A comparison of the effects of nicotinamide and progesterone on functional recovery of cognitive behavior following cortical contusion injury in the rat

Abstract

The primary goal of this study was to compare clinically relevant doses of progesterone and nicotinamide within the same injury model. Progesterone has been shown to reduce edema and inflammation and improve functional outcomes following brain injury. Nicotinamide has also been shown to be an effective neuroprotective agent in a variety of neurological injury models. In the current study, nicotinamide was administered beginning 4 h post-cortical contusion injury (CCI) with a loading dose (75 mg/kg, i.p.) combined with continuous infusion (12 mg/h/kg, s.c.) for 72 h post-injury. Progesterone was administered beginning 4 h post-CCI at a dose of 10 or 20 mg/kg, i.p. every 12 h for 72 h. This resulted in the following groups: Injured-nicotinamide treated, Injured-progesterone-10 treated, Injured-progesterone-20 treated, Injured-vehicle treated, and Sham. Functional recovery was assessed with two spatial memory tasks in the Morris water maze (MWM) the acquisition of a reference memory task and a reversal learning task. Neuropathological assessments were conducted in the cortex and hippocampus. It was found that both progesterone (10 mg/kg) and nicotinamide improved reference memory acquisition and reversal learning in the MWM compared with vehicle treatment. The lower dose of progesterone and nicotinamide also reduced tissue loss in the injured cortex and ipsilateral hippocampus compared with vehicle. The beneficial effects of progesterone appear to be dose dependent with the lower 10 mg/kg dose producing significant effects that were not observed at the higher dose. Direct comparison between nicotinamide and low dose progesterone appears to suggest that both are equally effective. The general findings of this study suggest that both nicotinamide and progesterone produce significant improvements in recovery of function following CCI.

FIG. 1.

Morris Water Maze: Reference Learning. The average latency (+SEM) to reach the platform for the reference learning phase (days 20–22) (* represents significant differences [p<0.05] between the progesterone-10 and vehicle-injured group; # represents significant differences [p<0.05] between the nicotinamide [NAM] and vehicle-injured group).

FIG. 2.

Morris Water Maze: Reversal Learning Test. The average latency (+SEM) to reach the platform on day 26 (*represents significant differences [p<0.05] between the progesterone-10 and vehicle-injured group; # represents significant differences [p<0.05] between the nicotinamide [NAM] and vehicle-injured group).

FIG. 3.

Lesion Analysis. (A). The average (+SEM) percent reduction [1 – (ipsi/contra)×100] of cortical volume between the ipsilateral and contralateral sides to the injury. (B) The average (+SEM) percent reduction [1 – (ipsi/contra)×100] of hippocampal volume between the ipsilateral and contralateral sides to the injury. (* represents significant differences [p<0.05] between the progesterone-10 and vehicle-injured group; # represents significant differences [p<0.05] between the nicotinamide [NAM] and vehicle-injured group).

FIG. 4.

Histology Plate. Representative images of cresyl violet stained tissue throughout the injury coordinates; −0.08 mm, −1.8 mm, −2.8 mm, and −3.8 mm, relative to bregma. Scale bar=2.0 mm.

FIG. 5.

Serum Analysis. The average serum levels for nicotinamide and progesterone are shown for the corresponding treatment group.