with triterpenoic acid in a parkinsonian rat model. Neurotox Res 29(1):126–134.  https://doi.org/10.1007/s12640-015-9567-3 CrossRefPubMedGoogle Scholar
  50. Palkovits M, Somogyvari-Vigh A, Arimura A (1995) Concentrations of pituitary adenylate cyclase activating polypeptide (PACAP) in human brain nuclei. Brain Res 699(1):116–120.  https://doi.org/10.1016/0006-8993(95)00869-R CrossRefPubMedGoogle Scholar
  51. Pirger Z, Naskar S, Laszlo Z, Kemenes G, Reglodi D, Kemenes I (2014) Reversal of age-related learning deficiency by the vertebrate PACAP and IGF-1 in a novel invertebrate model of aging: the pond snail (Lymnaea stagnalis). J Gerontol A Biol Sci Med Sci 69(11):1331–1338.  https://doi.org/10.1093/gerona/glu068 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Racz B, Horvath G, Reglodi D, Gasz B, Kiss P, Gallyas F Jr, Sumegi B, Toth G, Nemeth A, Lubics A, Tamas A (2010) PACAP ameliorates oxidative stress in the chicken inner ear: an in vitro study. Regul Pept 160(1-3):91–98.  https://doi.org/10.1016/j.regpep.2009.12.003 CrossRefPubMedGoogle Scholar
  53. 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(1-2):303–312.  https://doi.org/10.1016/j.bbr.2003.09.007 CrossRefPubMedGoogle Scholar
  54. Reglodi D, Lubics A, Kiss P, Lengvari I, Gaszner B, Toth G, Hegyi O, Tamas A (2006a) Effect of PACAP in 6-OHDA-induced injury of the substantia nigra in intact young and ovariectomized female rats. Neuropeptides 40(4):265–274.  https://doi.org/10.1016/j.npep.2006.06.001 CrossRefPubMedGoogle Scholar
  55. Reglodi D, Tamas A, Lengvari I, Toth G, Szalontay L, Lubics A (2006b) Comparative study on the effects of PACAP in young, aging, and castrated males in a rat model of Parkinson’s disease. Ann N Y Acad Sci 1070(1):518–524.  https://doi.org/10.1196/annals.1317.072 CrossRefPubMedGoogle Scholar
  56. Reglodi D, Kiss P, Lubics A, Tamas A (2011) Review of the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. Curr Pharm Des 17(10):962–972.  https://doi.org/10.2174/138161211795589355 CrossRefPubMedGoogle Scholar
  57. Reglodi D, Kiss P, Szabadfi K, Atlasz T, Gabriel R, Horvath G, Szakaly P, Sandor B, Lubics A, Laszlo E, Farkas J, Matkovits A, Brubel R, Hashimoto H, Ferencz A, Vincze A, Zs H, Welke L, Lakatos A, Tamas A (2012) PACAP is an endogenous protective factor—insights from PACAP deficient mice. J Mol Neurosci 48(3):482–492.  https://doi.org/10.1007/s12031-012-9762-0 CrossRefPubMedGoogle Scholar
  58. Reglodi D, Renaud J, Tamas A, Tizabi Y, Socías SB, Del-Bel E, Raisman-Vozari R (2017) Novel tactics for neuroprotection in Parkinson’s disease: role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol 155:120–148.  https://doi.org/10.1016/j.pneurobio.2015.10.004 CrossRefPubMedGoogle Scholar
  59. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470(7335):492–497.  https://doi.org/10.1038/nature09856 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Richter Z, Janszky J, Sétáló G Jr, Horváth R, Horváth Z, Dóczi T, Seress L, Ábrahám H (2016) Characterization of neurons in the cortical white matter in human temporal lobe epilepsy. Neuroscience 333:140–150.  https://doi.org/10.1016/j.neuroscience.2016.07.011 CrossRefPubMedGoogle Scholar
  61. Segura-Aguilar J, Kostrzewa RM (2015) Neurotoxin mechanisms and processes relevant to Parkinson's disease: an update. Neurotox Res 27(3):328–354.  https://doi.org/10.1007/s12640-015-9519-y CrossRefPubMedGoogle Scholar
  62. Shioda S, Nakamachi T (2015) PACAP as a neuroprotective factor in ischemic neuronal injuries. Peptides 72:202–207.  https://doi.org/10.1016/j.peptides.2015.08.006 CrossRefPubMedGoogle Scholar
  63. Shivers KY, Nikolopoulou A, Machlovi SI, Vallabhajosula S, Figueiredo-Pereira ME (2014) PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2. Biochim Biophys Acta 1842(9):1707–1719.  https://doi.org/10.1016/j.bbadis.2014.06.020 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Solis O, García-Sanz P, Herranz AS, Asensio MJ, Moratalla R (2016) L-DOPA reverses the increased free amino acids tissue levels induced by dopamine depletion and rises GABA and tyrosine in the striatum. Neurotox Res 30(1):67–75.  https://doi.org/10.1007/s12640-016-9612-x CrossRefPubMedGoogle Scholar
  65. Somogyvari-Vigh A, Reglodi D (2004) Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide. Review. Curr Pharm Des 10(23):2861–2889.  https://doi.org/10.2174/1381612043383548 CrossRefPubMedGoogle Scholar
  66. Stumm R, Kolodziej A, Prinz V, Endres M, Wu DF, Hollt V (2007) Pituitary adenylate cyclase activating polypeptide is up-regulated in cortical pyramidal cells after focal ischemia and protects neurons from hypoxia/ischemic damage. J Neurochem 103(4):1666–1681.  https://doi.org/10.1111/j.1471-4159.2007.04895.x CrossRefPubMedGoogle Scholar
