Abstract
Dysregulation of neuropeptides may play an important role in aging-induced impairments. In the long list of neuropeptides, pituitary adenylate cyclase–activating polypeptide (PACAP) represents a highly effective cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. PACAP has neuro- and general cytoprotective effects due to anti-apoptotic, anti-inflammatory, and antioxidant actions. As PACAP is also a part of the endogenous protective machinery, it can be hypothesized that the decreased protective effects in lack of endogenous PACAP would accelerate age-related degeneration and PACAP knockout mice would display age-related degenerative signs earlier. Recent results support this hypothesis showing that PACAP deficiency mimics aspects of age-related pathophysiological changes including increased neuronal vulnerability and systemic degeneration accompanied by increased apoptosis, oxidative stress, and inflammation. Decrease in PACAP expression has been shown in different species from invertebrates to humans. PACAP-deficient mice display numerous pathological alterations mimicking early aging, such as retinal changes, corneal keratinization and blurring, and systemic amyloidosis. In the present review, we summarize these findings and propose that PACAP deficiency could be a good model of premature aging.
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References
Abad C, Tan Y (2018) Immunomodulatory roles of PACAP and VIP: lessons from knockout mice. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1150-y
Allais A, Burel D, Isaac ER, Gray SL, Basille M, Ravni A, Sherwood NM, Vaudry H, Gonzalez BJ (2007) Altered cerebellar development in mice lacking pituitary adenylate cyclase-activating polypeptide. Eur J Neurosci 25:2604–2618. https://doi.org/10.1111/j.1460-9568.2007.05535.x
Armstrong BD, Abad C, Chhith S, Cheung-Lau G, Hajji OE, Nobuta H, Waschek JA (2008) Impaired nerve regeneration and enhanced neuroinflammatory response in mice lacking pituitary adenylyl cyclase activating peptide. Neuroscience 151:63–73. https://doi.org/10.1016/j.neuroscience.2007.09.084
Ashpole NM, Logan S, Yabluchanskiy A, Mitschelen MC, Yan H, Farley JA, Hodges EL, Ungvari Z, Csiszar A, Chen S, Georgescu C, Hubbard GB, Ikeno Y, Sonntag WE (2017) IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience 39:129–145. https://doi.org/10.1007/s11357-017-9971-0
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 70:665–674. https://doi.org/10.1093/gerona/glu116
Banks WA (2016) Transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barriers: consequences for disease states and therapeutic effects. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 815–832
Barrett KT, Daubenspeck JA, Wilson RJA (2017) Pituitary adenylate cyclase activating polypeptide (PACAP) drives cardiorespiratory responses to heat stress in neonatal mice. Am J Physiol Regul Integr Comp Physiol 313:R385–R394. https://doi.org/10.1152/ajpregu.00118.2017
Basille M, Vaudry D, Coulouarn Y, Jegou S, Lihrmann I, Fournier A, Vaudry H, Gonzalez B (2000) Comparative distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) binding sites and PACAP receptor mRNAs in the rat brain during development. J Comp Neurol 425:495–509. https://doi.org/10.1002/1096-9861(20001002)425:4<495::AID-CNE3>3.0.CO;2-A
Bennis MT, Schneider A, Victoria B, Do A, Wiesenborn DS, Spinel L, Gesing A, Kopchick JJ, Siddiqi SA, Masternak MM (2017) The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience 39:51–59. https://doi.org/10.1007/s11357-017-9957-y
Boni LJ, Ploug KB, Olesen I, Jansen-Olesen I, Gupta S (2009) The in vivo effect of VIP, PACAP-38 and PACAP-27 and mRNA expression of their receptors in rat middle meningeal artery. Cephalalgia 29:837–847. https://doi.org/10.1111/j.1468-2982.2008.01807.x
Brifault C, Vaudry D, Wurtz O (2016) The neuropeptide PACAP, a potent disease modifier candidate for brain stroke treatment. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 583–606
Cabezas-Llobet N, Vidal-Sancho L, Masana M, Fournier A, Alberch J, Vaudry D, Xifró X (2018) Pituitary adenylate cyclase-activating polypeptide (PACAP) enhances hippocampal synaptic plasticity and improves memory performance in Huntington’s disease. Mol Neurobiol. https://doi.org/10.1007/s12035-018-0972-5
Castorina A, Tiralongo A, Giunta S, Carnazza ML, Rasi G, D’Agata V (2008) PACAP and VIP prevent apoptosis in schwannoma cells. Brain Res 1241:29–35. https://doi.org/10.1016/j.brainres.2008.09.035
Chung CY, 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 14:1709–1725. https://doi.org/10.1093/hmg/ddi178
Delcourt N, Thouvenot E, Chanrion B, Galéotti N, Jouin P, Bockaert J, Marin P (2007) PACAP type I receptor transactivation is essential for IGF-1 receptor signaling and antiapoptotic activity in neurons. EMBO J 26:1542–1551. https://doi.org/10.1038/sj.emboj.7601608
Delgado M, Leceta J, Ganea D (2003) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia. J Leukoc Biol 73:155–164. https://doi.org/10.1189/jlb.0702372
