Pituitary adenylate cyclase activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. In addition to its more classic role as a neuromodulator, PACAP functions as a neurotrophic factor. Several neurotrophic factors have been shown to play an important role in the endogenous response following both cerebral ischemia and traumatic brain injury and to be effective when given exogenously. A number of studies have shown the neuroprotective effect of PACAP in different models of ischemia, neurodegenerative diseases and retinal degeneration. The aim of this review is to summarize the findings on the neuroprotective potential of PACAP in models of different traumatic nerve injuries. Expression of endogenous PACAP and its specific PAC1 receptor is elevated in different parts of the central and peripheral nervous system after traumatic injuries. Some experiments demonstrate the protective effect of exogenous PACAP treatment in different traumatic brain injury models, in facial nerve and optic nerve trauma. The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in neuronal regeneration indicating that PACAP may also be a promising therapeutic agent in injuries of the nervous system.
References
[1]
Miyata, A.; Jiang, L.; Dahl, R.D.; Kitada, C.; Kubo, K.; Fujino, M.; Minamino, N.; 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 1990, 170, 643–648.
[2]
Sherwood, N.M.; Krueckl, S.L.; McRory, J.E. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr. Rev 2000, 21, 619–670.
[3]
Vaudry, D.; Falluel-Morel, A.; Bourgault, S.; Basille, M.; Burel, D.; Wurtz, O.; Fournier, A.; Chow, B.K.; Hashimoto, H.; Galas, L.; Vaudry, H. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev 2009, 61, 283–357.
[4]
Arimura, A.; Somogyvari-Vigh, A.; Weill, C.; Fiore, R.C.; Tatsuno, I.; Bay, V.; Brenneman, D.E. PACAP functions as a neurotrophic factor. Ann. N. Y. Acad. Sci 1994, 739, 228–243.
[5]
Somogyvari-Vigh, A.; Reglodi, D. Pituitary adenylate cyclase activating polypeptide: A potential neuroprotective peptide. Curr. Pharm. Des 2004, 10, 2861–2889.
[6]
Botia, B.; Basille, M.; Allais, A.; Raoult, E.; Falluel-Morel, A.; Galas, L.; Jolivel, V.; Wurtz, O.; Komuro, H.; Fournier, A.; et al. Neurotrophic effects of PACAP in the cerebellar cortex. Peptides 2007, 28, 1746–1752.
[7]
Ravni, A.; Bourgault, S.; Lebon, A.; Chan, P.; Galas, L.; Fournier, A.; Vaudry, H.; Gonzalez, B.; Eiden, L.E.; Vaudry, D. The neurotrophic effects of PACAP in PC12 cells: Control by multiple transduction pathways. J. Neurochem 2006, 98, 321–329.
[8]
Dejda, A.; Soko？owska, P.; Nowak, J.Z. Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. Pharmacol. Rep 2005, 57, 307–320.
[9]
Dejda, A.; Jolivel, V.; Bourgault, S.; Seaborn, T.; Fournier, A.; Vaudry, H.; Vaudry, D. Inhibitory effect of PACAP on caspase activity in neuronal apoptosis: A better understanding towards therapeutic applications in neurodegenerative diseases. J. Mol. Neurosci 2008, 36, 26–37.
[10]
Brenneman, D.E. Neuroprotection: A comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Peptides 2007, 28, 1720–1726.
[11]
Ohtaki, H.; Nakamachi, T.; Dohi, K.; Shioda, S. Role of PACAP in ischemic neural death. J. Mol. Neurosci 2008, 36, 16–25.
[12]
Bourgault, S.; Vaudry, D.; Dejda, A.; Doan, N.D.; Vaudry, H.; Fournier, A. Pituitary adenylate cyclase-activating polypeptide: Focus on structure-activity relationships of a neuroprotective peptide. Curr. Med. Chem 2009, 16, 4462–4480.
[13]
Bourgault, S.; Chatenet, D.; Wurtz, O.; Doan, N.D.; Leprince, J.; Vaudry, H.; Fournier, A.; Vaudry, D. Strategies to convert PACAP from a hypophysiotropic neurohormone into a neuroprotective drug. Curr. Pharm. Des 2011, 17, 1002–1024.
