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Journal of Molecular Neuroscience

, Volume 54, Issue 3, pp 370–379 | Cite as

PACAP38 Suppresses Cortical Damage in Mice with Traumatic Brain Injury by Enhancing Antioxidant Activity

  • Kazuyuki Miyamoto
  • Tomomi Tsumuraya
  • Hirokazu Ohtaki
  • Kenji Dohi
  • Kazue Satoh
  • Zhifang Xu
  • Sachiko Tanaka
  • Norimitsu Murai
  • Jun Watanabe
  • Koichi Sugiyama
  • Tohru Aruga
  • Seiji ShiodaEmail author
Article

Abstract

The production of reactive oxygen species (ROS) and the resulting oxidative stress in mice in response to a controlled cortical impact (CCI) are typical exacerbating factors associated with traumatic brain injury (TBI). Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) is a multifunctional peptide that has been shown to exhibit neuroprotective effects in response to a diverse range of injuries to neuronal cells. We recently reported that PACAP38 might regulate oxidative stress in mice. The aim of the present study was to determine whether PACAP38 exerts neuroprotective effects by regulating oxidative stress in mice with TBI. Reactive oxidative metabolites (ROMs) and biological antioxidant potential (BAP) were measured in male C57Bl/6 mice before and 3, 4, and 24 h after CCI. PACAP38 was administered intravenously immediately following CCI, and immunostaining for the oxidative stress indicator nitrotyrosine (NT), and for neuronal death as an indicator of the area affected by TBI, was measured 24 h later. Western blot experiments to determine antioxidant activity [as indicated by superoxide dismutase-2 (SOD-2) and glutathione peroxidase 1 (GPx-1)] in the neocortical region were also performed 3 h post-CCI. Results showed that plasma BAP and ROM levels were dramatically increased 3 h after CCI. PACAP38 suppressed the extent of TBI and NT-positive regions 24 h after CCI, and increased SOD-2 and GPx-1 levels in both hemispheres. Taken together, these results suggest that increasing antioxidant might be involving in the neuroprotective effect of PACAP38 in mice subjected to a CCI.

Keywords

PACAP38 Traumatic brain injury (TBI) Antioxidant enzyme Superoxide dismutase-2 (SOD-2 Mn-SOD) Glutathione peroxidase 1 (GPx-1) 

Notes

Acknowledgments

The project was supported by a Grant-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology. This work was also supported in part by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2008–2012.

Author Disclosure Statement

The authors have no competing financial interests to declare.