Dickson L, Finlayson K (2009) VPAC and PAC receptors: from ligands to function. Pharmacol Ther 121:294–316. https://doi.org/10.1016/j.pharmthera.2008.11.006
Douiri S, Bahdoudi S, Hamdi Y, Cubì R, Basille M, Fournier A, Vaudry H, Tonon MC, Amri M, Vaudry D, Masmoudi-Kouki O (2016) Involvement of endogenous antioxidant systems in the protective activity of pituitary adenylate cyclase-activating polypeptide against hydrogen peroxide-induced oxidative damages in cultured rat astrocytes. J Neurochem 137:913–930. https://doi.org/10.1111/jnc.13614
Du P, Lee CH, Choi JH, Yoo KY, Lee YL, Kang IJ, Hwang IK, Kim JD, Won MH (2011) Pituitary adenylate cyclase-activating polypeptide-immunoreactive cells in the ageing gerbil hippocampus. Anat Histol Embryol 40:389–396. https://doi.org/10.1111/j.1439-0264.2011.01083.x
Edvinsson L (2016) Pituitary adenylate cyclase activating polypeptide (PACAP) in maigraine pathophysiology. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 609–615
Egri P, Fekete C, Denes A, Reglodi D, Hashimoto H, Fulop BD, Gereben B (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates the hypothalamo-pituitary-thyroid (HPT) axis via type 2 deiodinase in male mice. Endocrinology 157:2356–2366. https://doi.org/10.1210/en.2016-1043
Endo K, Nakamachi T, Seki T, Kagami N, Wada Y, Nakamura K, Kishimoto K, Hori M, Tsuchikawa D, Shinntani N, Hashimoto H, Baba A, Koide R, Shioda S (2011) Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse. J Mol Neurosci 43:22–29. https://doi.org/10.1007/s12031-010-9434-x
Ergang P, Vodička M, Soták M, Klusoňová P, Behuliak M, Řeháková L, Zach P, Pácha J (2015) Differential impact of stress on hypothalamic-pituitary-adrenal axis: gene expression changes in Lewis and Fisher rats. Psychoneuroendocrinology 53:49–59. https://doi.org/10.1016/j.psyneuen.2014.12.013
Fang Y, McFadden S, Darcy J, Hill CM, Huber JA, Verhulst S, Kopchick JJ, Miller RA, Sun LY, Bartke A (2017) Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice. Geroscience 39:347–356. https://doi.org/10.1007/s11357-017-9978-6
Farkas J, Sandor B, Tamas A, Kiss P, Hashimoto H, Nagy AD, Fulop BD, Juhasz T, Manavalan S, Reglodi D (2017) Early neurobehavioral development of mice lacking endogenous PACAP. J Mol Neurosci 61:468–478. https://doi.org/10.1007/s12031-017-0887-z
Feher M, Gaszner B, Tamas A, Gil-Martinez AL, Fernandez-Villalba E, Herrero MT, Reglodi D (2018) Alteration of the PAC1 receptor expression in the basal ganglia of MPTP-induced parkinsonian macaque monkeys. Neurotox Res 33:702–715. https://doi.org/10.1007/s12640-017-9841-7
Ferencz A, Kiss P, Weber G, Helyes Z, Shintani N, Baba A, Reglodi D (2010) Comparison of intestinal warm ischemic injury in PACAP knockout and wild-type mice. J Mol Neurosci 42:435–442. https://doi.org/10.1007/s12031-010-9357-6
Ferencz A, Racz B, Tamas A, Reglodi D, Lubics A, Nemeth J, Nedvig K, Kalmar-Nagy K, Horvath OP, Weber G, Roth E (2009) Influence of PACAP on oxidative stress and tissue injury following small-bowel autotransplantation. J Mol Neurosci 37:168–176. https://doi.org/10.1007/s12031-008-9132-0
Fukuchi M, Kuwana Y, Tabuchi A, Tsuda M (2016) Balance between cAMP and Ca(2+) signals regulates expression levels of pituitary adenylate cyclase-activating polypeptide gene in neurons. Genes Cells 21:921–929. https://doi.org/10.1111/gtc.12393
Fukuchi M, Tabuchi A, Kuwana Y, Watanabe S, Inoue M, Takasaki I, Izumi H, Tanaka A, Inoue R, Mori H, Komatsu H, Takemori H, Okuno H, Bito H, Tsuda M (2015) Neuromodulatory effect of Gαs- or Gαq-coupled G-protein-coupled receptor on NMDA receptor selectively activates the NMDA receptor/Ca2+/calcineurin/cAMP response element-binding protein-regulated transcriptional coactivator 1 pathway to effectively induce brain-derived neurotrophic factor expression in neurons. J Neurosci 35:5606–5624. https://doi.org/10.1523/JNEUROSCI.3650-14.2015
Fulop BD, Sandor B, Szentleleky E, Karanyicz E, Reglodi D, Gaszner B, Zakany R, Hashimoto H, Juhasz T, Tamas A (2018a) Altered notch signaling in developing molar teeth of pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1146-7
Fulop GA, Ramirez-Perez FI, Kiss T, Tarantini S, Valcarcel Ares MN, Toth P, Yabluchanskiy A, Conley SM, Ballabh P, Martinez-Lemus LA, Ungvari Z, Csiszar A (2018b) IGF-1 deficiency promotes pathological remodeling of cerebral arteries: a potential mechanism contributing to the pathogenesis of Intracerebral hemorrhages in aging. J Gerontol A Biol Sci Med Sci. https://doi.org/10.1093/gerona/gly144
Garami A, Pakai E, Rumbus Z, Solymar M (2016) The role of PACAP in the regulation of body temperature. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 239–257
Gaszner B, Kormos V, Kozicz T, Hashimoto H, Reglodi D, Helyes Z (2012) The behavioral phenotype of pituitary adenylate cyclase activating polypeptide deficient mice in anxiety and depression tests is accompanied by blunted c-Fos expression in the bed nucleus of the stria terminalis, central projecting Edinger Westphal nucleus, ventral lateral septum and dorsal raphe nucleus. Neuroscience 202:283–299. https://doi.org/10.1016/j.neuroscience.2011.11.046