[14]
Atlasz, T.; Szabadfi, K.; Kiss, P.; Racz, B.; Gallyas, F.; Tamas, A.; Gaal, V.; Marton, Z.; Gabriel, R.; Reglodi, D. Pituitary adenylate cyclase activating polypeptide in the retina: Focus on the retinoprotective effects. Ann. N. Y. Acad. Sci 2010, 1200, 128–139.
[15]
Nakamachi, T.; Farkas, J.; Watanabe, J.; Ohtaki, H.; Dohi, K.; Arata, S.; Shioda, S. Role of PACAP in neural stem/progenitor cell and astrocyte—From neural development to neural repair. Curr. Pharm. Des 2011, 17, 973–984.
[16]
Reglodi, D.; Kiss, P.; Lubics, A.; Tamas, A. Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. Curr. Pharm. Des 2011, 17, 962–972.
[17]
Dietrich, W.D.; Alonso, O.; Busto, R.; Finklestein, S.P. Posttreatment with intravenous basic fibroblast growth factor reduces histopathological damage following fluid-percussion brain injury in rats. J. Neurotrauma 1996, 13, 309–316.
[18]
Kawamata, T.; Dietrich, W.D.; Schallert, T.; Gotts, J.E.; Cocke, R.R.; Benowitz, L.I.; Finklestein, S.P. Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc. Natl. Acad. Sci. USA 1997, 94, 8179–8184.
[19]
Truettner, J.; Schmidt-Kastner, R.; Busto, R.; Alonso, O.F.; Loor, J.Y.; Dietrich, W.D.; Ginsberg, M.D. Expression of brain-derived neurotrophic factor, nerve growth factor, and heat shock protein HSP70 following fluid percussion brain injury in rats. J. Neurotrauma 1999, 16, 471–486.
[20]
Leker, R.R.; Shohami, E. Cerebral ischemia and trauma-different etiologies yet similar mechanisms: Neuroprotective opportunities. Brain Res. Rev 2002, 39, 55–73.
Maxwell, W.L.; Povlishock, J.T.; Graham, D.L. A mechanistic analysis of nondisruptive axonal injury: A review. J. Neurotrauma 1997, 14, 419–440.
[23]
Buki, A.; Okonkwo, D.O.; Wang, K.K.; Povlishock, J.T. Cytochrome c release and caspase activation in traumatic axonal injury. J. Neurosci 2000, 20, 2825–2834.
[24]
Bramlett, H.M.; Dietrich, W.D. Pathophysiology of cerebral ischemia and brain trauma: Similarities and differences. J. Cereb. Blood Flow Metab 2004, 24, 133–150.
[25]
Uchida, D.; Arimura, A.; Somogyvari-Vigh, A.; Shioda, S.; Banks, W.A. Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide. Brain Res 1996, 736, 280–286.
[26]
Reglodi, D.; Somogyvari-Vigh, A.; Vigh, S.; Kozicz, T.; Arimura, A. Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat. Stroke 2000, 31, 1411–1417.
[27]
Reglodi, D.; Tamas, A.; Somogyvari-Vigh, A.; Szanto, Z.; Kertes, E.; Lenard, L.; Arimura, A.; Lengvari, I. Effects of pretreatment with PACAP on the infarct size and functional outcome in rat permanent focal cerebral ischemia. Peptides 2002, 23, 2227–2234.
[28]
Tamas, A.; Reglodi, D.; Szanto, Z.; Borsiczky, B.; Nemeth, J.; Lengvari, I. Comparative neuroprotective effects of preischemic PACAP and VIP administration in permanent occlusion of the middle cerebral artery in rats. Neuroendocrinol. Lett 2002, 23, 249–254.
[29]
Waschek, J.A. Multiple action of pituitary adenyly cyclase activating peptide in nervous system development and regeneration. Dev. Neurosci 2002, 24, 14–23.
[30]
Rink, A.; Fung, K.M.; Trojanowski, J.Q.; Lee, V.M.; Neugebauer, E.; McIntosh, T.K. Evidence of apoptotic cell death after experimental traumatic brain injury in the rat. Am. J. Pathol 1995, 147, 1575–1583.
[31]
Skoglosa, Y.; Takei, N.; Lindholm, D. Distribution of pituitary adenylate cyclase activating polypeptide mRNA in the developing rat brain. Mol. Brain Res 1999, 65, 1–13.
