Browsing by Author "Al-Juboori, Mohammed"

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    459 Caspase-1 mediated inflammatory response - a critical player in concussive mild traumatic brain injury (mTBI) associated long term pain
    (Cambridge University Press, 2023-04-24) Nguyen, Tyler; Talley, Sarah; Nguyen, Natalie; Cochran, Ashlyn G.; Al-Juboori, Mohammed; Smith, Jared A.; Saxena, Saahil; Campbell, Edward M.; Obukhov, Alexander G.; White, Fletcher A.; Anesthesia, School of Medicine
    OBJECTIVES/GOALS: Patients who have experienced conjunctive mild traumatic brain injuries (mTBIs) suffer from a number of comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation after mTBI and its contribution to long-term pain are still poorly understood. METHODS/STUDY POPULATION: Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes and their 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 tissues following repetitive closed head mTBIs. This allowed us to reveal the spatiotemporal dynamics of caspase-1 activation in individual animals over time. Furthermore, we utilize various proteomic and behavioral assays to evaluate the role of caspase-1 mediated inflammation in the development and progression of injury-associated chronic pain. Lastly, by blocking inflammasome caspase-1 activation with a specific inhibitor, we assess its clinical potential as the next therapeutic approach to pain. RESULTS/ANTICIPATED RESULTS: We established that there were significant increases in bioluminescent signals upon protease cleavage in the brain, thorax, abdomen, and paws in vivo, which lasted for at least one week after each injury. Enhanced inflammation was also observed in ex vivo brain slice preparations following injury events that lasted for at least 3 days. Concurrent with the in vivo detection of the bioluminescent signal were persistent decreases in mouse hind paw withdrawal thresholds that lasted for more than two months postinjury. Using MCC950, a potent small molecule inhibitor of NLRP3 inflammasome-caspase 1 activity, we observed reductions in both caspase-1 bioluminescent signals in vivo and caspase-1 p45 expression by immunoblotting and an increase in hind paw withdrawal thresholds. DISCUSSION/SIGNIFICANCE: 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.
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    Transcranial optogenetic mapping revealed longitudinal changes in motor maps of ipsi-lesional and contra-lesional cortex following mild traumatic brain injury
    (Office of the Vice Chancellor for Research, 2016-04-08) Nguyen, Tyler; Al-Juboori, Mohammed; Walerstein, Jakub; Moore, Allison; Ping, Xingjie; Jin, Xiaoming
    Abstract: Victims of traumatic brain injury (TBI) suffer short- and long-term physical, cognitive, behavioral and emotional impairments that depend on the severity of the injury. Mechanical and cellular alterations in mild TBI can cause global change in inhibition and excitation on the neuronal network level even in the absence of histologically significant cell injury. To understand functional changes of the motor cortex following closed-head mTBI, we applied an optogenetic stimulation method to map motor cortex activity in channelrhodopsins 2 (ChR2) transgenic mice. A closed-head mTBI was performed via a cortical impact device and longitudinal optogenetic mapping of the forelimb areas of the ipsilateral and contralateral motor cortex were done at multiple time points post injury. Optogenetically evoked responses were recorded with electromyography (EMG) in the bicep brachii of the forelimb and with electroencephalography (EEG) in the brain. The mapping revealed immediate suppression of EMG response of the injured ipsilateral motor cortex post mTBI, which was then followed by an enhanced response. The maps also showed a marked increased in the number of responsive spots in the contralateral motor cortex within the first 12 hours. In addition, rotarod behavioral test show a decrease in motor response within first two days after mTBI follows by recovery. In vitro calcium imaging of GCaMP6 cortical slice showed a decrease in intracellular calcium signal at 2 hours post in injury. These data suggest that excitable cortical neurons exhibit short-term impairment locally (epsilateral) as a result of the injury while long-term contralateral hyperexcitability may act as a functional compensatory mechanism. Our data suggests optogenetic mapping of the motor cortex is a valuable technique for longitudinal study of brain functions following mTBI, and that it revealed post-injury hyperexcitability may play an adaptive role in modifying the functional organization of the cortex in response to the short-term activity lost. These longitudinal sequelae may underlie posttraumatic neurological deficits and brain functional recovery.