Girard BA, Lelievre V, Braas KM, Razinia T, Vizzard MA, Ioffe Y, El Meskini R, Ronnett GV, Waschek JA, May V (2006) Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice. J Neurochem 99:499–513. https://doi.org/10.1111/j.1471-4159.2006.04112.x
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 37:32–39. https://doi.org/10.1016/j.peptides.2012.06.004
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 72:333–339. https://doi.org/10.1001/jamaneurol.2014.3625
Han P, Liang W, Baxter LC, Yin J, Tang Z, Beach TG, Caselli RJ, Reiman EM, Shi J (2014a) Pituitary adenylate cyclase-activating polypeptide is reduced in Alzheimer disease. Neurology 82:1724–1728. https://doi.org/10.1212/WNL.0000000000000417
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 nice and rhesus macaques. Front Aging Neurosci 9(180). https://doi.org/10.3389/fnagi.2017.00180
Han P, Tang Z, Yin J, Maalouf M, Beach TG, Reiman EM, Shi J (2014b) Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity. Neurobiol Aging 35:2064–2071. https://doi.org/10.1016/j.neurobiolaging.2014.03.022
Hashimoto R, Hashimoto H, Shintani N, Ohi K, Hori H, Saitoh O, Kosuga A, Tatsumi M, Iwata N, Ozaki N, Kamijima K, Baba A, Takeda M, Kunugi H (2010) Possible association between the pituitary adenylate cyclase activating polypeptide (PACAP) gene and major depression. Neurosci Lett 468:300–302. https://doi.org/10.1016/j.neulet.2009.11.019
Hatanaka M, Tanida M, Shintani N, Isojima Y, Kawaguchi C, Hashimoto H, Kakuda M, Haba R, Nagai K, Baba A (2008) Lack of light-induced elevation of renal sympathetic nerve activity and plasma corticosterone levels in PACAP-deficient mice. Neurosci Lett 444:153–156. https://doi.org/10.1016/j.neulet.2008.08.030
Heimesaat MM, Dunay IR, Bölke S, Fischer A, Grundmann U, Alutis M, Kühl AA, Tamas A, Toth G, Dunay MP, Göbel UB, Reglődi D, Bereswill S (2014) Pituitary adenylate cyclase activating polypeptide ameliorates experimental acute ileitis and extra-intestinal sequelae. PLoS One 9:e108389. https://doi.org/10.1371/journal.pone.0108389
Heimesaat MM, Reifenberger G, Vicena V, Illes A, Horvath G, Tamas A, Fulop BD, Bereswill S, Reglodi D (2017) Intestinal microbiota changes in mice lacking pituitary adenylate cyclase activating polypeptide (PACAP) – bifidobacteria make the difference. Eur J Microbiol Immunol (Bp) 7:187–199. https://doi.org/10.1556/1886.2017.00021
Helyes Z, Kun J, Dobrosi N, Sandor K, Nemeth J, Perkecz A, Pinter E, Szabadfi K, Gaszner B, Tekus V, Szolcsanyi J, Steinhoff M, Hashimoto H, Reglodi D (2015) Biro T (2015) pituitary adenylate cyclase activating polypeptide (PACAP) is up-regulated in murine skin inflammation and mediates transient receptor potential vanilloid-induced neurogenic edema. J Invest Dermatol 135:2209–2218. https://doi.org/10.1038/jid.2015.156
Heppner TJ, Hennig GW, Nelson MT, May V, Vizzard MA (2018) PACAP38-mediated bladder afferent nerve activity hyperexcitability and Ca2+ activity in urothelial cells from mice. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1119-x
Holighaus Y, Mustafa T, Eiden LE (2011) PAC1hop, null and hip receptors mediate differential signaling through cyclic AMP and calcium leading to splice variant-specific gene induction in neural cells. Peptides 32:1647–1655. https://doi.org/10.1016/j.peptides.2011.06.004
Horvath G, Illes A, Heimesaat MM, Bardosi A, Bardosi S, Tamas A, Fulop BD, Opper B, Nemeth J, Ferencz A, Reglodi D (2016) Protective intestinal effects of pituitary adenylate cyclase activating polypeptide. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 271–288
Horvath G, Kiss P, Nemeth J, Lelesz B, Tamas A, Reglodi D (2015) Environmental enrichment increases PACAP levels in the CNS of adult rats. Neuro Endocrinol Lett 36:143–147
Horvath G, Mark L, Brubel R, Szakaly P, Racz B, Kiss P, Tamas A, Helyes Z, Lubics A, Hashimoto H, Baba A, Shintani N, Furjes G, Nemeth J, Reglodi D (2010) Mice deficient in pituitary adenylate cyclase activating polypeptide display increased sensitivity to renal oxidative stress in vitro. Neurosci Lett 469:70–74. https://doi.org/10.1016/j.neulet.2009.11.046
Horvath G, Reglodi D, Czetany P, Illes A, Reman G, Fekete A, Toth G, Laszlo E, Opper B (2018) Effects of pituitary adenylate cyclase activating polypeptide in human proximal tubule cells against gentamicin toxicity. Int J Pept Res Ther. https://doi.org/10.1007/s10989-017-9666-5
Iemolo A, Seiglie M, Blasio A, Cottone P, Sabino V (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nucleus of the amygdala induces anxiety via melanocortin receptors. Psychopharmacology 233:3269–3277. https://doi.org/10.1007/s00213-016-4366-y
Ivic I, Fulop BD, Juhasz T, Reglodi D, Toth G, Hashimoto H, Tamas A, Koller A (2017a) Backup mechanism maintains PACAP/VIP-induced arterial relaxations in PACAP-deficient mice. J Vasc Res 54:180–192. https://doi.org/10.1159/000457798
Ivic I, Solymar M, Fulop BD, Hashimoto H, Toth G, Tamas A, Koller A, Reglodi D (2017b) Aging-induced modulation of pituitary adenylate cyclase-activating peptide- and vasoactive intestinal peptide-induced vasomotor responses in the arteries of mice. J Vasc Res 54:359–366. https://doi.org/10.1159/000481781
