Variation in chronic nicotinamide treatment after traumatic brain injury can alter components of functional recovery independent of histological damage.

Michael R Hoane,Jeremy L Pierce,Nicholas A Kaufman,Jason E Beare

doi:10.4161/oxim.1.1.6694

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.

Highlights

Each year approximately 50,000 people die from traumatic brain injuries (TBI) and another 80,000 to 90,000 become permanently disabled in the US.[1,2,3] Currently, no therapeutics is available to attenuate damage following TBI
This study sought to extend the window of opportunity for NAM therapy by prolonging administration to include time points covering metabolic dysfunction post-TBI
The results of this study have shown that administration of NAM following cortical contusion injuries (CCI) had a task dependent effect on the window of opportunity of recovery of function

Summary

Introduction

Each year approximately 50,000 people die from traumatic brain injuries (TBI) and another 80,000 to 90,000 become permanently disabled in the US.[1,2,3] Currently, no therapeutics is available to attenuate damage following TBI. A number of novel therapeutics have shown robust behavioral and histological protection in preclinical animal models, but have failed to show beneficial effect in clinical trials. The reason for the lack of translation from animal to human models of TBI is multifaceted, including methodological errors in the clinical setting and errors in preclinical modeling. Methodological errors have included patient inclusion criteria and number of patients enrolled to achieve statistical significance.[1] Some patients may be too severely injured to show any real improvement (GCS ≤ 8); enrolling these patients may artificially deflate any treatment effect.[4] It has been shown that only 8 of the 203 clinical TBI trials evaluating novel therapeutics were sufficiently powered to detect a 10% reduction in mortality rate. It is unlikely that one or two administrations of a compound will completely arrest its target pathological mechanism and it is possible that acute therapeutic intervention may only delay an inevitable injury cascade; it may take days or weeks of therapeutic intervention to attain efficacy

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