Abstract
The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.
Highlights
THE ENDOCANNABINOID SYSTEMTraumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (Langlois et al, 2006)
A 2007 study estimated that traumatic brain injury (TBI) results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (Faul et al, 2007), demonstrating both the long term financial and human toll of TBI
Three predominant categories are currently in use; plant-derived phytocannabinoids, synthetically produced cannabinoids used as research (Wiley et al, 2014) or recreational drugs (Mills et al, 2015), and the endogenous cannabinoids, N-arachidonoylethanolamine (Devane et al, 1992) and 2-arachidonyl glycerol (2-AG) (Mechoulam et al, 1995; Sugiura et al, 1995)
Summary
Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (Langlois et al, 2006). Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in Gertsch et al, 2010), synthetically produced cannabinoids used as research (Wiley et al, 2014) or recreational drugs (Mills et al, 2015), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) (Devane et al, 1992) and 2-AG (Mechoulam et al, 1995; Sugiura et al, 1995) These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 (Devane et al, 1988) and CB2 (Munro et al, 1993). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in Di Marzo, 2008) many of which are impacted following TBI Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. While 2-AG is known to be synthesized by DAGL-α and DAGL-β (Bisogno et al, 2003), the mechanisms mediating anandamide production are incompletely understood (Blankman and Cravatt, 2013)
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