This study examined the ability of nicotinamide (vitamin B3) to improve functional outcome in a dose-dependent manner following fluid percussion injury (FPI). Injured (duration of unconsciousness mean = 85.8 sec; apnea = 9.9 sec), rats were administered nicotinamide (500 or 50 mg/kg; ip) or saline at 15 min and 24 h. Serum analysis of nicotinamide concentrations were conducted 1 h following the last injection. Sensorimotor and cognitive tests were conducted for 35 days following FPI. Both the 500 and 50 mg/kg doses of nicotinamide significantly facilitated recovery on the vibrissae-forelimb placing test compared to saline treatment, which showed chronic impairments. Both treatments also significantly improved performance on the bilateral tactile adhesive removal test. On the cognitive tests, the 500 mg/kg dose, but not the 50 mg/kg dose, improved performance on a working memory task in the Morris water maze (MWM). However, acquisition of a reference memory task in the MWM was not improved. Serum analysis showed that the 500 mg/kg dose significantly raised nicotinamide concentrations by 30-fold and the 50 mg/kg dose by 3-fold compared to the saline administration. This study demonstrated that raising nicotinamide concentrations resulted in the reduction of the behavioral impairments following FPI. In fact, the 500 mg/kg dose prevented the occurrence of the behavioral deficits on the bilateral tactile removal and working memory tests. Both doses significantly reduced tissue loss and glial fibrillary acid protein (GFAP) expression in the cortex. The 500 mg/kg dose reduced GFAP expression in the hippocampus. This data suggests that nicotinamide has substantial preclinical efficacy for TBI, and there appears to be some differences in the ability of the doses to improve performance in the MWM.

Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of 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 hrs, or 8 hrs post-injury, followed by five boosters at 24 hr 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 to 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-hr groups. In the working memory task both the 15-min and 4-hr groups also improved working memory compared to saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 hrs for the sensorimotor tests but only extends to 4 hrs 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 hrs may result in attenuated injury severity in the human TBI population.

Previously, we have shown that the window of opportunity for nicotinamide (NAM) therapy (50 mg/kg) following cortical contusion injuries (CCI) extended to 4–8 hrs post-CCI when administered over a six day post-CCI interval. The purpose of the present study was to determine if a more chronic NAM treatment protocol administered following CCI would extend the current window of opportunity for effective treatment onset. Groups of rats received either unilateral CCI's or sham procedures. Initiation of NAM therapy (50 mg/kg, ip) began at either 15-min, 4-hrs, 8-hrs or 24-hrs post-injury. All groups received daily systemic treatments for 12 days post-CCI at 24 hr intervals. Behavioral assessments were conducted for 28 days post injury and included: vibrissae forelimb placing, bilateral tactile adhesive removal, forelimb asymmetry task and locomotor placing testing. Behavioral analysis on both the tactile removal and locomotor placing tests showed that all NAM-treated groups facilitated recovery of function compared to saline treatment. However, on the vibrissae-forelimb placing and forelimb asymmetry tests only the 4-hr and 8-hr NAM-treated groups were significantly different from the saline-treated group. The lesion analysis showed that treatment with NAM out to 8 hrs post-CCI significantly reduced the size of the injury cavity. The window of opportunity for NAM treatment is task-dependent and in some situations can extend to 24 hrs post-CCI. These results suggest that a long term treatment regimen of 50 mg/kg of NAM starting at the clinically relevant time points may prove efficacious in human TBI.

No abstract

It has previously been shown that small peptide molecules derived from the apolipoprotein E (ApoE) receptor binding region are anti-inflammatory in nature and can improve outcome following head injury. The present study evaluated the preclinical efficacy of COG1410, a small molecule ApoE-mimetic peptide (1410 daltons), following cortical contusion injury (CCI). Animals were prepared with a unilateral CCI of the sensorimotor cortex (SMC) or sham procedure. Thirty mins post-CCI the animals received i.v. infusions of 0.8 mg/kg COG1410, 0.4 mg/kg COG1410, or vehicle. Starting on day 2, the animals were tested on a battery of behavioral measures to assess sensorimotor (vibrissae-forelimb placing and forelimb use-asymmetry), and motor (tapered balance beam) performance. Administration of the 0.8 mg/kg dose of COG1410 significantly improved recovery on the vibrissae-forelimb and limb asymmetry tests. However, no facilitation was observed on the tapered beam. The low dose (0.4 mg/kg) of COG1410 did not show any significant differences compared to vehicle. Lesion analysis revealed that the 0.8 mg/kg dose of COG1410 significantly reduced the size of the injury cavity compared to the 0.4 mg/kg dose and vehicle. The 0.8 mg/kg dose also reduced the number of glial fibrillary acid protein (GFAP+) reactive cells in the injured cortex. These results suggest that a single dose of COG1410 facilitates behavioral recovery and provides neuroprotection in a dose and task-dependent manner. Thus, the continued clinical development of ApoE based therapeutics is warranted and could represent a novel strategy for the treatment of traumatic brain injuries.