Title : Targeting the endocannabinoid system: A novel approach to the treatment of traumatic brain injury and stroke
Abstract:
Cannabis is one of the most widely used plant drugs in the world and was used for millennia for its medicinal and mind-altering effects. The latter are known to be mediated via the activation of the endocannabinoid (eCB) receptor CB1. Developments in medicinal chemistry of novel non-psychoactive synthetic cannabinoids have indicated that it is possible to separate some of the therapeutic effects from the undesirable psychoactivity. Indeed, Cannabidiol (CBD) the major non-psychotropic cannabinoid found in cannabis sativa, has low affinity to the cannabinoid receptor types and has no "mind altering" properties. Nevertheless, it exerts properties affording neuroprotection in animal models of brain disorders, similar to those reported for the eCB system.
The eCB system includes ligands, such as anandamide and 2-arachidonoyl glycerol (2-AG), which bind to receptors (CB1, CB2, TRPV1), and a group of cannabionoid-like lipids, identified as fatty acid amides of ethanol amines and amino acids [N-acyl aminoacids e.g. arachidonoyl-serine, AraS), which do not bind to the eCB receptors yet exert pharmacological activities similar to these of the "classical" cannabinoids. The pharmacological profile of the eCB includes modulation of neurotransmitter systems and of the BBB along with antioxidants and anti-inflammatory activities. Our earlier studies, using mouse model of traumatic brain injury (TBI), revealed a 10-fold increase in 2-AG in the injured hemisphere 4h after TBI. Importantly, treatment with synthetic 2-AG attenuated edema formation, infarct volume, BBB permeability, neuronal cell loss at the CA3 hippocampal region, and neuroinflammation. Moreover, AraS exerted eCB-mediated neuroprotection after TBI via the induction of a pro-survival and antiapoptotic cascade, and involves Akt and ERK phosphorylation in its downstream signaling. These effects were partly blocked by CB1, CB2 and TRPV1 antagonists, despite the lack of directing eCB binding to them. The properties of the newly described eCB system provide a mechanistic basis to support its role in reducing the effects of the harmful mechanisms of the primary events post-TBI, and to offer a basis for the long-term neuro-recovery effects on the secondary injury.