References

  1. Abad C, Martinez C, Leceta J et al (2002) Pituitary adenylate-cyclase-activating polypeptide expression in the immune system. Neuroimmunomodulation 10:177–186PubMedCrossRefGoogle Scholar
  2. Arimura A, Li M, Batuman V (2006) Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury. Blood 107:661–668PubMedCrossRefGoogle Scholar
  3. Brown AW, Elovic EP, Kothari S et al (2008) Congenital and acquired brain injury. 1. Epidemiology, pathophysiology, prognostication, innovative treatments, and prevention. Arch Phys Med Rehabil 89:S3–S8PubMedCrossRefGoogle Scholar
  4. Crack PJ, Taylor JM, Flentjar NJ et al (2001) Increased infarct size and exacerbated apoptosis in the glutathione peroxidase-1 (Gpx-1) knockout mouse brain in response to ischemia/reperfusion injury. J Neurochem 78:1389–1399PubMedCrossRefGoogle Scholar
  5. Crack PJ, Taylor JM, de Haan JB et al (2003) Glutathione peroxidase-1 contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic mouse in response to ischemia/reperfusion injury. J Cereb Blood Flow Metab 23:19–22PubMedCrossRefGoogle Scholar
  6. Delgado M, Ganea D (2001) Inhibition of endotoxin-induced macrophage chemokine production by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide in vitro and in vivo. J Immunol 167:966–975PubMedCrossRefGoogle Scholar
  7. Dohi K, Satoh K, Mihara Y et al (2006) Alkoxyl radical-scavenging activity of edaravone in patients with traumatic brain injury. J Neurotrauma 23:1591–1599PubMedCrossRefGoogle Scholar
  8. Dohi K, Ohtaki H, Nakamachi T et al (2010) Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury. J Neuroinflammation 7:41PubMedCentralPubMedCrossRefGoogle Scholar
  9. Farkas O, Tamás A, Zsombok A et al (2004) Effects of pituitary adenylate cyclase activating polypeptide in a rat model of traumatic brain injury. Regul Pept 123:69–75PubMedCrossRefGoogle Scholar
  10. Flynn JM, Melov S (2013) SOD2 in mitochondrial dysfunction and neurodegeneration. Free Radic Biol Med 62:4–12PubMedCrossRefGoogle Scholar
  11. Frechilla D, García-Osta A, Palacios S et al (2001) BDNF mediates the neuroprotective effect of PACAP-38 on rat cortical neurons. Neuroreport 12:919–923PubMedCrossRefGoogle Scholar
  12. Ganea D, Delgado M (2002) Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as modulators of both innate and adaptive immunity. Crit Rev Oral Biol Med 13:229–237PubMedCrossRefGoogle Scholar
  13. Gasz B, Rácz B, Roth E et al (2006) Pituitary adenylate cyclase activating polypeptide protects cardiomyocytes against oxidative stress-induced apoptosis. Peptides 27:87–94PubMedCrossRefGoogle Scholar
  14. Kövesdi E, Tamás A, Reglodi D et al (2008) Posttraumatic administration of pituitary adenylate cyclase activating polypeptide in central fluid percussion injury in rats. Neurotox Res 13:71–78Google Scholar
  15. Lebovitz RM, Zhang H, Vogel H et al (1996) Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci U S A 93:9782–9787PubMedCentralPubMedCrossRefGoogle Scholar
  16. Lewén A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890PubMedCrossRefGoogle Scholar
  17. Manno EM, Rabinstein AA, Wijdicks EF et al (2008) A prospective trial of elective extubation in brain injured patients meeting extubation criteria for ventilatory support: a feasibility study. Crit Care 12:R138PubMedCentralPubMedCrossRefGoogle Scholar
  18. Mao SS, Hua R, Zhao XP et al (2012) Exogenous administration of PACAP alleviates traumatic brain injury in rats through a mechanism involving the TLR4/MyD88/NF-κB pathway. J Neurotrauma 29:1941–1959Google Scholar
  19. Martinez C, Abad C, Delgado M et al (2002) Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor. Proc Natl Acad Sci U S A 99:1053–1058PubMedCentralPubMedCrossRefGoogle Scholar
  20. Miyamoto K, Ohtaki H, Dohi K et al (2013) Therapeutic time window for edaravone treatment of traumatic brain injury in mice. Biomed Res Int 2013:379206PubMedCentralPubMedCrossRefGoogle Scholar
  21. Miyata A, Arimura A, Dahl RR et al (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574PubMedCrossRefGoogle Scholar
  22. Mori H, Nakamachi T, Ohtaki H et al (2010) Cardioprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on Doxorubicin-induced cardiomyopathy in mice. Circ J 74:1183–1190PubMedCrossRefGoogle Scholar
  23. Nakamachi T, Tsuchida M, Kagami N et al (2012) IL-6 and PACAP receptor expression and localization after global brain ischemia in mice. J Mol Neurosci 48:518–525PubMedCrossRefGoogle Scholar
  24. Ohtaki H, Nakamachi T, Dohi K et al (2006) Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proc Natl Acad Sci U S A 103:7488–7493PubMedCentralPubMedCrossRefGoogle Scholar
