An Antioxidant and Anti-ER Stress Combo Therapy Decreases Inflammation, Secondary Brain Damage and Promotes Neurological Recovery following Traumatic Brain Injury in Mice
Charles K. Davis, Saivenkateshkomal Bathula, Martin Hsu, Kahlilia C. Morris-Blanco, Anil K. Chokkalla, Soomin Jeong, Jeong‐Woo Choi, Shruti Subramanian, Jin‐Soo Park, Zsuzsanna Fábry, Raghu Vemuganti
Abstract
The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species), tert-butylhydroquinone (promotes disposal of reactive oxygen species), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo-treated mice. Moreover, the tri-combo treatment prevented TBI-induced white matter volume loss in both sexes. The beneficial effects of tri-combo treatment were long-lasting and were also seen in aged mice. Thus, the present study supports the tri-combo treatment to curtail oxidative stress and endoplasmic reticulum stress concomitantly as a therapeutic strategy to improve TBI outcomes.