Endocannabinoids and Traumatic Brain Injury

Abstract

In response to traumatic brain injury, there is local and transient accumulation of 2-AG at the site of injury, peaking at 4 h and sustained up to at least 24 h. Neuroprotection exerted by exogenous 2-AG suggests that the formation of 2-AG may serve as a molecular regulator of pathophysiological events, attenuating the brain damage. Inhibition of this protective effect by SR-141716A, a CB1 cannabinoid receptor antagonist, and the lack of effect of 2-AG in CB1 knockout mice suggest that 2-AG and the CB1 receptor may be important in the pathophysiology of traumatic brain injury. 2-AG exerts its neuroprotective effect after traumatic brain injury, at least in part, by inhibition of NF-κB transactivation. 2-AG also inhibits, at an early stage (2–4 h), the expression of the main proinflammatory cytokines, TNF-α, IL-6, and IL-1β, and is accompanied by reduction of BBB permeability. Moreover, the CB1, CB2, and TRVP1 receptors are expressed on microvascular endothelial cells, and their activation by 2-AG counteracts endothelin (ET-1)-induced cerebral microvascular responses (namely, Ca2+ mobilization and cytoskeleton rearrangement). This suggests that the functional interaction between 2-AG and ET-1 may provide a potential alternative pathway for abrogating ET-1-inducible vasoconstriction after brain injury and play a role in the neuroprotective effects exerted by 2-AG, as a potent vasodilator.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Panikashvili D, Mechoulam R, Beni SM, Alexandrovitch A, Shohami E (2005) CB1 cannabinoid receptors are involved in neuroprotection via NF-kB inhibition. J Cerebral Blood Flow Metabol 25:477–484

    Article  CAS  Google Scholar 

  3. 3.

    Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovitch A, Shohami E (2006) The endocannabinoid 2-AG protects the blood brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Disease 22:257–264

    Article  CAS  Google Scholar 

  4. 4.

    Mechoulam R, Panikashvili D, Shohami E (2002) Cannabinoids and brain injury: therapeutic implications. Trends Mol Med 8:58–61

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Hansen HS, Moesgaard B, Petersen G, Hansen HH (2002) Putative neuroprotective actions of N-acyl-ethanolamines. Pharmacol Therap 95:119–126

    Article  CAS  Google Scholar 

  6. 6.

    van der Stelt M, Veldhuis WB, Maccarrone M, Bar PR, Nicolay K, Veldink GA, Di Marzo V, Vliegenthart JF (2002) Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol 26:317–346

    PubMed  Article  Google Scholar 

  7. 7.

    Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin KL, Greenberg DA (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19:2987–2995

    PubMed  CAS  Google Scholar 

  8. 8.

    Gallily R, Breuer A, Mechoulam R (2000) 2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-production in murine macrophages, and in mice. Eur J Pharmacol 406:R5–R7

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96:5780–5785

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Parmentier-Batteur S, Jin K, Mao Xo Xie L, Greenberg DA (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22:9771–9775

    PubMed  CAS  Google Scholar 

  11. 11.

    Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, Mechoulam R (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl–glycerol cannabinoid activity. Eur J Pharmacol 353:23–31

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Shohami E, Shapira Y, Yadid G, Reisfeld N, Yedgar S (1989) Brain phospholipase A2 is activated after experimental closed head injury in rats. J Neurochem 53:1541–1546

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Di Marzo V, Matias I (2006) Endocannabinoid synthesis and degradation, and their regulation in the framework of energy balance. J Endocrinol Invest 29(3 Suppl):15–26

    PubMed  Google Scholar 

  14. 14.

    Marsicano G, Lutz B (2006) Neuromodulatory functions of the endocannabinoid system. J Endocrinol Invest 29:27–46

    PubMed  CAS  Google Scholar 

  15. 15.

    Fernández-Ruiz J, González S, Romero J, Ramos JA (2005) Cannabinoids in neurodegeneration and neuroprotection. In Mechoulam R (ed) Cannabinoids as Therapeutics. Birkhaüser Verlag, Switzerland, pp 79–109

    Google Scholar 

  16. 16.

    Leker RR, Gai N, Mechoulam R, Ovadia H (2003) Drug-induced hypothermia reduces ischemic damage. Effect the cannabinoid HU-210. Stroke 34:2000–2006

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Chen Y, McCarron RM, Ohara Y, Bembry J, Azzam N, Lenz FA, Shohami E, Mechoulam R, Spatz M (2000) Human brain capillary endothelium: 2-arachidonoglycerol (endocannabinoid) interacts with endothelin-1. Circ Res 87:323–327

    PubMed  CAS  Google Scholar 

  18. 18.

    McCarron RM, Chen Y, Tomori T, Strasser A, Mechoulam R, Shohami E, Spatz M (2006) Endothelial-mediated regulation of cerebral microcirculation. J Physiol Pharmacol 57(suppl 11):133–144

    PubMed  Google Scholar 

  19. 19.

    Milman G, Maor Y, Abu-Lafi S, Horowitz M, Gallily R, Batkai S, Mo FM, Offertaler L, Pacher P, Kunos G, Mechoulam R (2006) N-Arachidonoyl l-serine, a novel endocannabinoid-like brain constituent with vasodilatory properties. Proc Natl Acad Sci USA 103:2428–2433

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Sofia RD, Nalepa SD, Vassar HB, Knobloch LC (1974) Comparative anti-phlogistic activity of delta 9-tetrahydrocannabinol, hydrocortisone and aspirin in various rat paw edema models. Life Sci 15:251–260

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E (1999) HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 96:14228−14233

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Herring AC, Kaminski NE (1999) Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes. J Pharmacol Exp Ther 291:1156–1163

    PubMed  CAS  Google Scholar 

  23. 23.

    Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621−663

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Malek S, Chen Y, Huxford T, Ghosh G (2001) IκBβ but not IκBα functions as a classical cytoplasmic inhibitor of NF-κB dimers by masking both NF-κB nuclear localization sequences in resting cells. J Biol Chem 276:45225–45235

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Beni-Adani L, Gozes I, Cohen Y, Assaf Y, Steingart RA, Brenneman DE, Eizenberg O, Trembolver V, Shohami E (2001) Reduced mortality and improved recovery after treatment with a femtomolar-acting peptide in a mouse model of closed head injury. J Pharmacol Exp Ther 296:57–63

    PubMed  CAS  Google Scholar 

  26. 26.

    Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T (1997) Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF inhibitor and an effective neuroprotectant. J Neuroimmunol 72:169–177

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Zingarelli B, Sheehan M, Wong HR (2003) Nuclear factor-κB as a therapeutic target in critical care medicine. Crit Care Med 31:S105–S111

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Shohami E, Mechoulam R (2000) Dexanabinol (HU-211): a nonpsychotropic cannabinoid with neuroprotective properties. Drug Dev Res 50:211–215

    Article  CAS  Google Scholar 

  30. 30.

    McCarron RM, Shohami E, Panikashvili D, Chen Y, Golech S, Strasser A, Mechoulam R, Spatz M (2003) Antioxidant properties of the vasoactive endocannabinoid, 2-arachidonoyl glycerol (2-AG). Acta Neurochir Suppl 86:271–275

    Google Scholar 

  31. 31.

    Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Vollgraf U, Wegner M, Richter-Landsberg C (1999) Activation of AP-1 and nuclear factor-kappa B transcription factors is involved in hydrogen peroxide-induced apoptotic cell death of oligodendrocytes. J Neurochem 73:2501–2509

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Moro MA, Hurtado O, Cardenas A, Romera C, Madrigal JL, Fernandez-Tome P, Leza JC, Lorenzo P, Lizasoain I (2003) Expression and function of tumour necrosis factor-alpha-converting enzyme in the central nervous system. Neurosignals 12:53–58

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    von Gertten C, Holmin S, Mathiesen T, Nordqvist AC (2003) Increases in matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 mRNA after cerebral contusion and depolarization. J Neurosci Res 73:803–810

    Article  CAS  Google Scholar 

  36. 36.

    Mori T, Wang X, Aoki T, Lo EH (2002) Downregulation of matrix metalloproteinase-9 and attenuation of edema via inhibition of ERK mitogen activated protein kinase in traumatic brain injury. J Neurotrauma 19:1411–1419

    PubMed  Article  Google Scholar 

  37. 37.

    Beit-Yannai E, Zhang R, Trembovler V, Samuni A, Shohami E (1996) Cerebroprotective effect of stable nitroxide radicals in closed head injury in the rat. Brain Res 717:22–28

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Shohami E, Beit-Yannai E, Horowitz M, Kohen R (1997) Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional outcome. J Cereb Blood Flow Metab 17:1007–1019

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Beit-Yannai E, Kohen R, Horowitz M, Trembovler V, Shohami E (1997) Changes in biological reducing activity in rat brain following closed head injury: a cyclic voltammetry study in normal and acclimated rats. J Cereb Blood Flow Metab 17:273–279

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Trembovler V, Beit-Yannai E, Younis F, Gallily R, Horowitz M, Shohami E (1999) Antioxidants attenuate acute toxicity of tumor necrosis factor-alpha induced by brain injury in rat. J Interferon Cytokine Res 19:791–795

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F, Manzanares J, Ikonomidou C, Schmid HH, Fernandez-Ruiz JJ, Hansen HS (2001) Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 78:1415–1427

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Sancho R, Calzado MA, Di Marzo V, Appendino G, Munoz E (2003) Anandamide inhibits nuclear factor-kappaB activation through a cannabinoid receptor-independent pathway. Mol Pharmacol 63:429–438

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Chen Y, Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther 293:807–812

    PubMed  CAS  Google Scholar 

  44. 44.

    Fernández-Ruiz J, Romero J, Velasco G, Tolón RM, Ramos JA, Guzmán M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28:39–45

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Ashton JC, Glass M (2007) The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 5:73–80

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Molina-Holgado F, Pinteaux E, Moore JD, Molina-Holgado E, Guaza C, Gibson RM, Rothwell NJ (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23:6470–6474

    PubMed  CAS  Google Scholar 

  47. 47.

    Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Piomelli D (2005) The endocannabinoid system: a drug discovery perspective. Curr Opin Investig Drugs 6:622–679

    Google Scholar 

Download references

Acknowledgements

We thank the US National Institute on Drug Abuse, the US-Israel Binational Foundation, and the Miriam and Sheldon Adelson Program in Neural Repair and Rehabilitation for generous support.

Author information

Affiliations

Authors

Corresponding author

Correspondence to R. Mechoulam.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mechoulam, R., Shohami, E. Endocannabinoids and Traumatic Brain Injury. Mol Neurobiol 36, 68–74 (2007). https://doi.org/10.1007/s12035-007-8008-6

Download citation

Keywords

  • 2-AG
  • Blood–brain barrier
  • Brain endothelial cells
  • Cannabinoids
  • Cytokines
  • Endocannabinoids
  • NF-κB
  • TNF-α
  • Vasodilation