Combination therapies for traumatic brain injury: Retrospective considerations

Susan Margulies, Gail Anderson, Fahim Atif, Jerome Badaut, Robert Clark, Philip Empey, Maria Guseva, Michael Hoane, Jimmy Huh, Jim Pauly, Ramesh Raghupathi, Stephen Scheff, Donald Stein, Huiling Tang, Mona Hicks

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine whether combination therapies might be more effective than monotherapy at attenuating moderate TBI or promoting recovery, the National Institutes of Health funded six preclinical studies in adult and immature male rats to evaluate promising acute treatments alone and in combination. Each of the studies had a solid rationale for its approach based on previous research, but only one reported significant improvements in long-term outcomes across a battery of behavioral tests. Four studies had equivocal results because of a lack of sensitivity of the outcome assessments. One study demonstrated worse results with the combination in comparison with monotherapies. While specific research findings are reported elsewhere, this article provides an overview of the study designs, insights, and recommendations for future research aimed at therapy development for TBI.

Original languageEnglish
Pages (from-to)101-112
Number of pages12
JournalJournal of Neurotrauma
Issue number1
StatePublished - Jan 1 2016

Bibliographical note

Funding Information:
We thank Beth Ansel and Michael Weinrich of the NIH for their leadership in developing and administering the research initiative that supported these studies. We also thank Stephen Ashwal, Richard Hartman, and Andre Obenaus of Loma Linda University for their thoughtful discussions. The research was supported by NIH grants R01 HD061944, R01 HD061946, R01 HD061963, R01 HD061966, R01 HD061971, R01 NS069247, and U01 NS069545.

Publisher Copyright:
© Mary Ann Liebert, Inc. 2016.


  • pharmacological interventions
  • preclinical therapeutic development
  • treatments

ASJC Scopus subject areas

  • Clinical Neurology


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