Abstract T P92: Remote Ischemic Conditioning (RIC) Attenuates Post-TBI Ischemic Injury and Improves Behavioral Outcomes

Abstract

Background: Others and we reported that RIC-therapy is safe in humans, and protective in rodents that can be repeatedly used under both, hemorrhagic and ischemic stroke. Since TBI shares some common features of ischemic and hemorrhagic injury as in stroke, we hypothesized that RIC-therapy will remain protective in TBI, too. Methods: We tested RIC-therapy in a closed-head injury model of pediatric TBI in male mice (28 days old). Mice were later randomized for either RIC-therapy or its sham-procedure once daily starting 1-hour post-TBI until sacrifice. Cerebral blood flow (CBF) was measured by laser speckle imager (LSCI), and MRI was used to estimate edema and cerebral perfusion. Mice were also tested for functional outcomes. Statistical significance was determined at p<0.05. Results: Micro-CT showed a shallow dent along the median suture of skull. Closed-head TBI led to progressive acute ischemia, which was attenuated with time. However, reduced CBF and significant edema was observed at 48-hours post-TBI, which was attenuated by RIC-therapy. Open-field test showed no significant difference at 3 days post-TBI but in the narrow beam-walk challenge, TBI mice showed significantly impaired activity, which was improved by RIC-therapy. Flowcytometry in brain tissue confirmed significantly increased opening of mitochondrial permeability transition pore and necro-apoptotic cell death at 3 days post-TBI that was blocked by RIC-therapy. In a 3-weeks follow up, the mice with TBI were apparently normal but showed depressive phenotype in challenged environments, such as lesser mobility during forced swim test, and reduced cerebrovascular reserve capacity (CVRC). Flowcytometric analysis of the brain tissue at 3-weeks post-TBI showed reduced neuronal activity as detected by the poor population of cFOS positive neurons. RIC-therapy after TBI significantly attenuated the depressive phenotype, improved CVRC and cFOS positive neurons, collectively indicating improved neurovascular coupling and function. Conclusion: Post-TBI RIC-therapy is safe and beneficial, and can be translated to prevent ischemic injury.