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An endogenous cannabinoid (2-AG) is neuroprotective after brain injury

Abstract

Traumatic brain injury triggers the accumulation of harmful mediators that may lead to secondary damage1,2. Protective mechanisms to attenuate damage are also set in motion2. 2-Arachidonoyl glycerol (2-AG) is an endogenous cannabinoid, identified both in the periphery3 and in the brain4, but its physiological roles have been only partially clarified5,6,7. Here we show that, after injury to the mouse brain, 2-AG may have a neuroprotective role in which the cannabinoid system is involved. After closed head injury (CHI) in mice, the level of endogenous 2-AG was significantly elevated. We administered synthetic 2-AG to mice after CHI and found significant reduction of brain oedema, better clinical recovery, reduced infarct volume and reduced hippocampal cell death compared with controls. When 2-AG was administered together with additional inactive 2-acyl-glycerols that are normally present in the brain, functional recovery was significantly enhanced. The beneficial effect of 2-AG was dose-dependently attenuated by SR-141761A, an antagonist of the CB1 cannabinoid receptor.

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Figure 1: Temporal profile of 2-AG changes after CHI.
Figure 2: Protective effects of 2-AG after CHI.
Figure 3: Hippocampal cell death after the effect of CHI is reduced by 2-AG.
Figure 4: Effects of 2-AG treatment on the neuronal cell loss in the CA3 hippocampal subfield.
Figure 5: ‘Entourage’ of congeners enhances the effect of 2-AG.
Figure 6: The protective effect of 2-AG is mediated by the CB1 cannabinoid receptor.

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References

  1. Povlishock, J. T. & Christman, C. W. The pathobiology of traumatically induced axonal injury in animals and humans: A review of current thoughts. J. Neurotrauma 12, 555–564 (1995).

    Article  CAS  Google Scholar 

  2. Kochanek, P. M. et al. Biochemical, cellular, and molecular mechanisms in the evolution of secondary damage after severe traumatic brain injury in infants and children: Lessons learned from the bedside. Pediatr. Crit. Care Med. 1, 4–19 (2000).

    Article  Google Scholar 

  3. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).

    Article  CAS  Google Scholar 

  4. Sugiura, T. et al. 2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    Article  CAS  Google Scholar 

  5. Mechoulam, R., Fride, E. & Di Marzo, V. Endocannabinoids. Eur. J. Pharmacol. 359, 1–18 (1998).

    Article  CAS  Google Scholar 

  6. Piomelli, D., Giuffrida, A., Calignano, A. & Rodriguez de Fonseca, F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21, 218–223 (2000).

    Article  CAS  Google Scholar 

  7. Axelrod, J. & Felder, C. C. Cannabinoid receptors and their endogenous agonist, anandamide. Neurochem. Res. 23, 575–581 (1998).

    Article  CAS  Google Scholar 

  8. McIntosh, T. K., Juhler, M. & Wieloch, T. Novel pharmacologic strategies in the treatment of experimental traumatic brain injury J. Neurotrauma 15, 731–769 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Chan, P. H. Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab. 21, 2–14 (2001).

    Article  CAS  Google Scholar 

  11. Shohami, E., Ginis, I. & Hallenbeck, J. M. Dual role of tumor necrosis factor α in brain injury. Cytokines Growth Factor Rev. 10, 119–130 (1999).

    Article  CAS  Google Scholar 

  12. Chen, Y., Constantini, S., Trembovler, V., Weinstock, M. & Shohami, E. An experimental model of closed head injury in mice: Pathophysiology, histopathology and cognitive deficits. J. Neurotrauma 13, 557–568 (1996).

    Article  CAS  Google Scholar 

  13. Beni-Adani, L. et al. A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J. Pharmacol. Exp. Ther. 296, 57–63 (2001).

    CAS  PubMed  Google Scholar 

  14. Mathews, K. S. et al. Rapid quantification of ischaemic injury and cerebroprotection in brain slices using densitometric assessment of 2,3,5-triphenyltetrazolium chloride staining. J. Neurosci. Meth. 102, 43–51 (2000).

    Article  CAS  Google Scholar 

  15. Ben-Shabat, S. et al. An entourage effect: Inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23–31 (1998).

    Article  CAS  Google Scholar 

  16. Adams, I. E., Compton, D. R. & Martin, B. R. Assessment of anandamide interaction with the cannabinoid brain receptor: SR141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. J. Pharmacol. Exp. Ther. 284, 1209–1217 (1998).

    CAS  PubMed  Google Scholar 

  17. Smith, S. R., Terminelli, C. & Denhardt, G. Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice. J. Pharmacol. Exp. Ther. 293, 136–150 (2000).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Nadler, V., Biegon, A., Beit-Yannai, E., Adamchik, J. & Shohami, E. 45Ca accumulation in rat brain after closed head injury; attenuation by the novel neuroprotective agent HU-211. Brain Res. 685, 1–11 (1995).

    Article  CAS  Google Scholar 

  20. Reggio, P. H. & Traore, H. Conformational requirements for endocannabinoid interaction with the cannabinoid receptors, the anandamide transporter and fatty acid amidohydrolase. Chem. Phys. Lipids 108, 15–35 (2000).

    Article  CAS  Google Scholar 

  21. Goparaju, S. K., Ueda, N., Yamaguchi, H. & Yamamoto, S. Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett. 422, 69–73 (1998).

    Article  CAS  Google Scholar 

  22. Sinor, A. D., Irvin, S. M. & Greenberg, D. A. Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci. Lett. 278, 157–160 (2000).

    Article  CAS  Google Scholar 

  23. Shen, M. & Thayer, S. A. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol. Pharmacol. 54, 459–462 (1998).

    Article  CAS  Google Scholar 

  24. Nagayama, T. et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci. 19, 2987–2995 (1999).

    Article  CAS  Google Scholar 

  25. van der Stelt, M. et al. Neuroprotectin by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J. Neurosci. 21, 6475–6479 (2001).

    Article  CAS  Google Scholar 

  26. Hansen, H. S., Moesgaard, B., Hansen, H. H. & Petersen, G. N-acylethanolamines and percursor phospholipids—relation to cell injury. Chem. Phys. Lipids 108, 135–150 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Sugiura, T., Yoshinaga, N., Kondo, S., Waku, K. & Ishima, Y. Generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain. Biochem. Biophys. Res. Comm. 271, 654–658 (2000).

    Article  CAS  Google Scholar 

  29. Klein, T. W., Lane, B., Newton, C. A. & Friedman, H. The cannabinoid system and cytokine network. Proc. Soc. Exp. Biol. Med. 225, 1–8 (2000).

    Article  CAS  Google Scholar 

  30. Ovadia, H., Wohlman, A., Mechoulam, R. & Weidenfeld, J. Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens. Neuropharmacology 34, 175–180 (1995).

    Article  CAS  Google Scholar 

  31. Chen, Y. et al. Human brain capillary endothelium. 2-Arachidonoylglycerol (endocannabinoid) interacts with endothelin-1. Circ. Res. 87, 323–327 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the US National Institute of Drug Abuse and the Israel Science Foundation for support (grants to R.M.). E.S. and R.M. are affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem's School of Pharmacy.

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Correspondence to Esther Shohami.

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Panikashvili, D., Simeonidou, C., Ben-Shabat, S. et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531 (2001). https://doi.org/10.1038/35097089

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