Elsevier

Neuroscience

Volume 154, Issue 3, 26 June 2008, Pages 861-868
Neuroscience

Behavioural neuroscience
Nicotinamide treatment induces behavioral recovery when administered up to 4 hours following cortical contusion injury in the rat

https://doi.org/10.1016/j.neuroscience.2008.04.044Get rights and content

Abstract

Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of traumatic brain injury (TBI). However, research on this compound has been limited to administration regimens starting shortly after injury. This study was conducted to establish the window of opportunity for NAM administration following controlled cortical impact (CCI) injury to the frontal cortex. Groups of rats were assigned to NAM (50 mg/kg), saline (1 ml/kg), or sham conditions and received contusion injuries or sham procedures. Injections of NAM or saline were administered at 15 min, 4 h, or 8 h post-injury, followed by five boosters at 24 h intervals. Following the last injection, blood was taken for serum NAM analysis. Animals were tested on a variety of tasks to assess somatosensory performance (bilateral tactile adhesive removal and vibrissae–forelimb placement) and cognitive performance (reference and working memory) in the Morris water maze. The results of the serum NAM analysis showed that NAM levels were significantly elevated in treated animals. Behavioral analysis on the tactile removal test showed that all NAM-treated groups facilitated recovery of function compared with saline treatment. On the vibrissae–forelimb placing test all NAM-treated groups also were significantly different from the saline-treated group. However, the acquisition of reference memory was only significantly improved in the 15-min and 4-h groups. In the working memory task both the 15-min and 4-h groups also improved working memory compared with saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 h for the sensorimotor tests but only extends to 4 h post-injury in the cognitive tests. These results suggest that a 50 mg/kg treatment regimen starting at the clinically relevant time point of 4 h may result in attenuated injury severity in the human TBI population.

Section snippets

Subjects

Thirty-four Sprague–Dawley rats (Harlan, Indianapolis, IN, USA), 3–4 months of age were included in this experiment. All experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee and the study was conducted in a facility certified by the American Association for the Accreditation of Laboratory Animal Care on the ethical use of animals and every attempt was made to minimize the number of animals used and their suffering. Rats were maintained on a

NAM analysis

There were significant serum NAM concentration differences between groups as analyzed by a one-way ANOVA [F(4,27)=34.52, P<0.05]. Post hoc analyses revealed that all NAM treatment groups had significantly higher serum concentrations than saline or sham groups (P<0.05) (see Fig. 1).

Bilateral tactile adhesive removal task

The latency to remove both stimuli from each trial was averaged together for analysis using a 5×7 ANOVA with repeated measures. Group (15-min NAM, 4-h NAM, 8-h NAM, CCI-saline, sham) and day (2, 4, 6, 8, 10, 14, and

Discussion

This study demonstrated that administration of a six-dose regimen of NAM following frontal CCI had a dose-dependent effect on the level of circulating serum NAM. Administration of NAM starting at any of the initial time points post-CCI (15-min, 4-h, or 8-h) significantly elevated serum NAM compared with the animals not receiving NAM administration. Interestingly, the 15-min injection resulted in significantly higher levels of serum NAM than either of the two administration time points.

The main

Acknowledgments

Research supported by NINDS (NS045647-03) to M.R.H.

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