Ji H, Zhang Y, Shen XD, Gao F, Huang CY, Abad C, Busuttil RW, Waschek JA, Kupiec-Weglinski JW (2013) Neuropeptide PACAP in mouse liver ischemia and reperfusion injury: immunomodulation by the cAMP-PKA pathway. Hepatology 57:1225–1237. https://doi.org/10.1002/hep.25802
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 476:388–413. https://doi.org/10.1002/cne.20231
Joo KM, Chung YH, Lim HC, Lee KH, Cha CI (2005) Reduced immunoreactivities of a vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptor (VPAC1 receptor) in the cerebral cortex, hippocampal region, and amygdala of aged rats. Brain Res 1064:166–172. https://doi.org/10.1016/j.brainres.2005.09.006
Jozsa R, Somogyvari-Vigh A, Reglodi D, Hollosy T, Arimura A (2001) Distribution and daily variations of PACAP in the chicken brain. Peptides 22:1371–1377. https://doi.org/10.1016/S0196-9781(01)00477-6
Juhasz T, Szentleleky E, Cs SS, Takacs R, Dobrosi N, Engler M, Tamas A, Reglodi D, Zakany R (2015) Pituitary adenylate cyclase activating polypeptide (PACAP) pathway is induced by mechanical load and reduces the activity of hedghog signaling in chondrogenic micromass cell cultures. Int J Mol Sci 16:17344–17367. https://doi.org/10.3390/ijms160817344
Kallo I, Kalamatianos T, Piggins HD, Coen CW (2004) Ageing and the diurnal expression of mRNAs for vasoactive intestinal peptide and for the VPAC2 and PAC1 receptors in the suprachiasmatic nucleus of male rats. J Neuroendocrinol 16:758–766. https://doi.org/10.1111/j.1365-2826.2004.01232.x
Kemeny A, Reglodi D, Cseharovszky R, Hashimoto H, Baba A, Szolcsanyi J, Helyes Z (2010) Pituitary adenylate cyclase activating deficiency enhances oxazolone-induced allergic contact dermatitis in mice. J Mol Neurosci 42:443–449. https://doi.org/10.1007/s12031-010-9368-3
King SB, Lezak KR, O'Reilly M, Toufexis DJ, Falls WA, Braas K, May V, Hammack SE (2017) The effects of prior stress on anxiety-like responding to intra-BNST pituitary adenylate cyclase activating polypeptide in male and female rats. Neuropsychopharmacology 42:1679–1687. https://doi.org/10.1038/npp.2017.16
Kiss T, Pirger Z (2013) Multifunctional role of PACAP-like peptides in molluscs. Protein Pept Lett 20:628–635. https://doi.org/10.2174/0929866511320060003
Kiss P, Reglodi D, Tamas A, Lubics A, Lengvari I, Jozsa R, Somogyvari-Vigh A, Szilvassy Z, Nemeth J (2007) Changes of PACAP levels in the brain show gender differences following short-term water and food deprivation. Gen Comp Endocrinol 152:225–230. https://doi.org/10.1016/j.ygcen.2006.12.012
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. Get rights and content https://doi.org/10.1016/j.neuroscience.2016.06.004
Kovacs-Valasek A, Szabadfi K, Denes V, Szalontai B, Tamas A, Kiss P, Szabo A, Gy S, Reglodi D, Gabriel R (2017) Accelerated retinal aging in PACAP KO mice. Neuroscience 348:1–10. https://doi.org/10.1016/j.neuroscience.2017.02.003
Koves K (2016) Presence and role of PACAP in endocrine glands of mammals. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 161–178
Krajcs N, Hernadi L, Zs P, Reglodi D, Toth G, Kiss T (2015) PACAP modulates acetylcholine-elicited contractions at nicotinic neuromuscular contacts of the land snail. J Mol Neurosci 57:492–500. https://doi.org/10.1007/s12031-015-0605-7
Krajnak K, Lillis TO (2002) Aging alters light- and PACAP-induced cAMP accumulation in the suprachiasmatic nucleus of female rats. Brain Res 950:297–303. https://doi.org/10.1016/S0006-8993(02)03075-5
Lacombe A, Lelievre V, Roselli CE, Muller JM, Waschek JA, Vilain E (2007) Lack of vasoactive intestinal peptide reduces testosterone levels and reproductive aging in mouse testis. J Endocrinol 194:153–160. https://doi.org/10.1677/JOE-07-0102
Lacombe A, Lelievre V, Roselli CE, Salameh W, Lue YH, Lawson G, Muller JM, Waschek JA, Vilain E (2006) Delayed testicular aging in pituitary adenylate cyclase-activating peptide (PACAP) null mice. Proc Natl Acad Sci U S A 103:3793–3798. https://doi.org/10.1073/pnas.0505827103
Lajko A, Meggyes M, Fulop BD, Gede N, Reglodi D, Szereday L (2017) Comparative analysis of decidual and peripheral immune cells and immune-checkpoint molecules during pregnancy in wild-type and PACAP-deficient mice. Am J Reprod Immunol 9:e13035. https://doi.org/10.1111/aji.13035
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
Laszlo E, Varga A, Kovacs K, Jancso G, Kiss P, Tamas A, Szakaly P, Fulop B, Reglodi D (2015) Ischemia/reperfusion-induced kidney injury in heterozygous PACAP deficient mice. Transplant Proc 47:2210–2215. https://doi.org/10.1016/j.transproceed.2015.07.027
Lee JC, Cho YJ, Kim J, Kim N, Kang BG, Cha CI, Joo KM (2010) Region-specific changes in the immunoreactivity of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors (VPAC2, and PAC1 receptor) in the aged rat brains. Brain Res 1351:32–40. https://doi.org/10.1016/j.brainres.2010.06.048
Liao C, May V, Li J (2018) PAC1 receptors: shapeshifters in motion. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1132-0
