Mechanistic Links between PARP, NAD, and Brain Inflammation after TBI
Annual rept. 25 Sep 2013-24 Sep 2014
NORTHERN CALIFORNIA INST FOR RESEARCH AND EDUCATION SAN FRANCISCO
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This is a pre-clinical study to establish the effectiveness anti-inflammatory approaches on improving recovery from traumatic brain injury. The studies employ rats and pigs, and use blast injury and controlled cortical injury CCI models. We aim to transiently suppress inflammation with veliparib an inhibitor of polyADP-ribose polymerase which thereby suppresses NF-kB mediated inflammatory responses, intranasal NAD, a natural metabolite which we have in prior studies shown to also suppress polyADP-ribose polymerase activity and inflammatory responses and ketogenic diet. CtBP12 knockout mice will be generated to test a specific mechanisms by which ketogenic diet can have anti-inflammatory effects. For all studies, outcome measures include histological indices of inflammation, cell death, and axonal injury, with behavioral indices of motor coordination, cognitive function, and anxiety, and with electrocorticography measures of brain network activity. Studies accomplished in year one have established dose-effectiveness for veliparib, have characterized the physical features and histological effects of rat and pig CCI and blast models, and have established quantifiable indices of motor and cognitive recovery. These studies have also shown that electrocorticography can reliably track changes in brain network activity as motor function recovers.
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