Nicotinamide Treatment in Traumatic Brain Injury

Operation Brain Trauma Therapy

Deborah A. Shear, C. Edward Dixon, Helen Bramlett, Stefania Mondello, W. Dalton Dietrich, Ying Deng-Bryant, Kara E. Schmid, Kevin K W Wang, Ronald L. Hayes, John T. Povlishock, Patrick M. Kochanek, Frank C. Tortella

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Nicotinamide (vitamin B3) was the first drug selected for cross-model testing by the Operation Brain Trauma Therapy (OBTT) consortium based on a compelling record of positive results in pre-clinical models of traumatic brain injury (TBI). Adult male Sprague-Dawley rats were exposed to either moderate fluid percussion injury (FPI), controlled cortical impact injury (CCI), or penetrating ballistic-like brain injury (PBBI). Nicotinamide (50 or 500 mg/kg) was delivered intravenously at 15 min and 24 h after injury with subsequent behavioral, biomarker, and histopathological outcome assessments. There was an intermediate effect on balance beam performance with the high (500 mg/kg) dose in the CCI model, but no significant therapeutic benefit was detected on any other motor task across the OBTT TBI models. There was an intermediate benefit on working memory with the high dose in the FPI model. A negative effect of the low (50 mg/kg) dose, however, was observed on cognitive outcome in the CCI model, and no cognitive improvement was observed in the PBBI model. Lesion volume analysis showed no treatment effects after either FPI or PBBI, but the high dose of nicotinamide resulted in significant tissue sparing in the CCI model. Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-1 (UCH-L1) in blood at 4 or 24 h after injury. Negative effects (both doses) were detected on biomarker levels of GFAP after FPI and on biomarker levels of UCH-L1 after PBBI. The high dose of nicotinamide, however, reduced GFAP levels after both PBBI and CCI. Overall, our results showed a surprising lack of benefit from the low dose nicotinamide. In contrast, and partly in keeping with the literature, some benefit was achieved with the high dose. The marginal benefits achieved with nicotinamide, however, which appeared sporadically across the TBI models, has reduced enthusiasm for further investigation by the OBTT Consortium.

Original languageEnglish (US)
Pages (from-to)523-537
Number of pages15
JournalJournal of Neurotrauma
Volume33
Issue number6
DOIs
StatePublished - Mar 15 2016

Fingerprint

Niacinamide
Wounds and Injuries
Percussion
Brain Injuries
Glial Fibrillary Acidic Protein
Biomarkers
Therapeutics
Hydrolases
Ubiquitin
Traumatic Brain Injury
Short-Term Memory
Sprague Dawley Rats
Outcome Assessment (Health Care)

Keywords

  • biomarker
  • controlled cortical impact
  • fluid percussion
  • neuroprotection
  • penetrating ballistic-like brain injury
  • rat
  • therapy
  • Vitamin B

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Nicotinamide Treatment in Traumatic Brain Injury : Operation Brain Trauma Therapy. / Shear, Deborah A.; Dixon, C. Edward; Bramlett, Helen; Mondello, Stefania; Dalton Dietrich, W.; Deng-Bryant, Ying; Schmid, Kara E.; Wang, Kevin K W; Hayes, Ronald L.; Povlishock, John T.; Kochanek, Patrick M.; Tortella, Frank C.

In: Journal of Neurotrauma, Vol. 33, No. 6, 15.03.2016, p. 523-537.

Research output: Contribution to journalArticle

Shear, DA, Dixon, CE, Bramlett, H, Mondello, S, Dalton Dietrich, W, Deng-Bryant, Y, Schmid, KE, Wang, KKW, Hayes, RL, Povlishock, JT, Kochanek, PM & Tortella, FC 2016, 'Nicotinamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy', Journal of Neurotrauma, vol. 33, no. 6, pp. 523-537. https://doi.org/10.1089/neu.2015.4115
Shear, Deborah A. ; Dixon, C. Edward ; Bramlett, Helen ; Mondello, Stefania ; Dalton Dietrich, W. ; Deng-Bryant, Ying ; Schmid, Kara E. ; Wang, Kevin K W ; Hayes, Ronald L. ; Povlishock, John T. ; Kochanek, Patrick M. ; Tortella, Frank C. / Nicotinamide Treatment in Traumatic Brain Injury : Operation Brain Trauma Therapy. In: Journal of Neurotrauma. 2016 ; Vol. 33, No. 6. pp. 523-537.
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