Methylene blue attenuates traumatic brain injury-associated neuroinflammation and acute depressive-like behavior in mice

Ashley M. Fenn, John P. Skendelas, Daniel N. Moussa, Megan M. Muccigrosso, Phillip G. Popovich, Jonathan Lifshitz, Daniel S. Eiferman, Jonathan P. Godbout

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)127-138
Number of pages12
JournalJournal of Neurotrauma
Issue number2
StatePublished - Jan 15 2015


  • cytokines
  • fluid percussion injury
  • intervention
  • microglia
  • recovery

ASJC Scopus subject areas

  • Clinical Neurology


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