51. Preclinical efficacy testing in middle-aged rats: nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact.
- Author
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Swan AA, Chandrashekar R, Beare J, and Hoane MR
- Subjects
- Age Factors, Analysis of Variance, Animals, Astrocytes drug effects, Astrocytes metabolism, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Blood-Brain Barrier physiopathology, Brain Edema metabolism, Brain Edema physiopathology, Brain Injuries metabolism, Brain Injuries physiopathology, Cerebral Cortex metabolism, Cerebral Cortex physiopathology, Cognition drug effects, Glial Fibrillary Acidic Protein metabolism, Immunohistochemistry, Male, Maze Learning drug effects, Motor Activity drug effects, Niacinamide pharmacology, Rats, Rats, Sprague-Dawley, Recovery of Function drug effects, Vitamin B Complex pharmacology, Brain Edema drug therapy, Brain Injuries drug therapy, Cerebral Cortex drug effects, Cerebral Cortex injuries, Niacinamide therapeutic use, Vitamin B Complex therapeutic use
- Abstract
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.
- Published
- 2011
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