[32]
Watanabe, J.; Nakamachi, T.; Matsuno, R.; Hayashi, D.; Nakamura, M.; Kikuyama, S.; Nakajo, S.; Shioda, S. Localization, characterization and function of pituitary adenylate cyclase-activating polypeptide during brain development. Peptides 2007, 28, 1713–1719.
[33]
Skoglosa, Y.; Lewen, A.; Takei, N.; Hillered, L.; Lindholm, D. Regulation of pituitary adenylate cyclase activating polypeptide and its receptor type 1 after traumatic brain injury: Comparison with brain-derived neurotrophic factor and the induction of neuronal cell death. Neuroscience 1999, 90, 235–247.
[34]
Van Landeghem, F.K.; Weiss, T.; Oehmichen, M.; von Deimling, A. Cellular localization of pituitary adenylate cyclase-activating peptide (PACAP) following traumatic brain injury in humans. Acta Neuropathol 2007, 113, 683–693.
[35]
Jaworski, D.M. Expression of pituitary adenylate cyclase-activating polypeptide (PACAP) and the PACAP-selective receptor in cultured rat astrocytes, human brain tumors, and in response to acute intracranial injury. Cell Tissue Res 2000, 300, 219–230.
[36]
Ma, W.; Bisby, M.A. Ultrastructural localization of increased neuropeptide immunoreactivity in the axons and cells of the gracile nucleus following chronic constriction injury of the sciatic nerve. Neuroscience 1999, 93, 335–348.
[37]
Dun, N.J.; Miyazaki, T.; Tang, H.; Dun, E.C. Pituitary adenylate cyclase activating polypeptide immunoreactivity in the rat spinal cord and medulla: Implication of sensory and autonomic functions. Neuroscience 1996, 73, 677–686.
[38]
Pettersson, L.M.; Heine, T.; Verge, V.M.; Sundler, F.; Danielsen, N. PACAP mRNA is expressed in rat spinal cord neurons. J. Comp. Neurol 2004, 471, 85–96.
[39]
Kim, W.K.; Kan, Y.; Ganea, D.; Hart, R.P.; Gozes, I.; Jonakait, G.M. Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor-alpha production in injured spinal cord and in activated microglia via a cAMP-dependent pathway. J. Neurosci 2000, 20, 3622–3630.
[40]
Tsuchikawa, D.; Nakamachi, T.; Tsuchida, M.; Wada, Y.; Hori, M.; Farkas, J.; Yoshikawa, A.; Kagami, N.; Imai, N.; Shintani, N.; et al. Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury. J. Mol. Neurosi 2012, doi:10.1007/s12031-012-9817-2.
[41]
Zhang, Q.; Shi, T.J.; Ji, R.R.; Zhang, Y.Z.; Sundler, F.; Hannibal, J.; Fahrenkrug, J.; Hokfelt, T. Expression of pituitary adenylate cyclase-activating polypeptide in dorsal root ganglia following axotomy: Time course and coexistence. Brain Res 1995, 705, 149–158.
[42]
Zhang, Y.Z.; Hannibal, J.; Zhao, Q.; Moller, K.; Danielsen, N.; Fahrenkrug, J.; Sundler, F. Pituitary adenylate cyclase activating peptide expression in the rat dorsal root ganglia: Up-regulation after peripheral nerve injury. Neuroscience 1996, 74, 1099–1110.
[43]
Jongsma Wallin, H.; Danielsen, N.; Johnston, J.M.; Gratto, K.A.; Karchewski, L.A.; Verge, V.M. Exogenous NT-3 and NGF differentially modulate PACAP expression in adult sensory neurons, suggesting distinct roles in injury and inflammation. Eur. J. Neurosci 2001, 14, 267–282.
[44]
Pettersson, L.M.; Dahlin, L.B.; Danielsen, N. Changes in expression of PACAP in rat sensory neurons in response to sciatic nerve compression. Eur. J. Neurosci 2004, 20, 1838–1848.
[45]
Dickinson, T.; Mitchell, R.; Robberecht, P.; Fleetwood-Walker, S.M. The role of VIP/PACAP receptor subtypes in spinal somatosensory processing in rats with an experimental peripheral mononeuropathy. Neuropharmacology 1999, 38, 167–180.