Lugo JM, Carpio Y, Morales R, Rodríguez-Ramos T, Ramos L, Estrada MP (2013) First report of the pituitary adenylate cyclase activating polypeptide (PACAP) in crustaceans: conservation of its functions as growth promoting factor and immunomodulator in the white shrimp Litopenaeus vannamei. Fish Shellfish Immunol 35:1788–1796. https://doi.org/10.1016/j.fsi.2013.08.028
Ma BQ, Zhang M, Ba L (2015) Plasma pituitary adenylate cyclase-activating polypeptide concentrations and mortality after acute spontaneous basal ganglia hemorrhage. Clin Chim Acta 439:102–106. https://doi.org/10.1016/j.cca.2014.10.010
Maasz G, Zs P, Reglodi D, Petrovics D, Schmidt J, Kiss P, Rivnyak A, Hashimoto H, Avar P, Jambor E, Tamas A, Gaszner B, Mark L (2014) Comparative protein composition of the brains of PACAP deficient mice using mass spectrometry based proteomic analysis. J Mol Neurosci 54:310–319. https://doi.org/10.1007/s12031-014-0264-0
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 10:127–139. https://doi.org/10.1242/dmm.027185
Mai HN, Chung YH, Shin EJ, Sharma N, Jeong JH, Jang CG, Saito K, Nabeshima T, Reglodi D, Kim HC (2018) IL-6 knockout mice are protected from cocaine-induced kindling behaviors; possible involvement of JAK2/STAT3 and PACAP signaling. Food Chem Toxicol 116:249–263. https://doi.org/10.1016/j.fct.2018.04.031
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 enhances 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
Masmoudi-Kouki O, Douiri S, Hamdi Y, Kaddour H, Bahdoudi S, Vaudry D, Basille M, Leprince J, Fournier A, Vaudry H, Tonon MC, Amri M (2011) Pituitary adenylate cyclase-activating polypeptide protects astroglial cells against oxidative stress-induced apoptosis. J Neurochem 117:403–411. https://doi.org/10.1111/j.1471-4159.2011.07185.x
Matsumoto M, Nakamachi T, Watanabe J, Sugiyama K, Ohtaki H, Murai N, Sasaki S, Xu Z, Hashimoto H, Seki T, Miyazaki A, Shioda S (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in adult mouse hippocampal neurogenesis after stroke. J Mol Neurosci 59:270–279. https://doi.org/10.1007/s12031-016-0731-x
Mertens I, Husson SJ, Janssen T, Lindemans M, Schoofs L (2007) PACAP and PDF signaling in the regulation of mammalian and insect circadian rhythms. Peptides 28:1775–1783. https://doi.org/10.1016/j.peptides.2007.05.005
Miles OW, May V, Hammack SE (2018) Pituitary adenylate cyclase-activating peptide (PACAP) signaling and the dark side of addiction. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1147-6
Mohammed H, Hannibal J, Fahrenkrug J, Santer R (2002) Distribution and regional variation of pituitary adenylate cyclase activating polypeptide and other neuropeptides in the rat urinary bladder and ureter: effects of age. Urol Res 30:248–255. https://doi.org/10.1007/s00240-002-0261-6
Moody TW, Ito T, Osefo N, Jensen RT (2011) VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Curr Opin Endocrinol Diabetes Obes 18:61–67. https://doi.org/10.1097/MED.0b013e328342568a
Moody TW, Nuche-Berenguer B, Jensen RT (2016) Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes 23:38–47. https://doi.org/10.1097/MED.0000000000000218
Moody TW, Osefo N, Nuche-Berenguer B, Ridnour L, Wink D, Jensen RT (2012) Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the epidermal growth factor receptor in lung cancer cells. J Pharmacol Exp Ther 341:873–381. https://doi.org/10.1124/jpet.111.190033
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
Nemeth J, Tamas A, Jozsa R, Horvath JE, Jakab B, Lengvari I, Arimura A, Lubics A, Reglódi D (2006) Changes in PACAP levels in the central nervous system after ovariectomy and castration. Ann N Y Acad Sci 1070:468–473. https://doi.org/10.1196/annals.1317.063
Ng SY, Chow BK, Kasamatsu J, Kasahara M, Lee LT (2012) Agnathan VIP, PACAP and their receptors: ancestral origins of today’s highly diversified forms. PLoS One 7:e44691. https://doi.org/10.1371/journal.pone.0044691
Nonaka N, Banks WA, Mizushima H, Shioda S, Morley JE (2002) Regional differences in PACAP transport across the blood-brain barrier in mice: a possible influence of strain, amyloid beta protein, and age. Peptides 23:2197–2202. https://doi.org/10.1016/S0196-9781(02)00248-6
Ogata K, Shintani N, Hayata-Takano A, Kamo T, Higashi S, Seiriki K, Momosaki H, Vaudry D, Vaudry H, Galas L, Kasai A, Nagayasu K, Nakazawa T, Hashimoto R, Ago Y, Matsuda T, Baba A, Hashimoto H (2015) PACAP enhances axon outgrowth in cultured hippocampal neurons to a comparable extent as BDNF. PLoS One 10:e0120526. https://doi.org/10.1371/journal.pone.0120526
Ogren SO, Kuteeva E, Elvander-Tottie E, Hökfelt T (2010) Neuropeptides in learning and memory processes with focus on galanin. Eur J Pharmacol 626:9–17. https://doi.org/10.1016/j.ejphar.2009.09.070
Ohtaki H, Nakamachi T, Dohi K, Aizawa Y, Takaki A, Hodoyama K, Yofu S, Hashimoto H, Shintani N, Baba A, Kopf M, Iwakura Y, Matsuda K, Arimura A, Shioda S (2006) Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc Natl Acad Sci U S A 103:7488–7493. https://doi.org/10.1073/pnas.0600375103
