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


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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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).

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