Molecular Neurobiology

, Volume 36, Issue 1, pp 68–74 | Cite as

Endocannabinoids and Traumatic Brain Injury

  • R. MechoulamEmail author
  • E. Shohami


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.


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



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.


  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 413:527–531PubMedCrossRefGoogle 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 25:477–484CrossRefGoogle 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 22:257–264CrossRefGoogle Scholar
  4. 4.
    Mechoulam R, Panikashvili D, Shohami E (2002) Cannabinoids and brain injury: therapeutic implications. Trends Mol Med 8:58–61PubMedCrossRefGoogle Scholar
  5. 5.
    Hansen HS, Moesgaard B, Petersen G, Hansen HH (2002) Putative neuroprotective actions of N-acyl-ethanolamines. Pharmacol Therap 95:119–126CrossRefGoogle 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 26:317–346PubMedCrossRefGoogle 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 19:2987–2995PubMedGoogle 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–R7PubMedCrossRefGoogle 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 96:5780–5785PubMedCrossRefGoogle 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 22:9771–9775PubMedGoogle 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 353:23–31PubMedCrossRefGoogle 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 53:1541–1546PubMedCrossRefGoogle 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):15–26PubMedGoogle Scholar
  14. 14.
    Marsicano G, Lutz B (2006) Neuromodulatory functions of the endocannabinoid system. J Endocrinol Invest 29:27–46PubMedGoogle 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 79–109CrossRefGoogle Scholar
  16. 16.
    Leker RR, Gai N, Mechoulam R, Ovadia H (2003) Drug-induced hypothermia reduces ischemic damage. Effect the cannabinoid HU-210. Stroke 34:2000–2006PubMedCrossRefGoogle 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 87:323–327PubMedGoogle 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):133–144PubMedGoogle 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 103:2428–2433PubMedCrossRefGoogle 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 15:251–260PubMedCrossRefGoogle 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 96:14228−14233PubMedCrossRefGoogle 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 291:1156–1163PubMedGoogle Scholar
  23. 23.
    Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621−663PubMedCrossRefGoogle 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 276:45225–45235PubMedCrossRefGoogle 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 296:57–63PubMedGoogle 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 72:169–177PubMedCrossRefGoogle 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–S111PubMedCrossRefGoogle Scholar
  28. 28.
    Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273PubMedCrossRefGoogle Scholar
  29. 29.
    Shohami E, Mechoulam R (2000) Dexanabinol (HU-211): a nonpsychotropic cannabinoid with neuroprotective properties. Drug Dev Res 50:211–215CrossRefGoogle 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 86:271–275Google Scholar
  31. 31.
    Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890PubMedCrossRefGoogle 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 73:2501–2509PubMedCrossRefGoogle Scholar
  33. 33.
    Walter L, Stella N (2004) Cannabinoids and neuroinflammation. Br J Pharmacol 141:775–785PubMedCrossRefGoogle 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 12:53–58PubMedCrossRefGoogle 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 73:803–810CrossRefGoogle 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 19:1411–1419PubMedCrossRefGoogle 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 717:22–28PubMedCrossRefGoogle 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 17:1007–1019PubMedCrossRefGoogle 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 17:273–279PubMedCrossRefGoogle 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 19:791–795PubMedCrossRefGoogle 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 78:1415–1427PubMedCrossRefGoogle 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 63:429–438PubMedCrossRefGoogle Scholar
  43. 43.
    Chen Y, Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther 293:807–812PubMedGoogle 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 28:39–45PubMedCrossRefGoogle Scholar
  45. 45.
    Ashton JC, Glass M (2007) The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 5:73–80CrossRefPubMedGoogle 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 23:6470–6474PubMedGoogle Scholar
  47. 47.
    Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462PubMedCrossRefGoogle Scholar
  48. 48.
    Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122PubMedCrossRefGoogle Scholar
  49. 49.
    Piomelli D (2005) The endocannabinoid system: a drug discovery perspective. Curr Opin Investig Drugs 6:622–679Google Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry and Natural ProductsHebrew University Medical FacultyJerusalemIsrael
  2. 2.Department of PharmacologyHebrew University School of PharmacyJerusalemIsrael

Personalised recommendations