Title: Role of Cannabinoid 2 Receptor Activity in post CNS injury immunodeficiency
Background and Goal of Study: Patients after acute CNS injury have a high risk for an infection due to post-injury disturbance of the normally well-balanced interplay between the immune system and the CNS resulting in systemic immunosuppression. The endocannabinoid system (ECS) is composed of endocannabinoids, specific receptors and metabolizing enzymes, and is involved in key homeostatic functions in the CNS and the immune system. It is suggested that local upregulation of the ECS occurs following CNS injury and represents an adaptive mechanism. Cannabinoid type 2 receptors (CB2R) are expressed in higher levels on microglia and peripheral immune cells and are shown to have an immunosuppressive role, suggesting that the activation of CB2R may be contributing to the immunosuppression seen after CNS injury. Our pharmacological approach presents experimental evidence that targeting the CB2R may have beneficial effects on the outcome after an acute CNS injury.
Materials and Methods: CNS injury was induced in C57Bl/6 mice (male,6-8 weeks) via an intracerebral injection of the vasoconstrictor peptide, endothelin-1 (ET-1, 2µg/µl). Immune response to lipopolysaccharide (LPS) challenge was assessed 24 hr later using intravital microscopy within the intestinal microcirculation. The brain tissue was extracted and stained with tetrazolium chloride (TTC) to confirm CNS injury. The effect of genetic CB2R knockout on the severity of CIDS was also assessed. 
Results and Discussion: Consistent with the induction of CIDS, intravital microscopy confirmed that immunochallenged animals with CNS injury have a reduced count of activated leukocytes within the intestinal microcirculation when compared to immunochallenged animals without CNS injury. AM630 (2.5 mg/kg, i.v.) administration 15 min prior to LPS challenge, reversed this measure of suppressed immune function and did not have any detrimental impact on the infarct size. Genetic knockout of CB2R revealed that the CIDS was not induced after an acute CNS injury, confirming the involvement of the ECS in CIDS. Early administration of HU308 (2.5 mg/kg, i.v.) provided neuroprotective effect by reducing the size of CNS Injury.
Conclusion: Our findings suggest that CB2R pathway may be directly involved in post CNS injury pathophysiology. Various treatment time points, as well as pharmacologic confirmation of CB2R pathway involvement is needed.