Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Physiology and Biophysics
First Advisor
Dong Sun
Second Advisor
A. Rory McQuiston
Third Advisor
Qinglian Liu
Abstract
Traumatic brain injury (TBI) is a significant health issue, with the elderly population at the age of 75 and older among the highest incidence group. Currently there is no effective treatment for TBI. Moreover, there is limited research examining the effects of TBI on the aged brain. Following TBI, the neuroinflammatory response acts as a secondary injury leading to further brain damage. Inflammasomes are important multiprotein complexes that regulate the innate immune response, production of inflammatory cytokines such as interleukin-1 beta (IL 1β), activation of caspase-1 and induction of cell death. Among inflammasome family members, leucine-rich repeat and pyrin containing protein 3 (NLRP3) is the most extensively studied in neurological diseases including TBI. In this study, we examined TBI-induced activation of NLRP3 inflammasome and its downstream effectors, and assessed the therapeutic potential of a novel NLRP3 inhibitor (YM-III-109) for neuroprotection of the aged brain following a moderate focal brain injury. Briefly, a group of 20-month-old Sprague Dawley male rats were subjected to a moderate cortical impact injury (CCI). Following TBI, rats were treated with 4 doses of YM III-109 (20mg/kg, i.p., at 30 minutes, 6, 24 and 30 hours post-injury). Animals were sacrificed at 2 days post-injury and brain tissues were harvested. For neuropathological assessment, cortical lesion volume, the extent of injury-induced degenerative neurons and the number of activated microglia/macrophages were quantified. Additionally, protein expression levels of inflammatory mediators including pro-inflammatory cytokines TNF-α and IL-1β were measured via ELISA. Furthermore, protein expression levels of inflammatory markers including nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB), high mobility group box 1 (HMGB1), and caspase -1 along with NLRP3 and its adaptor protein apoptotic speck-containing protein (ASC) were measured via Western blotting. We found that focal brain injury induces significant 8 activations of NLRP3 inflammasome and downstream effectors in both the ipsilateral cortex and hippocampus. Post-injury treatment with our novel NLRP3 inhibitor YM-III-109 can mitigate the injury-induced inflammatory responses and neurodegeneration. Further studies assessing the therapeutic potential for YM-III-109 are ongoing. Our findings provide further insight on the NLRP3 inflammatory response following TBI in the aged brain and the prospect of NLRP3 as a potential therapeutic target.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-8-2024