Posttraumatic administration of pituitary adenylate cyclase activating polypeptide in central fluid percussion injury in rats

  • Erzsébet Kóvesdi
  • Andrea Tamás
  • Dóra Reglodi
  • Orsolya Farkas
  • József PáL
  • Gábor Tóth
  • Péter Bukovics
  • Tamás Dóczi
  • András Büki


Severalin vitro andin vivo experiments have demonstrated the neuroprotective effects of pituitary adenylate cyclase activating polypeptide (PACAP) in focal cerebral ischemia, Parkinson’s disease and traumatic brain injury (TBI). The aim of the present study was to analyze the effect of PACAP administration on diffuse axonal injury (DAI), an important contributor to morbidity and mortality associated with TBI, in a central fluid percussion (CFP) model of TBI. Rats were subjected to moderate (2 Atm) CFP injury. Thirty min after injury, 100 μg PACAP was administered intracerebroventricularly. DAI was assessed by immunohistochemical detection of β-amyloid precursor protein, indicating impaired axoplasmic transport, and RMO-14 antibody, representing foci of cytoskeletal alterations (neurofilament compaction), both considered classical markers of axonal damage. Analysis of damaged, immunoreactive axonal profiles revealed significant axonal protection in the PACAP-treated versus vehicletreated animals in the corticospinal tract, as far as traumatically induced disturbance of axoplasmic transport and cytoskeletal alteration were considered. Similarly to our former observations in an impact acceleration model of diffuse TBI, the present study demonstrated that PACAP also inhibits DAI in the CFP injury model. The finding indicates that PACAP and derivates can be considered potential candidates for further experimental studies, or purportedly for clinical trials in the therapy of TBI.