[46]
Moller, K.; Reimer, M.; Ekblad, E.; Hannibal, J.; Fahrenkrug, J.; Kanje, M.; Sundler, F. The effects of axotomy and preganglionic denervation on the expression of pituitary adenylate cyclase activating peptide (PACAP), galanin and PACAP type 1 receptors in the rat superior cervical ganglion. Brain Res 1997, 775, 166–182.
[47]
Klimaschewski, L.; Hauser, C.; Heym, C. PACAP immunoreactivity in the rat superior cervical ganglion in comparison to VIP. Neuroreport 1996, 7, 2797–2801.
[48]
Zhou, X.; Rodriguez, W.I.; Casillas, R.A.; Ma, V.; Tam, J.; Hu, Z.; Lelievre, V.; Chao, A.; Waschek, J.A. Axotomy-induced changes in pituitary adenylate cyclase activating polypeptide (PACAP) and PACAP receptor gene expression in the adult rat facial motor nucleus. J. Neurosci. Res 1999, 57, 953–961.
Larsen, J.O.; Hannibal, J.; Knudsen, S.M.; Fahrenkrug, J. Expression of pituitary adenylate cyclase-activating polypeptide (PACAP) in the mesencephalic trigeminal nucleus of the rat after transsection of the masseteric nerve. Brain Res. Mol. Brain Res 1997, 46, 109–117.
[51]
Buki, A.; Povlishock, J.T. All roads lead to disconnection?—Traumatic axonal injury revisited. Acta Neurochir. Wien 2006, 148, 181–193.
[52]
Buki, A.; Kovesdi, E.; Pal, J.; Czeiter, E. Clinical and Model Research of Neurotrauma. In Neuroproteomics; Ottens, A.K., Wang, K.K., Eds.; Humana Press: New York, NY, USA, 2009; pp. 41–57.
[53]
Foda, M.A.; Marmarou, A. A new model of diffuse brain injury in rats. Part II: Morphological characterization. J. Neurosurg 1994, 80, 301–313.
[54]
Marmarou, A.; Foda, M.A.; van den Brink, W.; Campbell, J.; Kita, H.; Demetriadou, K. A new model of diffuse brain injury in rats. Part I: Pathophysiology and biomechanics. J. Neurosurg 1994, 80, 291–300.
[55]
Gentleman, S.M.; Nash, M.J.; Sweeting, C.J.; Graham, D.I.; Roberts, G.W. Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci. Lett 1993, 160, 139–144.
[56]
Stone, J.R.; Singleton, R.H.; Povlishock, J.T. Antibodies to the C-terminus of the beta-amyloid precursor protein (APP): A site specific marker for the detection of traumatic axonal injury. Brain Res 2000, 871, 288–302.
[57]
Lee, V.M.; Carden, M.J.; Schlaepfer, W.W.; Trojanowski, J.Q. Monoclonal antibodies distinguish several differentially phosphorylated states of the two largest rat neurofilament subunits (NF-H and NF-M) and demonstrate their existence in the normal nervous system of adult rats. J. Neurosci 1987, 7, 3474–3488.
[58]
Povlishock, J.T.; Marmarou, A.; McIntosh, T.; Trojanowski, J.Q.; Moroi, J. Impact acceleration injury in the rat: Evidence for focal axolemmal change and related neurofilament sidearm alteration. J. Neuropathol. Exp. Neurol 1997, 56, 347–359.
[59]
Okonkwo, D.O.; Pettus, E.H.; Moroi, J.; Povlishock, J.T. Alteration of the neurofilament sidearm and its relation to neurofilament compaction occurring with traumatic axonal injury. Brain Res 1998, 784, 1–6.
[60]
Farkas, O.; Tamas, A.; Zsombok, A.; Reglodi, D.; Pal, J.; Buki, A.; Lengvari, I.; Povlishock, J.T.; Doczi, T. Effects of pituitary adenylate cyclase activating polypeptide in a rat model of traumatic brain injury. Regul. Pept 2004, 123, 69–75.
[61]
Tamas, A.; Zsombok, A.; Farkas, O.; Reglodi, D.; Pal, J.; Buki, A.; Lengvari, I.; Povlishock, J.T.; Doczi, T. Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats. J. Neurotrauma 2006, 23, 686–695.
