Repeated Closed-Head Mild Traumatic Brain Injury Induces Robust Caspase-1 Mediated Inflammation that Contributes to Nociplastic Pain.

Abstract

Abstract Patients who have experienced concussive mild traumatic brain injuries (mTBIs) suffer from a number of comorbidities including chronic pain. Despite extensive studies investigating the underlining mechanisms of mTBIs-associated chronic pain, the role of inflammation after brain injury, and its contribution towards long-term pain, are still poorly understood. Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes and its effects on TBI-related pain. Utilizing a recently developed transgenic caspase-1 luciferase reporter mouse, we characterized the bioluminescence signal evident in both in vivo and ex vivo tissue following repetitive closed head mTBIs. This allowed us to reveal the spatiotemporal dynamics of caspase-1 activation in individual animals across time. We established that there are significant increases in bioluminescent signal upon protease cleavage in the brain, thorax, abdomen, and paws in vivo which lasted for at least one week after each injury. Enhanced inflammation also was also in ex vivo brain slice preparations following injury event that lasted for at least 3 days. Concurrent with the in vivo detection of bioluminescent signal were persistent decreases in mouse hind paw withdrawal thresholds that lasted for more than two months post-injury. Using a potent small molecule inhibitor of NLRP3 inflammasome-caspase 1 activity, MCC950, we observed reductions in both caspase-1 bioluminescent signal in vivo, caspase-1 p45 expression by immunoblot and increase in hind paw withdrawal thresholds. Overall, these findings suggest that neuroinflammation in the brain following repeated mTBIs is coincidental with a chronic nociplastic pain state, and repeated mTBI associated events can be ameliorated by a highly specific small molecule inhibitor of NLRP3 inflammasome activation.