Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

Abstract

Abstract Traumatic brain injury (TBI) increases the risk of neuropsychiatric disorders, particularly anxiety disorders. Yet, there are presently no therapeutic interventions to prevent the development of post-traumatic anxiety or effective treatments once it has developed. This is because, in large part, of a lack of understanding of the underlying pathophysiology. Recent research suggests that chronic neuroinflammatory responses to injury may play a role in the development of post-traumatic anxiety in rodent models. Acute peri-injury administration of immunosuppressive compounds, such as Ibudilast (MN166), have been shown to prevent reactive gliosis associated with immune responses to injury and also prevent lateral fluid percussion injury (LFPI)-induced anxiety-like behavior in rats. There is evidence in both human and rodent studies that post-traumatic anxiety, once developed, is a chronic, persistent, and drug-refractory condition. In the present study, we sought to determine whether neuroinflammation is associated with the long-term maintenance of post-traumatic anxiety. We examined the efficacy of an anti-inflammatory treatment in decreasing anxiety-like behavior and reactive gliosis when introduced at 1 month after injury. Delayed treatment substantially reduced established LFPI-induced freezing behavior and reactive gliosis in brain regions associated with anxiety and continued neuroprotective effects were evidenced 6 months post-treatment. These results support the conclusion that neuroinflammation may be involved in the development and maintenance of anxiety-like behaviors after TBI.