16. Methylene blue infusion for treatment of traumatic brain injury-associated neuroinflammation and depressive-like behavior

Traumatic brain injury (TBI) induces immediate neuroinflammation that contributes to impaired functional recovery and long-lasting deficits, including depression. We hypothesized that treatment with methylene blue (MB), a blood brain barrier permeable antioxidant, would ameliorate TBI-induced inflammation and depressive-like behavior. To address this hypothesis, young adult male mice received a sham operation or moderate TBI. After 15–30 min mice were injected intravenously with vehicle or 2 mg/kg MB. After 24 h, mice that received a TBI had an increased percentage of inflammatory myeloid cells in circulation corresponding to increased edema in the cortex and inflammatory gene expression (e.g., CD14, IL-1b) in the hippocampus. These TBI-associated effects, however, were markedly reduced in mice treated with MB. Moreover, MB treatment significantly attenuated TBI-induced inflammatory gene expression in microglia, whereas anti-inflammatory gene expression (i.e., IL-10) was exaggerated in TBI-MB mice compared to all other groups. Although MB did not improve nest building or motor coordination during the first week after injury, MB did attenuate TBI-associated depressive-like behavior at seven days post injury. Together these results indicate that early intervention with MB selectively reduced inflammatory gene expression while promoting anti-inflammatory gene expression and attenuated TBI-associated complications including edema and depressive-like behavior. Thus, MB treatment could reduce immediate life-threatening complications increasing survival after TBI while also promoting long-lasting neurological and behavioral improvements making it a promising candidate for clinical trial.