Ohtaki H, Satoh A, Nakamachi T, Yofu S, Dohi K, Mori H, Ohara K, Miyamoto K, Hashimoto H, Shintani N, Baba A, Matsunaga M, Shioda S (2010) Regulation of oxidative stress by pituitary adenylate cyclase-activating polypeptide (PACAP) mediated by PACAP receptor. J Mol Neurosci 42:397–403. https://doi.org/10.1007/s12031-010-9350-0
Onoue S, Ohmori Y, Endo K, Yamada S, Kimura R, Yajima T (2004) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide attenuate the cigarette smoke extract-induced apoptotic death of rat alveolar L2 cells. Eur J Biochem 271:1757–1767. https://doi.org/10.1111/j.1432-1033.2004.04086.x
Padua D, Vu JP, Germano PM, Pisegna JR (2016) The role of neuropeptides in mouse models of colitis. J Mol Neurosci 59:203–210. https://doi.org/10.1007/s12031-015-0688-1
Parsons RL, May V (2018) PACAP-induced PAC1 receptor internalization and recruitment of endosomal signaling regulate cardiac neuron excitability. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1127-x
Pettersson LM, Geremia NM, Ying Z, Verge VM (2014) Injury-associated PACAP expression in rat sensory and motor neurons is induced by endogenous BDNF. PLoS One 9:e100730. https://doi.org/10.1371/journal.pone.0100730
Pirger Z, Laszlo Z, Kemenes I, Toth G, Reglodi D, Kemenes G (2010) A homologue of vertebrate adenylate cyclase activating polypeptide is both necessary and instructive for the rapid formation of associative memory in an invertebrate. J Neurosci 30:13766–13773. https://doi.org/10.1523/JNEUROSCI.2577-10.2010
Pirger Z, Naskar S, Laszlo Z, Gy K, Reglodi D, Kemenes I (2014) Reversal of age related learning deficiency by the vertebrate pituitary adenylate cyclase activating polypeptide (PACAP) and insulin-like growth factor-1 (IGF-1) in a novel invertebrate model of aging: the pond snail (Lymnaea stagnalis). J Gerontol A Biol Sci Med Sci 69:1331–1338. https://doi.org/10.1093/gerona/glu068
Pirger Z, Nemeth J, Hiripi L, Toth G, Kiss P, Lubics A, Tamas A, Hernadi L, Kiss T, Reglodi D (2008) PACAP has anti-apoptotic effect in the salivary gland of an invertebrate species, Helix pomatia. J Mol Neurosci 36:105–114. https://doi.org/10.1007/s12031-008-9070-x
Podlutsky A, Valcarcel-Ares MN, Yancey K, Podlutskaya V, Nagykaldi E, Gautam T, Miller RA, Sonntag WE, Csiszar A, Ungvari Z (2017) The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer. Geroscience 39:147–160. https://doi.org/10.1007/s11357-017-9966-x
Racz B, Gasz B, Borsiczky B, Gallyas F Jr, Tamas A, Jozsa R, Lubics A, Kiss P, Roth E, Ferencz A, Toth G, Hegyi O, Wittmann I, Lengvari I, Somogyvari-Vigh A, Reglodi D (2007) Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis. Gen Comp Endocrinol 153:115–123. https://doi.org/10.1016/j.ygcen.2006.12.006
Reglodi D, Cseh S, Somoskoi B, Fulop BD, Szentleleky E, Szegeczki V, Kovacs A, Varga A, Kiss P, Hashimoto H, Tamas A, Bardosi A, Manavalan S, Bako E, Zakany R, Juhasz T (2018a) Disturbed spermatogenic signaling in pituitary adenylate cyclase activating polypeptide deficient mice. Reproduction 155:129–139. https://doi.org/10.1530/REP-17-0470
Reglodi D, Zs F, Tamás A, Lubics A, Szeberényi J, Alexy T, Tóth K, Zs M, Borsiczky B, Rőth E, Szalontay L, Lengvári I (2004) Effects of PACAP on in vitro and in vivo neuronal cell death, platelet aggregation, and production of reactive oxygen radicals. Regul Pept 123:51–59. https://doi.org/10.1016/j.regpep.2004.05.012
Reglodi D, Helyes Zs, Nemeth J, Vass RA, Tamas A (2016) PACAP as a potential biomarker: alterations of PACAP levels in human physiological and pathological conditions. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 815–832
Reglodi D, Illes A, Opper B, Schafer E, Tamas A, Nemeth J, Horvath G (2018b) Presence and effects of pituitary adenylate cyclase activating polypeptide under physiological and pathological conditions in the stomach. Front Endocrinol (Lausanne) 9(90). https://doi.org/10.3389/fendo.2018.00090
Reglodi D, Jungling A, Longuespée R, Kriegsmann J, Casadonte R, Kriegsmann M, Juhasz T, Bardosi A, Tamas A, Fulop BD, Kovacs K, Zs N, Sparks J, Miseta A, Mazzucchelli G, Hashimoto H, Bardosi A (2018c) Accelerated pre-senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age-related degenerative processes. J Pathol 245:478–490. https://doi.org/10.1002/path.5100
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 17:962–972. https://doi.org/10.2174/138161211795589355
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, Helyes Z, Welke L, Lakatos A, Tamas A (2012) PACAP is an endogenous protective factor-insights from PACAP-deficient mice. J Mol Neurosci 48:482–492. https://doi.org/10.1007/s12031-012-9762-0
Reglodi D, Renaud J, Tamas A, Tizabi Y, Socías B, 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
Reglodi D, Tamas A (2016) Pituitary adenylate cyclase activating polypeptide – PACAP. Springer Nature, New York
Reglodi D, Tamas A, Jungling A, Vaczy A, Rivnyak A, Fulop BD, Szabo E, Lubics A, Atlasz T (2018d) Protective effects of pituitary adenylate cyclase activating polypeptide against neurotoxic agents. Neurotoxicology 66:185–194. https://doi.org/10.1016/j.neuro.2018.03.010
