TY - JOUR
T1 - Preclinical efficacy testing in middle-aged rats
T2 - Nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact
AU - Swan, Alicia A.
AU - Chandrashekar, Rupa
AU - Beare, Jason
AU - Hoane, Michael R.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500 mg/kg or 50 mg/kg) or saline alone (1 mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1 h and 24 h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood-brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50 mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials.
AB - Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500 mg/kg or 50 mg/kg) or saline alone (1 mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1 h and 24 h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood-brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50 mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials.
KW - CCI
KW - aging
KW - nicotinamide
KW - recovery of function
KW - therapy
KW - traumatic brain injury
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U2 - 10.1089/neu.2010.1519
DO - 10.1089/neu.2010.1519
M3 - Article
C2 - 21083416
AN - SCOPUS:79952774476
SN - 0897-7151
VL - 28
SP - 431
EP - 440
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
IS - 3
ER -