[62]
Kovesdi, E.; Tamas, A.; Reglodi, D.; Bukovics, P.; Toth, G.; Doczi, T.; Hernadi, I.; Buki, A. Behavioral aspects of posttraumatic administration of PACAP using a rat model of impact acceleration head injury. J. Mol. Neurosci 2007, 33, 330. (abstract).
[63]
Dixon, C.E.; Lyeth, B.G.; Povlishock, J.T.; Findling, R.L.; Hamm, R.J.; Marmarou, A.; Young, H.F.; Hayes, R.L. A fluid percussion model of experimental brain injury in the rat. J. Neurosurg 1987, 67, 110–119.
[64]
McIntosh, T.K.; Noble, L.; Andrews, B.; Faden, A.I. Traumatic brain injury in the rat: Characterization of a midline fluid-percussion model. Cent. Nerv. Syst. Trauma 1987, 4, 119–134.
[65]
Kovesdi, E.; Tamas, A.; Reglodi, D.; Farkas, O.; Pal, J.; Toth, G.; Bukovics, P.; Doczi, T.; Buki, A. Posttraumatic administration of pituitary adenylate cyclase activating polypeptide in central fluid percussion injury in rats. Neurotox. Res 2008, 13, 71–78.
[66]
Povlishock, J.T.; Stone, J.R. Traumatic Axonal Injury. In Head Trauma:Basic, Preclinical and Clinical Directions; Miller, L.P., Hayes, R.L., Eds.; Wiley: New York, NY, USA, 2001.
[67]
Suehiro, E.; Singleton, R.H.; Stone, J.R.; Povlishock, J.T. The immunophilin ligand FK506 attenuates the axonal damage associated with rapid rewarming following posttraumatic hypothermia. Exp. Neurol 2001, 172, 199–210.
[68]
Chen, W.H.; Tzeng, S.F. Pituitary adenylate cyclase-activating polypeptide prevents cell death in the spinal cord with traumatic injury. Neurosci. Lett 2005, 384, 117–121.
[69]
Fang, K.M.; Chen, J.K.; Hung, S.C.; Chen, M.C.; Wu, Y.T.; Wu, T.J.; Lin, H.I.; Chen, C.H.; Cheng, H.; Yang, C.S.; Tzeng, S.F. Effects of combinatorial treatment with pituitary adenylate cyclase activating peptide and human mesenchymal stem cells on spinal cord tissue repair. PLoS One 2010, 5, doi:10.1371/journal.pone.0015299.
[70]
Kimura, H.; Kawatani, M.; Ito, E.; Ishikawa, K. PACAP facilitate the nerve regeneration factors in the facial nerve injury. Regul. Pept 2004, 123, 135–138.
[71]
Seki, T.; Itoh, H.; Nakamachi, T.; Shioda, S. Suppression of ganglion cell death by PACAP following optic nerve transection in the rat. J. Mol. Neurosci 2008, 36, 57–60.
[72]
Mulder, H.; Jongsma, H.; Zhang, Y.; Gebre-Medhin, S.; Sundler, F.; Danielsen, N. Pituitary adenylate cyclase-activating polypeptide and islet amyloid polypeptide in primary sensory neurons: Functional implications from plasticity in expression on nerve injury and inflammation. Mol. Neurobiol 1999, 19, 229–253.
[73]
Aldskogius, H.; Arvidsson, J.; Grant, G. The reaction of primary sensory neurons to peripheral nerve injury with particular emphasis on transganglionic changes. Brain Res 1985, 357, 27–46.
[74]
Moller, K.; Zhang, Y.Z.; Hakanson, R.; Luts, A.; Sjolund, B.; Uddman, R.; Sundler, F. Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: Immunocytochemical and immunochemical evidence. Neuroscience 1993, 57, 725–732.
Dun, E.C.; Huang, R.L.; Dun, S.L.; Dun, N.J. Pituitary adenylate cyclase activating polypeptide-immunoreactivity in human spinal cord and dorsal root ganglia. Brain Res 1996, 721, 233–237.
[77]
Jongsma, H.; Danielsen, N.; Sundler, F.; Kanje, M. Alterations of PACAP and PACAP receptor binding in sensory neurons following peripheral axotomy. Soc. Neurosci. Abstr 1998, 24, 2049.