  67. Suzuki R, Arata S, Nakajo S, Ikenaka K, Kikuyama S, Shioda S (2003) Expression of the receptor for pituitary adenylate cyclase-activating polypeptide (PAC1-R) in reactive astrocytes. Brain Res Mol Brain Res 115(1):10–20.  https://doi.org/10.1016/S0169-328X(03)00172-4 CrossRefPubMedGoogle Scholar
  68. Szabadfi K, Atlasz T, Kiss P, Reglodi D, Szabo A, Kovacs K, Szalontai B, Setalo G Jr, Banki E, Csanaky K, Tamas A, Gabriel R (2012) Protective effects of the neuropeptide PACAP in diabetic retinopathy. Cell Tissue Res 348(1):37–46.  https://doi.org/10.1007/s00441-012-1349-0 CrossRefPubMedGoogle Scholar
  69. Szabadfi K, Reglodi D, Szabo A, Szalontai B, Valasek A, Setalo G Jr, Kiss P, Tamas A, Wilhelm M, Gabriel R (2016) Pituitary adenylate cyclase activating polypeptide, a potential therapeutic agent for diabetic retinopathy in rats: focus on the vertical information processing pathway. Neurotox Res 29(3):432–446.  https://doi.org/10.1007/s12640-015-9593-1 CrossRefPubMedGoogle Scholar
  70. Takei N, Skoglosa Y, Lindholm D (1998) Neurotrophic and neuroprotective effects of pituitary adenylate cyclase activating polypeptide (PACAP) on mesencephalic dopaminergic neurons. J Neurosci Res 54(5):698–706.  https://doi.org/10.1002/(SICI)1097-4547(19981201)54:5<698::AID-JNR15>3.0.CO;2-5 CrossRefPubMedGoogle Scholar
  71. Tamas A, Reglodi D, Farkas O, Kovesdi E, Pal J, Povlishock JT, Schwarcz A, Czeiter E, Szanto Z, Doczi T, Buki A, Bukovics P (2012) Effects of PACAP in central and peripheral nerve injuries. Int J Mol Sci 13(12):8430–8448.  https://doi.org/10.3390/ijms13078430 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Tripathy D, Sanchez A, Yin X, Martinez J, Grammas P (2012) Age-related decrease in cerebrovascular-derived neuroprotective proteins: effect of acetaminophen. Microvasc Res 84(3):278–285.  https://doi.org/10.1016/j.mvr.2012.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Vaczy A, Reglodi D, Somoskeoy T, Kovacs K, Lokos E, Szabo E, Tamas A, Atlasz T (2016) The protective role of PAC1-receptor agonist maxadilan in BCCAO-induced retinal degeneration. J Mol Neurosci 60(2):186–194.  https://doi.org/10.1007/s12031-016-0818-4 CrossRefPubMedGoogle Scholar
  74. Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61(3):283–357.  https://doi.org/10.1124/pr.109.001370 CrossRefPubMedGoogle Scholar
  75. 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(18):4005–4011.  https://doi.org/10.1016/j.febslet.2005.06.013 CrossRefPubMedGoogle Scholar
  76. Wang G, Pan J, Tan YY, Sun XK, Zhang YF, Zhou HY, Ren RJ, Wang XJ, Chen SD (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(3):267–276.  https://doi.org/10.1016/j.npep.2008.03.002 CrossRefPubMedGoogle Scholar
  77. Watson MB, Nobuta H, Abad C, Lee SK, Bala N, Zhu C, Richter F, Chesselet MF, Waschek JA (2013) PACAP deficiency sensitizes nigrostriatal dopaminergic neurons to paraquat-induced damage and modulates central and peripheral inflammatory activation in mice. Neuroscience 240:277–286.  https://doi.org/10.1016/j.neuroscience.2013.03.002 CrossRefPubMedPubMedCentralGoogle Scholar
  78. Yang R, Jiang X, Ji R, Meng L, Liu F, Chen X, Xin Y (2015) Therapeutic potential of PACAP for neurodegenerative diseases. Cell Mol Biol Lett 20(2):265–278.  https://doi.org/10.1515/cmble-2015-0008 CrossRefPubMedGoogle Scholar
  79. Yelkenli İH, Ulupinar E, Korkmaz OT, Şener E, Kuş G, Filiz Z, Tunçel N (2016) Modulation of corpus striatal neurochemistry by astrocytes and vasoactive intestinal peptide (VIP) in parkinsonian rats. J Mol Neurosci 59(2):280–289.  https://doi.org/10.1007/s12031-016-0757-0 CrossRefPubMedGoogle Scholar
  80. Zink M, Schmitt A, Henn FA, Gass P (2004) Differential expression of glutamate transporters EAAT1 and EAAT2 in mice deficient for PACAP-type I receptor. J Neural Transm (Vienna) 111(12):1537–1542.  https://doi.org/10.1007/s00702-004-0175-2 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • M. Feher
    • 1
    • 2
  • B. Gaszner
    • 1
  • A. Tamas
    • 1
  • A. L. Gil-Martinez
    • 3
  • E. Fernandez-Villalba
    • 3
  • M. T. Herrero
    • 3
  • D. Reglodi
    • 1
    Email author
  1. 1.Department of Anatomy, MTA-PTE PACAP Research Group, Centre for NeuroscienceUniversity of PecsPecsHungary
  2. 2.Department of NeurosurgeryKaposi Mór Teaching HospitalKaposvárHungary
  3. 3.Clinical and Experimental Neuroscience (NiCE), Institute of Bio-Health Research of Murcia (IMIB), Institute of Aging Research (IUIE), School of Medicine, Campus Mare NostrumUniversity of MurciaMurciaSpain

Personalised recommendations