Traumatic brain injury (TBI) is associated with
cerebral edema, blood brain barrier breakdown, and
neuroinflammation that contribute to the degree of injury severity and functional recovery. Unfortunately, there are no effective proactive treatments for limiting immediate or long-term consequences of TBI. Therefore, the objective of this study was to determine the efficacy of
methylene blue (MB), an
antioxidant agent, in reducing
inflammation and behavioral complications associated with a
diffuse brain injury. Here we show that immediate MB
infusion (intravenous; 15-30 minutes after TBI) reduced
cerebral edema, attenuated microglial activation and reduced
neuroinflammation, and improved behavioral recovery after midline fluid percussion injury in mice. Specifically, TBI-associated
edema and inflammatory gene expression in the hippocampus were significantly reduced by MB at 1 d post injury. Moreover, MB intervention attenuated TBI-induced inflammatory gene expression (
interleukin [IL]-1β,
tumor necrosis factor α) in enriched microglia/macrophages 1 d post injury. Cell culture experiments with
lipopolysaccharide-activated BV2 microglia confirmed that MB treatment directly reduced IL-1β and increased
IL-10 messenger
ribonucleic acid in microglia. Last, functional recovery and depressive-like behavior were assessed up to one week after TBI. MB intervention did not prevent TBI-induced reductions in
body weight or motor coordination 1-7 d post injury. Nonetheless, MB attenuated the development of acute depressive-like behavior at 7 d post injury. Taken together, immediate intervention with MB was effective in reducing
neuroinflammation and improving behavioral recovery after
diffuse brain injury. Thus, MB intervention may reduce life-threatening complications of TBI, including
edema and
neuroinflammation, and protect against the development of neuropsychiatric complications.