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

Abstract

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.

A Comparison of the Effects of Nicotinamide and Progesterone on Functional Recovery of Cognitive Behavior following Cortical Contusion Injury in the Rat

“…4,7,8,11,12 Nicotinamide resulted in significant improvements in reference memory acquisition in the MWM when tested beginning 20 days post-TBI compared with the vehicle group. In addition, a significant improvement in an MWM reversal learning task was also seen when performed on day 26 post-CCI.…”

“…The CCI model utilized in the present study was based on previous studies. 8,11 Animals were anesthetized using a mixture of isoflurane (2-4%) and oxygen (0.8 L/min). When the animal became unresponsive (no ocular or pedal reflexes) the head was shaved and scrubbed with 70% alcohol followed by betadine and placed into a stereotaxic device.…”

“…Much work has demonstrated that treatment with nicotinamide significantly reduced injury volume, decreased glial fibrillary acidic protein (GFAP) + activation, reduced blood-brain barrier (BBB) breach, reduced acute edema formation, improved motor performance, and generally reduced behavioral impairments and improved outcomes following cortical contusion injury (CCI) and fluid percussion injury (FPI). [4][5][6][7][8][9][10][11][12] Direct comparisons between a 50 mg/kg and a 500 mg/kg dosing regimen have resulted in some minor dose differences, but in general, both dosing regimens have been shown to be effective in facilitating recovery of function following FPI. 9 More importantly, we have also shown that the window of opportunity for the 50 mg/kg dose is between 6 and 24 h post-CCI, depending upon the task and treatment regimen.…”

“…9 More importantly, we have also shown that the window of opportunity for the 50 mg/kg dose is between 6 and 24 h post-CCI, depending upon the task and treatment regimen. 7,8 Therefore, there is substantial pre-clinical evidence in young animals (3-6 months) that nicotinamide significantly improves functional recovery and reduces many pathophysiological variables following TBI. We have also examined continuous delivery of nicotinamide (via osmotic mini-pumps) in order to establish steady state serum levels of nicotinamide following injury, and have also found significant improvements in behavioral recovery.…”

A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury

“…The NAM treatment in this study either confirmed or was more beneficial than previous preclinical data in animal models of TBI. [3][4][5][6][7]9,[11][12][13]55 NAM treatment resulted in significant improvements in both of the fine motor assessments. In the forelimb asymmetry task, the NAM-treated animals performed similar to previous research.…”