Increased Carbon Dioxide Respiration Prevents the Effects of Acceleration/Deceleration Elicited Mild Traumatic Brain Injury

Abstract

Acceleration/deceleration forces are a common component of various causes of mild traumatic brain injury (mTBI) and result in strain and shear forces on brain tissue. A small quantifiable volume dubbed the compensatory reserve volume (CRV) permits energy transmission to brain tissue during acceleration/deceleration events. The CRV is principally regulated by cerebral blood flow (CBF) and CBF is primarily determined by the concentration of inspired carbon dioxide (CO2). We hypothesized that experimental hypercapnia (i.e. increased inspired concentration of CO2) may act to prevent and mitigate the actions of acceleration/deceleration-induced TBI. To determine these effects C57Bl/6 mice underwent experimental hypercapnia whereby they were exposed to medical-grade atmospheric air or 5% CO2 immediately prior to an acceleration/deceleration-induced mTBI paradigm. mTBI results in significant increases in righting reflex time (RRT), reductions in core body temperature, and reductions in general locomotor activity-three hours post injury (hpi). Experimental hypercapnia immediately preceding mTBI was found to prevent mTBI-induced increases in RRT and reductions in core body temperature and general locomotor activity. Ribonucleic acid (RNA) sequencing conducted four hpi revealed that CO2 exposure prevented mTBI-induced transcriptional alterations of several targets related to oxidative stress, immune, and inflammatory signaling. Quantitative real-time PCR analysis confirmed the prevention of mTBI-induced increases in mitogen-activated protein kinase kinase kinase 6 and metallothionein-2. These initial proof of concept studies reveal that increases in inspired CO2 mitigate the detrimental contributions of acceleration/deceleration events in mTBI and may feasibly be translated in the future to humans using a medical device seeking to prevent mTBI among high-risk groups.