Synergistic effect of mild traumatic brain injury and alcohol aggravates neuroinflammation, amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations: Impact on psychological stress.

After a mild traumatic brain injury (mTBI), victims often experience emotional/psychological stress such as heightened irritability, anxiety, apathy, and depression. Severe mental health complications are common in military populations following a combat-acquired TBI and intensified unhealthy alcohol use. The high prevalence of alcohol abuse among TBI victims underscores how alcohol abuse exacerbates emotional/psychological symptoms such as depression and anxiety. The experimental mTBI was induced in vivo by fluid percussion injury (15 psi) in mice and ethanol diet feeding continued for 28 days. We analyzed different biomarkers of the biochemical mechanisms and pathophysiology of neurological damage, and functional outcome of psychological stress by sucrose preference, and light-dark tests. We demonstrated that the synergistic effect of TBI and alcohol leads to psychological stress such as depression and anxiety. The studies showed that oxidative stress, amyloidogenesis, tau pathology, neuroinflammation, and neurodegeneration markers were elevated, and glial activation and blood-brain barrier (BBB) damage were exacerbated during the synergistic effect of TBI and alcohol. Further, we studied the biochemical mechanisms of psychological stress that showed the significant reduction of 5-HT1AR, neuropeptide-Y, and norepinephrine, and an increase in monoamine oxidase-a in the combined effect of TBI and alcohol. This work suggested that the combined TBI and alcohol-induced effect leads to depression and anxiety, via sequential biochemical changes that cause neuroinflammation, amyloidogenesis, tau pathology, neurodegeneration, and BBB alterations. This clinically relevant study will contribute to developing a comprehensive therapeutic approach for patients suffering from TBI and alcohol-mediated neurological damage and psychological stress.