CANNABINOID 2 RECEPTOR-BASED MODULATION OF THE IMMUNE RESPONSE IN EXPERIMENTAL MODELS OF CNS INJURY

Abstract

One of the most important outcome-limiting medical risks after an acute CNS injury, such as stroke, spinal cord or traumatic brain injury, is an increased susceptibility to infections. This dysregulation of the immune system has been termed CNS injury-induced immunodeficiency syndrome (CIDS). The underlying mechanisms that are responsible for CIDS are still not elucidated but are hypothesized to be promoted by the injured brain. The endocannabinoid system (ECS) is responsible for key homeostatic functions in both the CNS and immune system. Local upregulation of the ECS occurs following CNS injury and represents an adaptive mechanism to limit neuroinflammation. It has been shown that activation of CB2Rs causes an immunosuppressive effect, suggesting that CB2R activity may contribute to peripheral immunosuppression after CNS injury. The work in this dissertation investigated whether CB2R modulation can prevent or reduce the severity of CIDS. Experimental CNS injury was induced in C57Bl/6 mice via two models – (1) an intracerebral injection of the vasoconstrictor peptide, endothelin-1 (ET-1) and (2) surgical hypoxia-ischemia. The immune response to bacterial endotoxin was studied 24 hours after the CNS injury by intravital microscopy (IVM) to assess leukocyte recruitment in the peripheral (gut), as well as in local (brain) microcirculation. Neurological impairment and brain infarct volume were evaluated across treatment groups. Circulating cytokine and adhesion molecule levels were also assessed. CB2R expression in peripheral tissue was measured with qRT-PCR. Results suggest that pharmacological manipulation of the CB2R may present a viable therapeutic approach – early CB2R activation with HU308 reduced brain injury size and ameliorated the immune function, whereas late CB2R inhibition with AM630 reduced the severity of immune suppression. In conclusion, CB2R modulation may prevent CIDS in acute CNS injury by reducing the initial damage to the brain or to directly improve the immune activity in cases where CIDS is already physiologically established. Future studies should focus on investigating various time points throughout the onset of CIDS, as well as on elucidation of the pathways involved in CIDS onset to identify the optimal treatment targets and time window for the proposed CB2R modulation therapies.