Reglodi D, Tamas A, Lengvari I, Toth G, Szalontay L, Lubics A (2006) 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 1070:518–524. https://doi.org/10.1196/annals.1317.072
Rivnyak A, Kiss P, Tamas A, Balogh D, Reglodi D (2018) Review on PACAP-induced transcriptomic and proteomic changes in neuronal development and repair. Int J Mol Sci 19:E1020. https://doi.org/10.3390/ijms19041020
Rubio-Beltrán E, Correnti E, Deen M, Kamm K, Kelderman T, Papetti L, Vigneri S, Maassen Van Den Brink A, Edvinsson L, European Headache Federation School of Advanced Studies (EHF-SAS) (2018) PACAP38 and PAC1 receptor blockade: a new target for headache? J Headache Pain 19:64. https://doi.org/10.1186/s10194-018-0893-8
Rudecki AP, Gray SL (2016) PACAP in the defense of energy homeostasis. Trends Endocrinol Metab 27:620–632. https://doi.org/10.1016/j.tem.2016.04.008
Sakamoto K, Kuno K, Takemoto M, He P, Ishikawa T, Onishi S, Ishibashi R, Okabe E, Shoji M, Hattori A, Yamaga M, Kobayashi K, Kawamura H, Tokuyama H, Maezawa Y, Yokote K (2015) Pituitary adenylate cyclase-activating polypeptide protects glomerular podocytes from inflammatory injuries. J Diabetes Res 2015:727152. https://doi.org/10.1155/2015/727152
Sandor K, Kormos V, Botz B, Imreh A, Bolcskei K, Gaszner B, Markovics A, Szolcsanyi J, Shintani N, Hashimoto H, Baba A, Reglodi D, Helyes Z (2010) Impaired nocifensive behaviours and mechanical hyperalgesia, but enhanced thermal allodynia in pituitary adenylate cyclase activating polypeptide deficient mice. Neuropeptides 44:363–371. https://doi.org/10.1016/j.npep.2010.06.004
Sarszegi Z, Szabo D, Gaszner B, Konyi A, Reglodi D, Nemeth J, Lelesz B, Polgar B, Jungling A, Tamas A (2018) Examination of pituitary adenylate cyclase activating polypeptide (PACAP) as a potential biomarker in heart failure patients. J Mol Neurosci. https://doi.org/10.1007/s12031-017-1025-7
Sekar R, Wang L, Chow BK (2017) Central control of feeding behavior by the secretin, PACAP, and glucagon family of peptides. Front Endocrinol (Lausanne) 8(18). https://doi.org/10.3389/fendo.2017.00018
Shioda S, Takenoya F, Hirabayashi T, Wada N, Seki T, Nonaka N, Nakamachi T (2018) Effects of PACAP on dry eye symptoms, and possible use for therapeutic application. J Mol Neurosci. https://doi.org/10.1007/s12031-018-1087-1
Solymar M, Ivic I, Balasko M, Fulop BD, Toth G, Tamas A, Gy R, Koller A, Reglodi D (2018) Pituitary adenylate cyclase activating polypeptide (PACAP) ameliorates vascular dysfunction induced by hyperglycemia. Diab Vasc Dis Res 15:277–285. https://doi.org/10.1177/1479164118757922
Somogyi I, Boros A, Engelmann P, Nemeth J, Lubics A, Tamas A, Kiss P, Reglodi D, Pollak E, Molnar L (2009) Pituitary adenylate cyclase activating polypeptide (PACAP)-like compounds could modulate the activity of coelomocytes in earthworm. Ann N Y Acad Sci 1163:521–523. https://doi.org/10.1111/j.1749-6632.2009.04431.x
Somogyvari-Vigh A, Jozsa R, Reglodi D, Hollósy T, Meggyesi R, Lengvari I, Arimura A (2002) Influence of pinealectomy on levels of PACAP and cAMP in the chicken brain. Regul Pept 109:9–13. https://doi.org/10.1016/S0167-0115(02)00164-7
Somogyvari-Vigh A, Reglodi D (2004) Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide. Curr Pharm Des 10:2861–2889. https://doi.org/10.2174/1381612043383548
Sonntag WE, Deak F, Ashpole N, Toth P, Csiszar A, Freeman W, Ungvari Z (2013) Insulin-like growth factor-1 in CNS and cerebrovascular aging. Front Aging Neurosci 5(27). https://doi.org/10.3389/fnagi.2013.00027
Szabadfi K, Atlasz T, Kiss P, Danyadi B, Tamas A, Helyes Z, Hashimoto H, Shintani N, Baba A, Toth G, Gabriel R, Reglodi D (2012) Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) are more susceptible to retinal ischemic injury in vivo. Neurotox Res 21:41–48. https://doi.org/10.1007/s12640-011-9254-y
Szakaly P, Horvath G, Kiss P, Laszlo E, Farkas J, Furjes G, Nemeth J, Reglodi D (2010) Changes in pituitary adenylate cyclase-activating polypeptide following renal ischemia-reperfusion in rats. Transplant Proc 42:2283–2286. https://doi.org/10.1016/j.transproceed.2010.05.012
Szakaly P, Laszlo E, Kovacs K, Racz B, Horvath G, Ferencz A, Lubics A, Kiss P, Tamas A, Brubel R, Opper B, Baba A, Hashimoto H, Farkas J, Matkovits A, Magyarlaki T, Zs H, Reglodi D (2011) Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) show increased susceptibility to in vivo renal ischemia/reperfusion injury. Neuropeptides 45:113–121. https://doi.org/10.1016/j.npep.2010.12.003
Tamas A, Lubics A, Lengvari I, Reglodi D (2006) Effects of age, gender, and gonadectomy on neurochemistry and behavior in animal models of Parkinson’s disease. Endocrine 29:275–287. https://doi.org/10.1385/ENDO:29:2:275
Tamas A, Lubics A, Szalontay L, Lengvari I, Reglodi D (2005) Age- and gender differences in behavioral and morphological outcome after 6-hydroxydopamine-induced lesion of the substantia nigra in rats. Behav Brain Res 158:221–229. https://doi.org/10.1016/j.bbr.2004.09.002
