CHARACTERIZATION AND TARGETING OF THE ENDOCANNABINOID SYSTEM IN TRAUMATIC BRAIN INJURY

Abstract

Traumatic Brain Injuries (TBI) are considered one of the leading causes of death and disability worldwide. One emerging area of TBI research is the involvement of the endocannabinoid system (ECS) in response to brain injury. The ECS is modulated by exogenous cannabinoids such as ∆9-tetrahydrocannabinol (THC) found in Cannabis sativa. THC is a partial agonist of both cannabinoid receptors CB1R and CB2R. CB1R activation is associated with neuroprotective effects and contributes to analgesia and anxiolytic effects, whereas CB2R activation reduces inflammation. Therefore, the treatment of rats subjected to TBI with THC post-injury may restore motor function and improve behavioral profiles of injured rats. In order to assess behavioral and physiological changes associated with TBI following a closed head impact injury in a rat model, two experiments were performed. Rats were subjected to a closed-head injury impact equivalent to a mild/moderate TBI, or sham injury, and subsequently treated with THC or vehicle treatment. In the first experiment, 9 rats of both sexes were randomly assigned to: 1) SHAM TBI + Vehicle; 2) SHAM TBI + 1 mg/kg THC; 3) TBI + Vehicle; or 4) TBI + 1 mg/kg THC. Rats were subjected to a number of behavioural measures to assess drug effect, anxiety, working memory, and locomotor function following injury. Rats were assessed prior to TBI to establish a baseline, and on the above measures for 7 days following TBI. In the second experiment, 3 rats of both sexes were randomly assigned to 1) TBI + Vehicle or 2) TBI + 10mg/kg THC and tested for locomotor performance only. According to the data collected, TBI significant decreased male but not female locomotor recovery on the rotarod. Additionally, 1 mg/kg THC administration 1 h post-TBI significantly decreased male Sham-TBI, but not female locomotor activity. In the second experiment, visible differences in locomotor recovery were seen between TBI-VEH vs. TBI+THC 10 mg/kg on day 1-4 following TBI and drug administration, but according to the data collected, 10 mg/kg THC administration 1 h post-TBI did not significantly impact locomotor recovery post injury. THC or TBI did not significantly change other behavioural measures collected. These data demonstrate the importance of exploring the therapeutic potential of cannabinoids such as THC following TBI, which could contribute to reducing the longevity of lasting post-injury symptomology.