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.

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.…”

“…The CCI model utilized in the present study was based on previous studies and was intended to produce a moderately severe injury. 8,9,12,41 Animals were anesthetized using a mixture of isoflurane (2-4%) and oxygen (0.8 L/m). 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.…”

“…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.…”

“…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. 9,12 NAM is a precursor to nicotinamide adenine dinucleotide (NAD + ), a coenzyme found in all living cells, and is commonly known for its role in the electron transport chain allowing for the production of adenosine triphosphate (ATP). 14,15 NAM indirectly supplements the bioavailability of ATP to cells, which provides additional energy when normal intake and metabolism are impaired following neural insult.…”