Variation in Chronic Nicotinamide Treatment after Traumatic Brain Injury Can Alter Components of Functional Recovery Independent of Histological Damage

Abstract

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.

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

“…13,[42][43][44] To assess sensory deficits, this test was administered on Days 4,6,8,11,17,24, and 28 post-injury. Rats were pre-tested for baseline levels on the two days prior to surgery.…”

“…We have reliably shown that this technique is sensitive enough to detect treatment-induced reductions in injury size. 6,9,13,47 Inter-rater reliability scores were calculated for approximately 25% of the data collected. Data were chosen randomly and the criterion for acceptance was a correlation coefficient of r > 0.90.…”

“…NAM treatment has been shown to significantly reduce injury volume, decrease glial fibrillary acidic protein (GFAP) + activation, reduce the blood brain barrier (BBB) breach, reduce acute edema formation, reduce behavioral impairments, and improve outcomes following cortical contusion injury (CCI) and fluid percussive injury (FPI). [3][4][5][6][7][8][9][10][11][12][13] A bolus dose of either 50 or 500 mg/kg following TBI provides improved behavioral outcomes and attenuation of cortical loss and this effectiveness is heightened one week following treatment. 6 To establish and maintain a steady-state and provide a more clinically relevant model of neuroprotection, we also demonstrated beneficial effects of a continuous infusion of NAM on both sensorimotor and cognitive tasks with both a low dose (150 mg/kg/d) 11 and a clinically achievable dose (288 mg/kg/d) following bilateral frontal and unilateral parietal injury.…”

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

“…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.…”

“…[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. 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.…”