Traumatic brain injury PACAP Axonoprotection APP RMO 



Amyloid precursor protein


Central fluid percussion


Corticospinal tract


Diffuse axonal injury; icv, intracerebroventricularly


Medial longitudinal fascicle


Pituitary adenylate cyclase activating polypeptide


Traumatic brain injury


  1. Atlasz T, N Babai, P Kiss, D Reglodi, A Tamas, K Szabadfi, G Toth, O Hegyi, A Lubics and R Gabriel (2007) Pituitary adenylate cyclase activating polypeptide is protective in bilateral carotid occlusion-induced retinal lesion in rats.Gen. Comp. Endocrinol. 153, 108–114.PubMedCrossRefGoogle Scholar
  2. Aubert N, A Falluel-Morel, D Vaudry, X Xifro, J Rodriguez-Alvarez, C Fisch, S de Jouffrey, JF Lebigot, A Fournier, H Vaudry and BJ Gonzalez (2006) PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase- dependent pathway: involvement of c-fos in PACAP-induced Bcl-2 expression.J. Neurochem. 99, 1237–1250.PubMedCrossRefGoogle Scholar
  3. Babai N, T Atlasz, A Tamás, D Reglodi, P Kiss and R Gábriel (2005) Degree of damage compensation by various PACAP treatments in monosodium glutamate-induced retina degeneration.Neurotox. Res. 8, 227–233.PubMedGoogle Scholar
  4. Beal MF, T Palomo, RM Kostrzewa and T Archer (2000) Neuroprotective and neurorestorative strategies for neuronal injury.Neurotox. Res. 2, 71–84.PubMedGoogle Scholar
  5. Blumbergs PC, G Scott, J Manavis, H Wainwright, DA Simpson and AJ McLean (1994) Staining of amyloid precursor protein to study axonal damage in mild head injury.Lancet 344, 1055–1056.PubMedCrossRefGoogle Scholar
  6. Bramlett HM and WD Dietrich (2004) Pathophysiology of cerebral ischemia and brain trauma: similarities and differences.J. Cereb. Blood Flow Metab. 24, 133–150.PubMedCrossRefGoogle Scholar
  7. Bramlett HM, S Kraydieh, EJ Green and WD Dietrich (1997) Temporal and regional patterns of axonal damage following traumatic brain injury: a β-amyloid precursor protein immunocytochemical study in rats.J. Neuropathol. Exp. Neurol. 56, 1132–1141.PubMedCrossRefGoogle Scholar
  8. Brenneman DE (2007) Neuroprotection: a comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide.Peptides 28, 1720–1726.PubMedCrossRefGoogle Scholar
  9. Buki A, H Koizumi and JT Povlishock (1999a) Moderate post-traumatic hypothermia decreases early calpain-mediated proteolysis and concomitant cytoskeletal compromise in traumatic axonal injury.Exp. Neurol. 159, 319–328.PubMedCrossRefGoogle Scholar
  10. Buki A, DO Okonkwo and JT Povlishock (1999b) Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury.J. Neurotrauma 16, 511–521.PubMedCrossRefGoogle Scholar
  11. Buki A, R Siman, JQ Trojanowski and JT Povlishock (1999c) The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury.J. Neuropathol. Exp. Neurol. 58, 365–375.PubMedCrossRefGoogle Scholar
  12. Buki A, DO Okonkwo, KK Wang and JT Povlishock (2000) Cytochromec release and caspase activation in traumatic axonal injury.J. Neurosci. 20, 2825–2834.PubMedGoogle Scholar
  13. Buki A, O Farkas, T Doczi and JT Povlishock (2003) Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury.J. Neurotrauma 20, 261–268.PubMedCrossRefGoogle Scholar
  14. Cernak I, S Chapman, G Hamlin and R Vink (2002) Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats.J. Clin. Neurosci. 9, 565–572.PubMedCrossRefGoogle Scholar
  15. Chen WH and SF Tzeng (2005) Pituitary adenylate cyclase activating polypeptide prevents cell death in the spinal cord with traumatic injury.Neurosci. Lett. 384, 117–121.PubMedCrossRefGoogle Scholar
  16. Dejda A, P Sokolowska and JZ Nowak (2005) Neuroprotective potential of three neuropeptides PACAP, VIP and PHI.Pharmacol. Rep. 57, 307–320.PubMedGoogle Scholar
  17. Delgado M, J Leceta and D Ganea (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.PubMedCrossRefGoogle Scholar
  18. De Yebenes JG and MA Mena (2000) Neurotrophic factors in neurodegenerative disorders: model of Parkinson’s disease.Neurotox. Res. 2, 115–137.PubMedGoogle Scholar
  19. Dixon CE, BG Lyeth, JT Povlishock, RL Findling, RJ Hamm, A Marmarou, HF Young and RL Hayes (1987) A fluid percussion model of experimental brain injury in the rat.J. Neurosurg. 67, 110–119.PubMedGoogle Scholar
  20. Doberer D, M Gschwandtner, W Mosgoeller, C Bieglmayer, H Heinzl and V Petkov (2007) Pulmonary and systemic effects of inhaled PACAP38 in healthy male subjects.Eur. J. Clin. Invest. 37, 665–672.PubMedCrossRefGoogle Scholar
  21. Dohi K, H Mizushima, S Nakajo, H Ohtaki, S Matsunaga, T Aruga and S Shioda (2002) Pituitary adenylate cyclase- activating polypeptide (PACAP) prevents hippocampal neurons from apoptosis by inhibiting JNK/SAPK and p38 signal transduction pathways.Regul. Pept. 109, 83–88.PubMedCrossRefGoogle Scholar