[78]
Mulder, H.; Uddman, R.; Moller, K.; Elsas, T.; Ekblad, E.; Alumets, J.; Sundler, F. Pituitary adenylate cyclase activating polypeptide is expressed in autonomic neurons. Regul. Pept 1995, 59, 121–128.
[79]
Sundler, F.; Ekblad, E.; Hannibal, J.; Moller, K.; Zhang, Y.Z.; Mulder, H.; Elsas, T.; Grunditz, T.; Danielsen, N.; Fahrenkrug, J.; Uddman, R. Pituitary adenylate cyclase-activating peptide in sensory and autonomic ganglia: Localization and regulation. Ann. N. Y. Acad. Sci 1996, 805, 410–426. discussion 427–428.
[80]
Uddman, R.; Tajti, J.; Moller, S.; Sundler, F.; Edvinsson, L. Neuronal messengers and peptide receptors in the human sphenopalatine and otic ganglia. Brain Res 1999, 826, 193–199.
[81]
May, V.; Braas, K.M. Pituitary adenylate cyclase activating polypeptide (PACAP) regulation of sympathetic neuron neuropeptide Y and cathecolamine expression. J. Neurochem 1995, 65, 978–987.
[82]
Rohlmann, A.; Laskawi, R.; Hofer, A.; Dermietzel, R.; Wolff, J.R. Astrocytes as rapid sensors of peripheral axotomy in the facial nucleus of rats. Neuroreport 1994, 5, 409–412.
[83]
Armstrong, B.D.; Hu, Z.; Abad, C.; Yamamoto, M.; Rodriguez, W.I.; Cheng, J.; Tam, J.; Gomariz, R.P.; Patterson, P.H.; Waschek, J.A. Lymphocyte regulation of neuropeptide gene expression after neuronal injury. J. Neurosci. Res 2003, 74, 240–247.
[84]
Suarez, V.; Guntinas-Lichius, O.; Streppel, M.; Ingorokva, S.; Grosheva, M.; Neiss, W.F.; Angelov, D.N.; Klimaschewski, L. The axotomy-induced neuropeptides galanin and pituitary adenylate cyclase-activating peptide promote axonal sprouting of primary afferent and cranial motor neurones. Eur. J. Neurosci 2006, 24, 1555–1564.
[85]
Murray, C.J.; Lopez, A.D. Global mortality, disability, and the contribution of risk factors: Global burden of disease study. Lancet 1997, 349, 1436–1442.
[86]
Langlois, J.A.; Rutland-Brown, W.; Wald, M.M. The epidemiology and impact of traumatic brain injury: A brief overview. J. Head Trauma Rehabil 2006, 21, 375–378.
[87]
Narayan, R.K.; Michel, M.E.; Ansell, B.; Baethmann, A.; Biegon, A.; Bracken, M.B.; Bullock, M.R.; Choi, S.C.; Clifton, G.L.; Contant, C.F.; et al. Clinical trials in head injury. J. Neurotrauma 2002, 19, 503–557.
[88]
Saatman, K.E.; Duhaime, A.C.; Bullock, R.; Maas, A.I.; Valadka, A.; Manley, G.T. Classification of traumatic brain injury for targeted therapies. J. Neurotrauma 2008, 25, 719–738.
[89]
Ghajar, J.E. The future of traumatic brain injury. Mt. Sinai J. Med 2009, 76, 190–193.
[90]
Canonico, P.L.; Copani, A.; D’Agata, V.; Musco, S.; Petralia, S.; Travali, S.; Stivala, F.; Cavallaro, S. Activation of pituitary adenylate cyclase-activating polypeptide receptors prevents apoptotic cell death in cultured cerebellar granule cells. Ann. N. Y. Acad. Sci 1996, 805, 470–472.
[91]
Tanaka, J.; Koshimura, K.; Murakami, Y.; Sohmiya, M.; Yanaihara, N.; Kato, Y. Neuronal protection from apoptosis by pituitary adenylate cyclase-activating polypeptide. Regul. Pept 1997, 72, 1–8.