Tamas A, Szabadfi K, Nemeth A, Fulop B, Kiss P, Atlasz T, Gabriel R, Hashimoto H, Baba A, Shintani N, Helyes Z, Reglodi D (2012) Comparative examination of inner ear in wild type and pituitary adenylate cyclase activating polypeptide (PACAP) deficient mice. Neurotox Res 21:435–444. https://doi.org/10.1007/s12640-011-9298-z
Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, Gautam T, Giles CB, Wren JD, Sonntag WE, Csiszar A, Ungvari Z (2017) Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell 16:469–479. https://doi.org/10.1111/acel.12583
Tripathy D, Sanchez A, Yin X, Martinez J, Grammas P (2012) Age-related decrease in cerebrovascular-derived neuroprotective proteins: effect of acetaminophen. Microvasc Res 8400:278–285. https://doi.org/10.1016/j.mvr.2012.08.004
Tsuchikawa D, Nakamachi T, Tsuchida M, Wada Y, Hori M, Farkas J, Yoshikawa A, Kagami N, Imai N, Shintani N, Hashimoto H, Atsumi T, Shioda S (2012) Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury. J Mol Neurosci 48:508–517. https://doi.org/10.1007/s12031-012-9817-2
Ungvari Z, Valcarcel-Ares MN, Tarantini S, Yabluchanskiy A, Fülöp GA, Kiss T, Csiszar A (2017) Connective tissue growth factor (CTGF) in age-related vascular pathologies. Geroscience 39:491–498
Vamos Z, Ivic I, Cseplo P, Toth G, Tamas A, Reglodi D, Koller A (2014) Pituitary adenylate cyclase activating polypeptide (PACAP) induces relaxations of peripheral and cerebral arteries, which are impaired differently by aging. J Mol Neurosc 54:535–542. https://doi.org/10.1007/s12031-014-0349-9
Varhalmi E, Somogyi I, Kiszler G, Nemeth J, Reglodi D, Lubics A, Kiss P, Tamas A, Pollak E, Molnar L (2008) Expression of PACAP-like compounds during the caudal regeneration of the earthworm Eisenia fetida. J Mol Neurosci 36:166–174. https://doi.org/10.1007/s12031-008-9125-z
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 61:283–357. https://doi.org/10.1124/pr.109.001370
Vaudry D, Hamelink C, Damadzic R, Eskay RL, Gonzalez B, Eiden LE (2005) Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult. Peptides 26:2518–2524. https://doi.org/10.1016/j.peptides.2005.05.015
Vincze A, Reglodi D, Zs H, Hashimoto H, Shintani H, Abraham H (2011) Role of pituitary adenylate cyclase activating polypeptide (PACAP) in myelination of the rodent brain: lessons from PACAP-deficient mice. Int J Dev Neurosci 29:923–935. https://doi.org/10.1016/j.ijdevneu.2011.06.008
Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, Hori M, Tsuchida M, Yoshikawa A, Matkovits A, Kagami N, Imai N, Fujisaka S, Usui I, Tobe K, Koide R, Takahashi H, Shioda S (2013) PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype. J Mol Neurosci 51:493–502. https://doi.org/10.1007/s12031-013-0017-5
Waschek JA (2002) Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Dev Neurosci 24:14–23. https://doi.org/10.1159/000064942
Watanabe J, Seki T, Shioda S (2016) PACAP and neural development. In: Reglodi and Tamas (ed) Pituitary adenylate cyclase activating polypeptide-PACAP, Current Topics in Neurotoxicity 11. Springer Nature, New York, pp 65–82
Werling D, Reglodi D, Banks WA, Salameh TS, Kovacs K, Kvarik T, Vaczy A, Kovacs L, Mayer F, Danyadi B, Lokos E, Tamas A, Toth G, Zs B, Tamas A, Atlasz T (2016) Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. Invest Ophthalmol Vis Sci 57:6683–6691. https://doi.org/10.1167/iovs.16-20630
Wu ZL, Ciallella JR, Flood DG, O'Kane TM, Bozyczko-Coyne D, Savage MJ (2006) Comparative analysis of cortical gene expression in mouse models of Alzheimer’s disease. Neurobiol Aging 27:377–386. https://doi.org/10.1016/j.neurobiolaging.2005.02.010
Yamada K, Matsuzaki S, Hattori T, Kuwahara R, Taniguchi M, Hashimoto H, Shintani N, Baba A, Kumamoto N, Yamada K, Yoshikawa T, Katayama T, Tohyama M (2010) Increased stathmin1 expression in the dentate gyrus of mice causes abnormal axonal arborizations. PLoS One 5:e8596. https://doi.org/10.1371/journal.pone.0008596
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 20:265–278. https://doi.org/10.1515/cmble-2015-0008
Zhang H, Yu R, Liu X, Guo X, Zeng Z (2012) The expression of PAC1 increases in the degenerative thymus and low dose PACAP protects female mice from cyclophosphamide induced thymus atrophy. Peptides 38:337–343. https://doi.org/10.1016/j.peptides.2012.09.009
Funding
This study received financial support from NAP2017-1.2.1-NKP-2017-00002; GINOP-2.3.2-15-2016-00050 “PEPSYS”, MTA-TKI14016; NKFIH K119759, FK129190, Bolyai Scholarship, PTE-AOK KA-2017-15, EFOP-3.6.3-VEKOP-16-2017-00009, EFOP-3.6.1.-16-2016-00004 Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pécs; New Excellence Program, UNKP-16-4 and 18-2, TAMOP 4.2.4.A/2-11-1-2012-0001, EFOP-3.6.3-VEKOP-16-15 2017-00008, “The role of neuro-inflammation in neurodegeneration: from molecules to clinics.” Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the 20765-3/2018/FEKUTSTRAT.
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Reglodi, D., Atlasz, T., Szabo, E. et al. PACAP deficiency as a model of aging. GeroScience 40, 437–452 (2018). https://doi.org/10.1007/s11357-018-0045-8
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DOI: https://doi.org/10.1007/s11357-018-0045-8