  22. Farkas O, A Tamas, A Zsombok, D Reglodi, J Pal, A Buki, I Lengvari, JT Povlishock and T Doczi (2004) Effects of pituitary adenylate cyclase activating polypeptide in a rat model of traumatic brain injury.Regul. Pept. 123, 69–75.PubMedCrossRefGoogle Scholar
  23. Farkas O, B Polgar, J Szekeres-Bartho, T Doczi, JT Povlishock and A Buki (2005) Spectrin breakdown products in the cerebrospinal fluid in severe head injury — preliminary observations.Acta Neurochir. (Wien.) 147, 855–861.CrossRefGoogle Scholar
  24. Feng SQ, XH Kong, SF Guo, P Wang, L Li, JH Zhong and XF Zhou (2005) Treatment of spinal cord injury with co-grafts of genetically modified Schwann cells and fetal spinal cord cell suspension in the rat.Neurotox. Res. 7, 169–177.PubMedGoogle Scholar
  25. Foda MA and A Marmarou (1994) A new model of diffuse brain injury in rats. Part II. Morphological characterization.J. Neurosurg. 80, 301–313.PubMedGoogle Scholar
  26. Gasz B, B Racz, E Roth, B Borsiczky, A Ferencz, A Tamas, B Cserepes, A Lubics, F Gallyas Jr, G Toth, I Lengvari and D Reglodi (2006) Pituitary adenylate cyclase activating polypeptide protects cardiomyocytes against oxidative stress- induced apoptosis.Peptides 27, 87–94.PubMedCrossRefGoogle Scholar
  27. Gentleman SM, MJ Nash, CJ Sweeting, DI Graham and GW Roberts (1993) β-Amyloid precursor protein (β-APP) as a marker for axonal injury after head injury.Neurosci. Lett. 160, 139–144.PubMedCrossRefGoogle Scholar
  28. Gerlach M, KL Double, MB Youdim and P Riederer (2000) Strategies for the protection of dopaminergic neurons against neurotoxicity.Neurotox. Res. 2, 99–114.PubMedGoogle Scholar
  29. Ghirnikar RS, YL Lee and LF Eng (1998) Inflammation in traumatic brain injury: role of cytokines and chemokines.Neurochem. Res. 23, 329–340.PubMedCrossRefGoogle Scholar
  30. Katahira M, K Yone, Y Arishima, T Nagamine, S Komiya and S Iwata (2003) The neuroprotective efffects of PACAP on spinal cord injury (SCI) in rats.Regul. Pept. 115, 49.Google Scholar
  31. Kim WK, Y Kan, D Ganea, RP Hart, I Gozes and GM Jonakait (2000) Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor- α production in injured spinal cord and in activated microglia via a cAMP-dependent pathway.J. Neurosci. 20, 3622–3630.PubMedGoogle Scholar
  32. Li M, JL Maderdrut, JJ Lertora and V Batuman (2007) Intravenous infusion of pituitary adenylate cyclase activating polypeptide (PACAP) in a patient with multiple myeloma and myeloma kidney injury: a case study.Peptides 28, 1891–1895.PubMedCrossRefGoogle Scholar
  33. Marmarou CR, SA Walker, CL Davis and JT Povlishock (2005) Quantitative analysis of the relationship between intra- axonal neurofilament compaction and impaired axonal transport following diffuse traumatic brain injury.J. Neurotrauma 22, 1066–1080.PubMedCrossRefGoogle Scholar
  34. McIntosh TK, L Noble, B Andrews and AI Faden (1987) Traumatic brain injury in the rat: characterization of a midline fluid-percussion model.Cent. Nerv. Syst. Trauma 4, 119–134.PubMedGoogle Scholar
  35. Miyata A, A Arimura, RR Dahl, N Minamino, A Uehara, L Jiang, MD Culler and DH Coy (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.Biochem. Biophys. Res. Commun. 164, 567–574.PubMedCrossRefGoogle Scholar
  36. Okonkwo DO and JT Povlishock (1999) An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury.J. Cereb. Blood Flow Metab. 19, 443–451.PubMedCrossRefGoogle Scholar
  37. Okonkwo DO, EH Pettus, J Moroi and JT Povlishock (1998) Alteration of the neurofilament sidearm and its relation to neurofilament compaction occurring with traumatic axonal injury.Brain Res. 784, 1–6.PubMedCrossRefGoogle Scholar
  38. Povlishock JT and EH Pettus (1996) Traumatically induced axonal damage: evidence for enduring changes in axolemmal permeability with associated cytoskeletal change.Acta Neurochir. Suppl. (Wien.) 66, 81–86.Google Scholar
  39. Povlishock JT, A Marmarou, T McIntosh, JQ Trojanowski and J Moroi (1997) Impact acceleration injury in the rat: evidence for focal axolemmal change and related neurofilament sidearm alteration.J. Neuropathol. Exp. Neurol. 56, 347–359.PubMedCrossRefGoogle Scholar
  40. Racz B, D Reglodi, P Kiss, N Babai, T Atlasz, R Gabriel, A Lubics, F Gallyas Jr, B Gasz, G Toth, E Roth, O Hegyi, I Lengvari and A Tamas (2006a)In vivo neuroprotection by PACAP in excitotoxic retinal injury: review of effects on retinal morphology and apoptotic signal transduction.Int. J. Neuroprot. Neurodeg. 2, 80–85.Google Scholar
  41. Racz B, F Gallyas Jr, P Kiss, G Toth, O Hegyi, B Gasz, B Borsiczky, A Ferencz, E Roth, A Tamas, I Lengvari, A Lubics and D Reglodi (2006b). The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involves inhibition of proapoptotic signaling pathways.Regul. Pept. 137, 20–26.PubMedCrossRefGoogle Scholar
  42. Racz B, F Gallyas Jr, P Kiss, A Tamas, A Lubics, I Lengvari, E Roth, G Toth, O Hegyi, ZS Verzar, CS Fabricsek and D Reglodi (2007) Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-Bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats.Neurotox. Res. 12, 95–104.PubMedGoogle Scholar
