Brief Oxygen Exposure after Traumatic Brain Injury Hastens Recovery and Promotes Adaptive Chronic Endoplasmic Reticulum Stress Responses

Traumatic brain injury (TBI) is a major public health concern, particularly in adolescents who have a higher mortality and incidence of visual pathway injury compared to adult patients. Likewise, we have found disparities between adult and adolescent TBI outcomes in rodents. Most interestingly, adolescents suffer a prolonged apneic period immediately post-injury, leading to higher mortality; therefore, we implemented a brief oxygen exposure paradigm to circumvent this increased mortality. Adolescent male mice experienced a closed-head weight-drop TBI and were then exposed to 100% O₂ until normal breathing returned or recovered in room air. We followed mice for 7 and 30 days and assessed their optokinetic response; retinal ganglion cell loss; axonal degeneration; glial reactivity; and retinal ER stress protein levels. O₂ reduced adolescent mortality by 40%, improved post-injury visual acuity, and reduced axonal degeneration and gliosis in optical projection regions. ER stress protein expression was altered in injured mice, and mice given O₂ utilized different ER stress pathways in a time-dependent manner. Finally, O₂ exposure may be mediating these ER stress responses through regulation of the redox-sensitive ER folding protein ERO1α, which has been linked to a reduction in the toxic effects of free radicals in other animal models of ER stress.