[92]
Shioda, S.; Ozawa, H.; Dohi, K.; Mizushima, H.; Matsumoto, K.; Nakajo, S.; Takaki, A.; Zhou, C.J.; Nakai, Y.; Arimura, A. PACAP protects hippocampal neurons against apoptosis: Involvement of JNK/SAPK signaling pathway. Ann. N. Y. Acad. Sci 1998, 865, 111–117.
[93]
Racz, B.; Gasz, B.; Borsiczky, B.; Gallyas, F., Jr; Tamas, A.; Jozsa, R.; Lubics, A.; Kiss, P.; Roth, E.; Ferencz, A.; et al. Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis. Gen. Comp. Endocrinol 2007, 153, 115–123.
[94]
Racz, B.; Gasz, B.; Gallyas, F., Jr; Kiss, P.; Tamas, A.; Szanto, Z.; Lubics, A.; Lengvari, I.; Toth, G.; Hegyi, O.; et al. PKA-Bad-14-3-3 and Akt-Bad-14-3-3 signaling pathways are involved in the protective effects of PACAP against ischemia/reperfusion-induced cardiomyocyte apoptosis. Regul. Pept 2008, 145, 105–115.
[95]
Seaborn, T.; Masmoudi-Kouli, O.; Fournier, A.; Vaudry, H.; Vaudry, D. Protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against apoptosis. Curr. Pharm. Des 2011, 17, 204–214.
[96]
Povlishock, J.T.; Katz, D.I. Update of neuropathology and neurological recovery after traumatic brain injury. J. Head Trauma Rehabil 2005, 20, 76–94.
[97]
Hirsch, T.; Susin, S.A.; Marzo, I.; Marchetti, P.; Zamzami, N.; Kroemer, G. Mitochondrial permeability transition in apoptosis and necrosis. Cell Biol. Toxicol 1998, 14, 141–145.
[98]
Susin, S.A.; Zamzami, N.; Kroemerm, G. Mitochondria as regulators of apoptosis: Doubt no more. Biochim. Biophys. Acta 1998, 1366, 151–165.
Yakovlev, A.G.; Faden, A.I. Mechanisms of neural cell death: Implications for development of neuroprotective treatment strategies. NeuroRx 2004, 1, 5–16.
[101]
Tabuchi, A.; Funaji, K.; Nakatsubo, J.; Fukuchi, M.; Tsuchiya, T.; Tsuda, M. Inactivation of aconitase during the apoptosis of mouse cerebellar granule neurons induced by a deprivation of membrane depolarization. J. Neurosci. Res 2003, 71, 504–515.
[102]
Racz, B.; Horvath, G.; Reglodi, D.; Gasz, B.; Kiss, P.; Gallyas, F., Jr; Sumegi, B.; Toth, G.; Nemeth, A.; Lubics, A.; et al. PACAP ameliorates oxidative stress in the chicken inner ear: An in vitro study. Regul. Pept. 2010, 160, 91–98.
[103]
Delgado, M.; Jonakait, G.M.; Ganea, D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in activated microglia. Glia 2002, 39, 148–161.
[104]
Delgado, M.; Abad, C.; Martinez, C.; Juarranz, M.G.; Leceta, J.; Ganea, D.; Gomariz, R.P. PACAP in immunity and inflammation. Ann. N. Y. Acad. Sci 2003, 992, 141–157.
[105]
Ganea, D.; Delgado, M. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity. Crit. Rev. Oral Biol. Med 2002, 13, 229–237.
[106]
Delgado, M.; Pozo, D.; Martinez, C.; Leceta, J.; Calvo, J.R.; Ganea, D.; Gomariz, R.P. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: In vitro and in vivo studies. J. Immunol 1999, 162, 2358–2367.
[107]
Buki, A.; Okonkwo, D.O.; Povlishock, J.T. Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury. J. Neurotrauma 1999, 16, 511–521.
[108]
Okonkwo, D.O.; Melon, D.E.; Pellicane, A.J.; Mutlu, L.K.; Rubin, D.G.; Stone, J.R.; Helm, G.A. Dose-response of cyclosporin A in attenuating traumatic axonal injury in rat. Neuroreport 2003, 14, 463–466.
[109]
Fukui, S.; Signoretti, S.; Dunbar, J.G.; Marmarou, A. The effect of cyclosporin A on brain edema formation following experimental cortical contusion. Acta Neurochir. Suppl 2003, 86, 301–303.