  43. Ravni A, S Bourgault, A Lebon, P Chan, L Galas, A Fournier, H Vaudry, B Gonzalez, LE Eiden and D Vaudry (2006) The neurotrophic effects of PACAP in PC 12 cells: control by multiple transduction pathways.J. Neurochem. 98, 321–329.PubMedCrossRefGoogle Scholar
  44. Ray SK, CE Dixon and NL Banik (2002) Molecular mechanisms in the pathogenesis of traumatic brain injury.Histol. Histopathol. 17, 1137–1152.PubMedGoogle Scholar
  45. Reglodi D, A Tamas, A Somogyvari-Vigh, Z Szanto, E Kertes, L Lenard, A Arimura and I Lengvari (2002) Effects of pretreatment with PACAP on the infarct size and functional outcome in rat permanent focal cerebral ischemia.Peptides 23, 2227–2234.PubMedCrossRefGoogle Scholar
  46. Reglodi D, A Tamas, A Lubics, L Szalontay and I Lengvari (2004) Morphological and functional effects of PACAP in 6-hydroxydopamine-induced lesion of the substantia nigra in rats.Regul. Pept. 123, 85–94.PubMedCrossRefGoogle Scholar
  47. Reglodi D, A Tamas, A Lubics, L Szalontay, A Zsombok, O Farkas, A Buki, T Doczi and I Lengvari (2005) Recent results on the neuroprotective effects of PACAP in rat models of focal cerebral ischemia, Parkinson’s disease and traumatic brain injury.Neurotox. Res. 8, 317.Google Scholar
  48. Reglodi D, A Lubics, P Kiss, I Lengvari, B Gaszner, G Toth, O Hegyi and A Tamas (2006) Effect of PACAP in 6-OHDA- induced injury of the substantia nigra in intact young and ovariectomized female rats.Neuropeptides 40, 265–274.PubMedCrossRefGoogle Scholar
  49. Segura-Aguilar J and RM Kostrzewa (2006) Neurotoxins and neurotoxicity mechanisms. An overview.Neurotox. Res. 10, 263–285.PubMedCrossRefGoogle Scholar
  50. Shioda S, H Ozawa, K Dohi, H Mizushima, K Matsumoto, S Nakajo, A Takaki, CJ Zhou, Y Nakai and A Arimura (1998) PACAP protects hippocampal neurons against apoptosis: involvement of JNK/SAPK signaling pathway.Ann. NY Acad. Sci. 865, 111–117.PubMedCrossRefGoogle Scholar
  51. Shioda S, H Ohtaki, T Nakamachi, K Dohi, J Watanabe, S Nakajo, S Arata, S Kitamura, H Okuda, F Takenoya and Y Kitamura (2006) Pleiotropic functions of PACAP in the CNS. Neuroprotection and neurodevelopment.Ann. NY Acad. Sci. 1070, 550–560.PubMedCrossRefGoogle Scholar
  52. Skoglosa Y, A Lewen, N Takei, L Hillered and D Lindholm (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, 235–247.PubMedCrossRefGoogle Scholar
  53. Somogyvari-Vigh A and D Reglodi (2004) Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide.Review. Curr. Pharm. Des. 10, 2861–2889.CrossRefGoogle Scholar
  54. Stone JR, SA Walker and JT Povlishock (1999) The visualization of a new class of traumatically injured axons through the use of a modified method of microwave antigen retrieval.Acta Neuropathol. (Berl.) 97, 335–345.CrossRefGoogle Scholar
  55. Stone JR, RH Singleton and JT Povlishock (2000) 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. 871, 288–302.PubMedCrossRefGoogle Scholar
  56. Stone JR, RH Singleton and JT Povlishock (2001) Intra-axonal neurofilament compaction does not evoke local axonal swelling in all traumatically injured axons.Exp. Neurol. 172, 320–331.PubMedCrossRefGoogle Scholar
  57. Tabuchi A, K Funaji, J Nakatsubo, M Fukuchi, T Tsuchiya and M Tsuda (2003) Inactivation of aconitase during the apoptosis of mouse cerebellar granule neurons induced by a deprivation of membrane depolarization.J. Neurosci. Res. 71, 504–515.PubMedCrossRefGoogle Scholar
  58. Tamas A, A Lubics, I Lengvari and D Reglodi (2006a) Protective effects of PACAP in excitotoxic striatal lesion.Ann. NY Acad. Sci. 1070, 570–574.PubMedCrossRefGoogle Scholar
  59. Tamas A, A Zsombok, O Farkas, D Reglodi, J Pal, A Buki, I Lengvari, JT Povlishock and T Doczi (2006b) Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats.J. Neurotrauma 23, 686–695.PubMedCrossRefGoogle Scholar
  60. van Landeghem FK, T Weiss, M Oehmichen and A von Deimling (2007) Cellular localization of pituitary adenylate cyclase activating peptide (PACAP) following traumatic brain injury in humans.Acta Neuropathol. 113, 683–693.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Erzsébet Kóvesdi
    • 1
  • Andrea Tamás
    • 2
  • Dóra Reglodi
    • 2
  • Orsolya Farkas
    • 3
  • József PáL
    • 1
  • Gábor Tóth
    • 4
  • Péter Bukovics
    • 1
    • 5
  • Tamás Dóczi
    • 1
  • András Büki
    • 1
  1. 1.Department of NeurosurgeryUniversity of Pécs, Medical FacultyHungary
  2. 2.Department of AnatomyUniversity of Pécs, Medical FacultyHungary
  3. 3.Department of RadiologyUniversity of Pécs, Medical FacultyHungary
  4. 4.Department of Medical ChemistryUniversity of SzegedHungary
  5. 5.Clinical Neuroscience Research GroupHungarian Academy of SciencesPécsHungary

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