Neurotoxicity Research

, Volume 21, Issue 3, pp 271–280 | Cite as

Cannabidiol-treated Rats Exhibited Higher Motor Score After Cryogenic Spinal Cord Injury

  • Marcelo Kwiatkoski
  • Francisco Silveira Guimarães
  • Elaine Del-Bel
Article

Abstract

Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5 s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20 mg/kg) immediately before, 3 h after and daily for 6 days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion + vehicle, day 1: zero, day 7: four, and lesion + Cannabidiol 20 mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions.

Keywords

Raquimedular trauma Experimental model BBB scale 

References

  1. Bamber N, Li H, Lu X, Oudega M, Aebischer P, Xu X (2001) Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur J Neurosci 13:257–268PubMedGoogle Scholar
  2. Basso M, Beattie S, Bresnahan C (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21PubMedCrossRefGoogle Scholar
  3. Basso M, Beattie S, Bresnahan C (1996a) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139:244–256PubMedCrossRefGoogle Scholar
  4. Basso M, Beattie S, Bresnahan C, Anderson K, Faden I, Gruner A, Holford R, Hsu Y, Noble J, Nockels L, Perot L, Salzman K, Young W (1996b) MASCIS evaluation of open field locomotor scores: effects of experience and teamwork on reliability. J Neurotrauma 13:343–359PubMedCrossRefGoogle Scholar
  5. Beattie S, Bresnahan C, Komon J, Tovar A, Van Meter M, Anderson K, Faden I, Hsu Y, Noble J, Salzman S, Young W (1997) Endogenous repair after spinal cord contusion injuries in the rat. Exp Neurol 148:453–463PubMedCrossRefGoogle Scholar
  6. Braida D, Pegorini S, Arcidiacono V, Consalez G, Croci L, Sala M (2003) Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci Lett 346:61–64PubMedCrossRefGoogle Scholar
  7. Carlson D, Gorden D, Oliff S, Pillai J, Lamanna C (2003) Sustained spinal cord compression: part I: time-dependent effect on long-term pathophysiology. J Bone Joint Surg Am 85-A:86–94PubMedGoogle Scholar
  8. Carrier J, Auchampach A, Hillard J (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA 103:7895–7900PubMedCrossRefGoogle Scholar
  9. Castillo A, Tolón M, Fernández-Ruiz J, Romero J, Martinez-Orgado J (2010) The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 37:434–440PubMedCrossRefGoogle Scholar
  10. Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendonça A (2007) Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation. Prog Neurobiol 83(5):310–331PubMedCrossRefGoogle Scholar
  11. Cheng H, Cao Y, Olson L (1996) Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273:510–513PubMedCrossRefGoogle Scholar
  12. Collins H, West R, Parmely D, Samson M, Ward A (1986a) The histopathology of freezing injury to the rat spinal cord. A light microscope study. I. Early degenerative changes. J Neurophatol Exp Neurol 45(6):721–741CrossRefGoogle Scholar
  13. Collins GH, West NR, Parmely JD (1986b) The histopathology of freezing injury to the rat spinal cord. A light and electron microscope study. II. Repair and regeneration. J Neuropathol Exp Neurol 45(6):742–757PubMedCrossRefGoogle Scholar
  14. Cunha J, Carlini A, Pereira E, Ramos O, Pimentel C, Gagliardi R, Sanvito L, Lander N, Mechoulam R (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21:175–185PubMedCrossRefGoogle Scholar
  15. Del Bel E, Borges A, Defino L, Guimaraes S (2000) Induction of Fos protein immunoreactivity by spinal cord contusion. Braz J Med Biol Res 33:521–528PubMedCrossRefGoogle Scholar
  16. Drysdale J, Platt B (2003) Cannabinoids: mechanisms and therapeutic applications in the CNS. Curr Med Chem 10:2719–2732PubMedCrossRefGoogle Scholar
  17. El-Remessy B, Khalil E, Matragoon S, Abou-Mohamed G, Tsai J, Roon P, Caldwell B, Caldwell W, Green K, Liou I (2003) Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-d-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008PubMedCrossRefGoogle Scholar
  18. Emery E, Aldana P, Bunge B, Puckett W, Srinivasan A, Keane W, Bethea J, Levi D (1998) Apoptosis after traumatic human spinal cord injury. J Neurosurg 89:911–920PubMedCrossRefGoogle Scholar