  25. Ohtaki H, Nakamachi T, Dohi K et al (2008) Role of PACAP in ischemic neural death. J Mol Neurosci 36:16–25PubMedCrossRefGoogle Scholar
  26. Ohtaki H, Satoh A, Nakamachi T et al (2010) Regulation of oxidative stress by pituitary adenylate cyclase-activating polypeptide (PACAP) mediated by PACAP receptor. J Mol Neurosci 42:397–403PubMedCrossRefGoogle Scholar
  27. Park E, Bell JD, Siddiq IP et al (2009) An analysis of regional microvascular loss and recovery following two grades of fluid percussion trauma: a role for hypoxia-inducible factors in traumatic brain injury. J Cereb Blood Flow Metab 29:575–584PubMedCrossRefGoogle Scholar
  28. Rácz B, Gasz B, Borsiczky B et al (2007) Protective effects of pituitary adenylate cyclase activating polypeptide in endothelial cells against oxidative stress-induced apoptosis. Gen Comp Endocrinol 153:115–123PubMedCrossRefGoogle Scholar
  29. Ravni A, Eiden LE, Vaudry H et al (2006) Cycloheximide treatment to identify components of the transitional transcriptome in PACAP-induced PC12 cell differentiation. J Neurochem 98:1229–1241PubMedCentralPubMedCrossRefGoogle Scholar
  30. Reglodi D, Somogyvari-Vigh A, Vigh S et al (2000a) Neuroprotective effects of PACAP38 in a rat model of transient focal ischemia under various experimental conditions. Ann N Y Acad Sci 921:119–128PubMedCrossRefGoogle Scholar
  31. Reglodi D, Somogyvari-Vigh A, Vigh S et al (2000b) Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat. Stroke 31:1411–1417PubMedCrossRefGoogle Scholar
  32. Reglodi D, Tamás A, Somogyvári-Vigh A et al (2002) Effects of pretreatment with PACAP on the infarct size and functional outcome in rat permanent focal cerebral ischemia. Peptides 23:2227–2234PubMedCrossRefGoogle Scholar
  33. Reglodi D, Kiss P, Lubics A et al (2011) Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. Curr Pharm Des 17:962–972PubMedCrossRefGoogle Scholar
  34. Reglodi D, Kiss P, Szabadfi K et al (2012) PACAP is an endogenous protective factor-insights from PACAP-deficient mice. J Mol Neurosci 48:482–492PubMedCrossRefGoogle Scholar
  35. Skoglösa Y, Lewén A, Takei N et al (1999) 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 90:235–247PubMedCrossRefGoogle Scholar
  36. Tamás A, Zsombok A, Farkas O et al (2006) Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats. J Neurotrauma 23:686–695PubMedCrossRefGoogle Scholar
  37. Tamas A, Reglodi D, Farkas O et al (2012) Effect of PACAP in central and peripheral nerve injuries. Int J Mol Sci 13:8430–8448PubMedCentralPubMedCrossRefGoogle Scholar
  38. Tan YV, Abad C, Lopez R et al (2009) Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 106:2012–2017PubMedCentralPubMedCrossRefGoogle Scholar
  39. Tanaka J, Koshimura K, Murakami Y et al (1997) Neuronal protection from apoptosis by pituitary adenylate cyclase-activating polypeptide. Regul Pept 72:1–8PubMedCrossRefGoogle Scholar
  40. Tsuchikawa D, Nakamachi T, Tsuchida M et al (2012) Neuroprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on spinal cord injury. J Mol Neurosci 48:508–517PubMedCrossRefGoogle Scholar
  41. Uchida D, Arimura A, Somogyvári-Vigh A et al (1996) Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide. Brain Res 736:280–286PubMedCrossRefGoogle Scholar
  42. van Landeghem FK, Weiss T, Oehmichen M et al (2007) Cellular localization of pituitary adenylate cyclase-activating peptide (PACAP) following traumatic brain injury in humans. Acta Neuropathol 113:683–693PubMedCrossRefGoogle Scholar
  43. Vaudry D, Pamantung TF, Basille M et al (2002) PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. Eur J Neurosci 15:1451–1460PubMedCrossRefGoogle Scholar
  44. Waschek JA (2013) VIP and PACAP: Neuropeptide modulators of CNS inflammation, injury, and repair. Br J Pharmacol 169:512–523PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Kazuyuki Miyamoto
    • 1
    • 2
  • Tomomi Tsumuraya
    • 1
  • Hirokazu Ohtaki
    • 1
  • Kenji Dohi
    • 1
  • Kazue Satoh
    • 1
  • Zhifang Xu
    • 1
  • Sachiko Tanaka
    • 3
  • Norimitsu Murai
    • 1
  • Jun Watanabe
    • 1
  • Koichi Sugiyama
    • 1
  • Tohru Aruga
    • 2
  • Seiji Shioda
    • 1
    Email author
  1. 1.Department of AnatomyShowa University School of MedicineShinagawa-kuJapan
  2. 2.Department of Emergency and Critical Care MedicineShowa University School of MedicineTokyoJapan
  3. 3.Department of Pharmacology, Toxicology and Therapeutics, Division of ToxicologyShowa University School of PharmacyTokyoJapan

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