Endocannabinoids and traumatic brain injury

Abstract

Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI. LINKED ARTICLESThis article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi. org/10.1111/bph.2011.163.issue-7 Abbreviations* 2-AG, 2-arachidonoyl-glycerol; AraS, N-arachidonoyl-L-serine; CB1, ENSG00000118432; CB2, ENSG00000162562; DGL, diacylglycerol lipase; eCB: endocannabinoid; TRPV1, ENSG00000043316; FAAH, fatty acid amide hydrolase; GPR55, ENSG00000135898; TBI, traumatic brain injury IntroductionOver the last two decades, since the endocannabinoid (eCB) system was discovered, our knowledge of its structure and functions has significantly expanded. This system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (CB1, CB2, possibly also TRPV1 and GPR55), transporters and enzymes, which are responsible for the synthesis [N-acyl-phosphatidylethanolaminephospholipase D, diacylglycerol lipase (DGL)] and degradation of these lipid mediators [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase] (Piomelli, 2003;Mackie, 2006).There is a multiplicity of eCB actions, mainly in the brain, under both physiological and pathological conditions. Unlike 'classical' neurotransmitters, the eCBs are not stored in presynaptic vesicles, rather, they are produced 'on demand' when increased intracellular Ca ++ is the major intracellular trigger for synthesis. The primary ligands produced in the brain are anandamide (Devane et al., 1992...

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…38 The anti-inflammatory and neuroprotective behaviors of 2-AG suggest that manipulation of 2-AG signaling may provide novel therapeutic interventions to prevent TBIinduced neuropathologic events. 22 MAGL is the primary enzyme degrading 2-AG in the brain. 14,15 Previous studies demonstrated that MAGL inactivation suppresses inflammatory cytokines in response to proinflammatory insults and neurodegeneration in an MPTP model of Parkinson's disease.…”

“…19,21,27 In addition, inhibition of CB1 receptors only partly blocks 2-AG-produced neuroprotective effects in TBI. 22 This suggests that there may be other mechanisms mediating the anti-neuroinflammatory and neuroprotective effects produced by inhibition of 2-AG metabolism. 38 It has been proposed that these beneficial effects may result from the reduction in metabolites of 2-AG when MAGL is inhibited.…”

Stimulatory and Inhibitory Roles of Brain 2-Arachidonoylglycerol in Bombesin-Induced Central Activation of Adrenomedullary Outflow in Rats

“…The 2-AG released into the synaptic cleft seems to be rapidly inactivated by uptake into neurons (23). This 2-AGinduced retrograde signaling process seems to be involved in widespread effects, including synaptic plasticity (24), analgesia (25), neuroprotection and neurotoxicity (26,27), food intake (24,28), and also in the baroreflexevoked central sympathetic modulation (29). Recently, we reported that central pretreatment with AM 251 (an antagonist of cannabinoid CB 1 receptors) or AM 404 (an uptake-inhibitor of endocannabinoid) potentiated or reduced the centrally administered bombesin-induced elevation of plasma catecholamines, respectively (16).…”

Glucocorticoid-endocannabinoid interaction in cardiac surgical patients: relationship to early cognitive dysfunction and late depression

“…Although there is currently no unequivocal biological explanation for this observation, there is clear evidence that ECs are markedly increased in response to pathogenic events in the brain (Shohami et al, 2011). Numerous experimental studies on models of brain toxicity, neuroinflammation, and trauma support the notion that ECs are part of the brain ' s compensatory or repair mechanisms (Shohami et al, 2011 possible neuroprotective effect of 2-AG (Kreutz et al, 2009;Lourbopoulos et al, 2011). Patients with an inadequately low perioperative 2-AG response might be at risk for early postoperative ACD/delirium and for the later development of depression.…”