  19. Esposito G, De Filippis D, Carnuccio R, Izzo A, Iuvone T (2006) The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med 84:253–258PubMedCrossRefGoogle Scholar
  20. Feng SQ, Kong XH, Guo SF, Wang P, Li L, Zhong JH, Zhou XF (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(1–2):169–177PubMedCrossRefGoogle Scholar
  21. García-Arencibia M, González S, De Lago E, Ramos Á, Mechoulam R, Fernández-Ruiz J (2007) Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res 1134:162–170PubMedCrossRefGoogle Scholar
  22. Guimarães S, Chiaretti M, Graeff G, Zuard W (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559CrossRefGoogle Scholar
  23. Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu X, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M (2007a) Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 52:1079–1087PubMedCrossRefGoogle Scholar
  24. Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, Orito K, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M et al (2007b) Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem 102(5):1488–1496PubMedCrossRefGoogle Scholar
  25. Houweling A, van Asseldonk J, Lankhorst A, Hamers F, Martin D, Bär R, Joosten A (1998) Local application of collagen containing brain-derived neurotrophic factor decreases the loss of function after spinal cord injury in the adult rat. Neurosci Lett 251:193–196PubMedCrossRefGoogle Scholar
  26. Hsu CY, Hogan EL, Gadsden RHS, Spicer KM, Shi MP, Cox RD (1985) Vascular permeability in experimental spinal cord injury. J Neurol Sci 70:275–282PubMedCrossRefGoogle Scholar
  27. Iannotti CA, Clark M, Horn KP, van Rooijen N, Silver J, Steinmetz MP (2011) A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI. Exp Neurol 230(1):3–15PubMedCrossRefGoogle Scholar
  28. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo A (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89:134–141PubMedCrossRefGoogle Scholar
  29. Izzo A, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527PubMedCrossRefGoogle Scholar
  30. Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P (1990) Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62:1189–1204PubMedCrossRefGoogle Scholar
  31. Jones L, Oudega M, Bunge M, Tuszynski M (2001) Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol 533:83–89PubMedCrossRefGoogle Scholar
  32. Karin M, Liu ZG, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9:240–246PubMedCrossRefGoogle Scholar
  33. Kitada M, Mizoguchi A, Tohyama K, Ohtsubo A, Fujimoto E, Chakrabortty S, Ide C (1999) Comparison of the axonal and glial reactions between the caudal and rostral border in the cryoinjured dorsal funiculus of the rat spinal cord. Restor Neurol Neurosci 14(4):251–263PubMedGoogle Scholar
  34. Lastres-Becker I, Molina-Holgado F, Ramos A, Mechoulam R, Fernández-Ruiz J (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19:96–107PubMedCrossRefGoogle Scholar
  35. Leweke M, Schneider U, Radwan M, Schmidt E, Emrich H (2000) Different effects of nabilone and cannabidiol on binocular depth inversion in Man. Pharmacol Biochem Behav 66:175–181PubMedCrossRefGoogle Scholar
  36. Liu Z, Xu M, Hu R, Du C, Zhang X, Mcdonald W, Dong X, Wu J, Fan S, Jacquin F, Hsu Y, Choi W (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17:5395–5406PubMedGoogle Scholar
  37. Ma M, Basso M, Walters P, Stokes T, Jakeman B (2001) Behavioral and histological outcomes following graded spinal cord contusion injury in the C57Bl/6 mouse. Exp Neurol 169:239–254PubMedCrossRefGoogle Scholar
  38. McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ (2004) DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res Mol Brain Res 132(2):146–154PubMedCrossRefGoogle Scholar
  39. Mechoulam R (2002) Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot Essent Fatty Acids 66:93–99PubMedCrossRefGoogle Scholar
  40. Menei P, Montero-Menei C, Whittemore S, Bunge R, Bunge M (1998) Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur J Neurosci 10:607–621PubMedCrossRefGoogle Scholar
  41. Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M (2005) Cannabidiol prevents cerebral infarction via a serotonergic 5-Hydroxytryptamine 1A receptor-dependent mechanism. Stroke 36:1071–1076CrossRefGoogle Scholar
