title: A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury.
abstract: Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post-injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI.
authors.affiliation: 1Department of Psychology, Southern Illinois University, Carbondale, Illinois.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Peterson
authors.affiliation: 1Department of Psychology, Southern Illinois University, Carbondale, Illinois.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hoane
authors.affiliation: 1Department of Psychology, Southern Illinois University, Carbondale, Illinois.
authors.forename: Keith S
authors.initials: KS
authors.lastname: McConomy
authors.affiliation: 2Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
authors.forename: Fred M
authors.initials: FM
authors.lastname: Farin
authors.affiliation: 2Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.affiliation: 2Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
authors.forename: James W
authors.initials: JW
authors.lastname: MacDonald
authors.affiliation: 3Department of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Kantor
authors.affiliation: 3Department of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D004359:Drug Therapy, Combination; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage*; D011374:Progesterone / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000235:genetics
chemical_list: D009536:Niacinamide; D011374:Progesterone
keywords: controlled cortical impact; nicotinamide; polytherapy; progesterone; recovery of function; traumatic brain injury