The role of Cannabinoid Receptor 2 in cerebrovascular protection following traumatic brain injury

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PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in the United States and worldwide. The result of a bump, blow, or jolt to the head or penetrating brain injury, TBI disrupts normal brain function in two stages: first, the primary injury at the moment of impact, and later, the immune/inflammatory response, also called secondary injury. The inflammatory response that occurs during secondary injury can contribute greatly to neurological changes including cognitive impairment, executive function deficits, emotional and behavioral dysregulation. Currently, there are no approved pharmacological treatments for TBI despite the incidence of TBI increasing over the past decade. Consequently, there is an urgent need for novel pharmacological targets to control the aberrant secondary injury response. A hallmark feature of TBI pathology is vascular disruption and Blood Brain Barrier (BBB) hyperpermeability. Strategies that target the neurovasculature could open the door to new, effective therapeutics. It is known that the endocannabinoid system is a major regulator of neuronal homeostasis and immune function. Of the endocannabinoid system, the Cannabinoid 2 Receptor (CB2) is a major contributor to inflammation resolution. Importantly, our lab previously showed CB2 is expressed at low basal levels on cerebral microvascular endothelial cells and is upregulated during neuroinflammation. However, an unstudied aspect of TBI research is the kinetics of CB2 and its potential as a therapeutic target at the level of the cerebral endothelium. Specifically, here we explore the ability of novel CB2 agonists to restore BBB integrity following experimental neurotrauma. Preliminary data in vitro using synthetic chromenopyrazole based CB2 agonists, featuring increased affinity and solubility, demonstrate improvements in restoring BBB function and attenuating endothelial activation. In addition, analysis of gene expression in microvessels isolated from the area of impact shows rapid upregulation of the CNR2 gene, which encodes for CB2. Therefore, we hypothesize that activation of endothelial CB2 following TBI promotes BBB repair and vascular protection. This hypothesis will be explored using the following specific aims: 1) to characterize the receptor dynamics of endothelial CB2 expression post-injury and the therapeutic potential for potent CB2 agonists to provide vascular protection in both in vitro and in vivo models of TBI. These studies feature advanced imaging techniques, neurobehavioral evaluations and novel highly specific CB2 agonists, 2) Identification of molecular mechanisms that bridge CB2 receptor signaling with pathways that modulate BBB function. Together the aims proposed in this study will provide insight into mechanisms of TBI- pathology and the effectiveness of novel CB2 agonists against the harmful effects of neuroinflammation.