  42. Molander C, Xu Q, Rivero-Melian C, Grant G (1989) Cytoarchitectonic organization of the spinal cord in the rat: II. The cervical and upper thoracic cord. J Comp Neurol 289:375–385PubMedCrossRefGoogle Scholar
  43. Nestler EJ (2008) Transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci 363(1507):3245–3255PubMedCrossRefGoogle Scholar
  44. Pertwee G (2001) Cannabinoids receptors and pain. Prog Neurobiol 63:569–611PubMedCrossRefGoogle Scholar
  45. Pertwee G (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 12:1307–1324CrossRefGoogle Scholar
  46. Plemel R, Duncan G, Chen W, Shannon C, Park S, Sparling S, Tetzlaff W (2008) A graded forceps crush spinal cord injury model in mice. J Neurotrauma 25:350–370PubMedCrossRefGoogle Scholar
  47. Ruggiero A, Anwar M, Kim J, Sica L, Gootman N, Gootman M (1997) Induction of c-fos gene expression by spinal cord transection in the rat. Brain Res 763:21–29PubMedCrossRefGoogle Scholar
  48. Ryan D, Drysdale J, Lafourcade C, Pertwee G, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063PubMedCrossRefGoogle Scholar
  49. Scuderi C, Filippis D, Iuvone T, Blasio A, Steardo A, Esposito G (2009) Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phytother Res 23:597–602PubMedCrossRefGoogle Scholar
  50. Sharma S, Westman J, Olsson Y, Alm P (1996) Involvement of nitric oxide in acute spinal cord injury: an immunocytochemical study using light and electron microscopy in the rat. Neurosci Res 24:373–384PubMedCrossRefGoogle Scholar
  51. Tator CH (1995) Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol 5(4):407–413PubMedCrossRefGoogle Scholar
  52. Tator CH (1996) Experimental and clinical studies of the pathophysiology and management of acute spinal cord injury. J Spinal Cord Med 19(4):206–214PubMedGoogle Scholar
  53. Tator CH (1998) Biology of neurological recovery and functional restoration after spinal cord injury. Neurosurgery 42(4):696–707PubMedCrossRefGoogle Scholar
  54. Thomas A, Baillie L, Phillips M, Razdan K, Ross A, Pertwee G (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623PubMedCrossRefGoogle Scholar
  55. Wada S, Yone K, Ishidou Y, Nagamine T, Nakahara S, Niiyama T, Sakou T (1999) Apoptosis following spinal cord injury in rats and preventative effect of N-methyl-d-aspartate receptor antagonist. J Neurosurg 91:S98–S104Google Scholar
  56. Watson C, Paxinos G, Kayalioglu G (2009) The spinal cord. A Christopher and Dana Reeve Foundantion text and atlas. Academic Press, San DiegoGoogle Scholar
  57. Webb A, Ngan S, Fowler D (2010) Spinal cord injury I: a synopsis of the basic science. Can Vet J 51:485–492PubMedGoogle Scholar
  58. Wisdom R (1999) AP-1: one switch for many signals. Exp Cell Res 253:180–185PubMedCrossRefGoogle Scholar
  59. Xu M, Guénard V, Kleitman N, Aebischer P, Bunge B (1995) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261–272PubMedCrossRefGoogle Scholar
  60. Xu J, Kim M, Ahmed H, Xu J, Yan P, Xu M, Hsu Y (2001) Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci 1:92–97Google Scholar
  61. Yang K, Mu S, Xue J, Whitson J, Salminen A, Dixon E, Liu K, Hayes L (1994) Increased expression of c-fos mRNA and AP-1 transcription factors after cortical impact injury in rats. Brain Res 664:141–147PubMedCrossRefGoogle Scholar
  62. Zhang ZF, Liao WH, Yang QF, Li HY, Wu YM, Zhou XF (2003) Protective effects of adenoviral cardiotrophin-1 gene transfer on rubrospinal neurons after spinal cord injury in adult rats. Neurotox Res 5:539–548PubMedCrossRefGoogle Scholar
  63. Zuardi A, Crippa J, Hallak J, Moreira F, Guimarães FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Marcelo Kwiatkoski
    • 1
    • 2
  • Francisco Silveira Guimarães
    • 3
  • Elaine Del-Bel
    • 1
    • 2
  1. 1.Department of Physiology, Faculty of Medicine of Ribeirão Preto (FMRP)Universidade de São PauloRibeirão PretoBrazil
  2. 2.Department MEF-Physiology, School of OdontologyUniversidade de São PauloRibeirão PretoBrazil
  3. 3.Department of Pharmacology, Faculty of Medicine of Ribeirão Preto (FMRP)University of São PauloRibeirão PretoBrazil

Personalised recommendations