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

Abstract

Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post-injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI.

A behavioral and histological comparison of fluid percussion injury and controlled cortical impact injury to the rat sensorimotor cortex

“…Extending these deficits with the SMC model allows for a more long-term evaluation of any potential strategies of improving recovery of function. This benefit of using the SMC as a target structure for TBI to measure combination therapy treatment has been demonstrated in the literature[47]. However, one benefit to the use of both the bilateral frontal model and the unilateral parietal model is the appearance of MWM deficits several weeks after injury[21, 23, 27].…”

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

“…PROG has also been shown in numerous studies to confer significant benefits after experimental brain injury (Cutler et al, 2007; Cekic et al, 2009; Cekic and Stein, 2010; Stein and Cekic, 2011). Both treatments work in part by regulating signaling pathways involved in neuroinflammation and as such, Peterson and colleagues (2015) hoped to augment this mechanism by administering these agents alone and in combination, to explore effects on behavioral outcome, lesion volume, neuronal degeneration, and astrocyte activation. To this end, adult male rats received a CCI injury of moderate severity and subsequently received NAM (75 mg/kg loading dose and 12 mg/kg/h infusion thereafter), PROG (75 mg/kg loading dose at 4 h post-injury and 10 mg/kg every 12 h thereafter until sacrifice), their combination, or vehicle.…”

“…Indicating a synergistic effect, the combination treatment was the only group exhibiting a reduction in cortical lesion volume 24 hr after TBI. However, that benefit was lost when lesion volume was again assessed at 29 days (Peterson et al, 2015). Albeit two large Phase III clinical trials evaluating PROG recently concluded with negative results (Stein, 2015), the current studies suggest that perhaps PROG may still be effective if combined with NAM or other therapeutic approaches at appropriate times after TBI.…”

Combination Therapies for Traumatic Brain Injury: Retrospective Considerations

“…19 Briefly, male adult (3.5 month old) rats were designated as surgical shams or experienced unilateral CCI TBI. Injured animals received Prog or NAM monotherapy, the NAM-Prog combination therapy, or only vehicle, for a total of four injured groups, plus shams.…”

“…Another critical challenge in the face of the negative TBI clinical trial results with PROG, 4,5 despite the compelling pre-clinical data supporting PROG use at lower doses, [18][19][20][21] is that it may be more difficult to find support to test whether other doses of PROG might have been more effective 18,19,22 or to evaluate combination therapies using PROG that might provide better salutary effects over PROG monotherapy.…”