Abstract
Therapeutic hypothermia (TH) is an attractive target for mild traumatic brain injury (mTBI) treatment, yet significant gaps in our mechanistic understanding of TH, especially at the cellular level, remain and need to be addressed for significant forward progress to be made. Using a recently-established 3D in-vitro neural hydrogel model for mTBI we investigated the efficacy of TH after compressive impact injury and established critical treatment parameters including target cooling temperature, and time windows for application and maintenance of TH. Across four temperatures evaluated (31.5, 33, 35, and 37°C), 33°C was found to be most neuroprotective after 24 and 48 hours post-injury. Assessment of TH administration onset time and duration showed that TH should be administered within 4 hours post-injury and be maintained for at least 6 hours for achieving maximum viability. Cellular imaging showed TH reduced the percentage of cells positive for caspases 3/7 and increased the expression of calpastatin, an endogenous neuroprotectant. These findings provide significant new insight into the biological parameter space that renders TH effective in mitigating the deleterious effects of cellular mTBI and provides a quantitative foundation for the future development of animal and preclinical treatment protocols.
Highlights
Despite the overwhelming amount of research and resources devoted, traumatic brain injury (TBI) continues to be a serious public health concern
Using a 3D, in-vitro neural injury model of mild traumatic brain injury (mTBI) previously described in Bar-Kochba et al (Sci Rep, 2016) and in Scimone et al (Nat Prot, 2018)[20,21] (Fig 1), we studied the efficacy of therapeutic hypothermia treatment after compressive injury, initially focusing on the optimal target temperature and the role of Therapeutic hypothermia (TH) administration onset time and duration
Population viability is assessed through a standard calcein AM, Ethidium homodimer-1cellular viability assay, where calcein AM represents healthy intracellular esterase activity, and ethidium homodimer staining indicates a loss of membrane integrity and cellular homeostasis
Summary
Despite the overwhelming amount of research and resources devoted, traumatic brain injury (TBI) continues to be a serious public health concern. Mild hypothermia mitigates neural injury in a 3D in-vitro model of mTBI additional external funding was received for this study. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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