title: Nicotinamide Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.
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.
authors.affiliation: 1 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Shear
authors.affiliation: 2 Department of Neurological Surgery, Brain Trauma Research Center, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.affiliation: 3 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.|4 Bruce W. Carter Department of Veterans Affairs Medical Center , Miami, Florida.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.affiliation: 5 Department of Neurosciences, University of Messina , Messina, Italy .
authors.forename: Stefania
authors.initials: S
authors.lastname: Mondello
authors.affiliation: 3 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.affiliation: 1 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Deng-Bryant
authors.affiliation: 1 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Kara E
authors.initials: KE
authors.lastname: Schmid
authors.affiliation: 6 Center of Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida , Gainesville, Florida.
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
authors.affiliation: 7 Center for Innovative Research, Center for Neuroproteomics and Biomarkers Research , Banyan Biomarkers, Inc., Alachua, Florida.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hayes
authors.affiliation: 8 Department of Anatomy and Neurobiology, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: John T
authors.initials: JT
authors.lastname: Povlishock
authors.affiliation: 9 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: 1 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D000070642:Brain Injuries, Traumatic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005904:Glial Fibrillary Acidic Protein / Q000097:blood; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D043222:Ubiquitin Thiolesterase / Q000097:blood; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D014803:Vitamin B Complex; D009536:Niacinamide; D043222:Ubiquitin Thiolesterase
keywords: biomarker; controlled cortical impact; fluid percussion; neuroprotection; penetrating ballistic-like brain injury; rat; therapy; vitamin B