Nicotinamide Treatment Reduces Behavioral Impairments and Provides Cortical Protection after Fluid Percussion Injury in the Rat

Abstract

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.

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

“…The 500 mg/kg treatment condition was effective in attenuating cognitive dysfunction (MWM), but the 50 mg/kg was not. Histologically, both treatment conditions significantly reduced cavity size and glial cell proliferation relative to saline-treated animals (Hoane et al, 2006c). A similar dose-effect with the 50 and 500 mg/kg doses of NAM were seen in their ability to reduce astrogliosis and neurodegeneration acutely following FPI (Holland et al, 2008).…”

“…(Sigma # N3376, St. Louis, MO, USA) at 15 min (n = 7), 4 hr (n = 7), or 8 hr (n = 7) post-injury, followed by five boosters (50 mg/kg, i.p.) at 24 hr intervals (Hoane et al, 2006c). Sham (n = 6) and injuredcontrol (n = 7) animals received saline injections (0.9%, 1.0 mL/kg, i.p.)…”

“…Based on a previous sampling study, 1 hr following the last injection, blood was collected from the tail vein (Hoane et al, 2006c). Samples were separated with a microcentrifuge and stored frozen at −80°C.…”

“…This test has been previously shown to be a sensitive assessment of somatosensory and attentional deficits following injury to the frontal lobes and has been described in detail (Schallert et al, 2000, Hoane et al, 2003, Schallert and Woodlee, 2005, Hoane et al, 2006c, Hoane et al, 2007. A slightly modified version of this task was used in this experiment.…”

“…Sensorimotor function was evaluated by scoring the forelimb placing reaction (Schallert et al, 2000, Schallert and Woodlee, 2005, Hoane et al, 2006c, Hoane et al, 2007. Each rat was held by the trunk ensuring the forelimbs were free to move.…”