Etifoxine Restores Mitochondrial Oxidative Phosphorylation and Improves Cognitive Recovery Following Traumatic Brain Injury.

Eilam Palzur,Reem Sakas,Jean Francois Soustiel,Doron Edelman

doi:10.3390/ijms222312881

Eilam Palzur, Reem Sakas + Show 2 more

Open Access

https://doi.org/10.3390/ijms222312881

Copy DOI

Abstract

The opening of the mitochondrial permeability transition pore (mPTP) has emerged as a pivotal event following traumatic brain injury (TBI). Evidence showing the impact of the translocator protein (TSPO) over mPTP activity has prompted several studies exploring the effect of TSPO ligands, including etifoxine, on the outcome of traumatic brain injury (TBI). Mitochondrial respiration was assessed by respirometry in isolated rat brain mitochondria (RBM) by measurements of oxidative phosphorylation capacity (OXPHOS). The addition of calcium to RBM was used to induce mitochondrial injury and resulted in significant OXPHOS reduction that could be reversed by preincubation of RBM with etifoxine. Sensorimotor and cognitive functions were assessed following controlled cortical impact and compared in vehicle and etifoxine-treated animals. There was no difference between the vehicle and etifoxine groups for sensorimotor functions as assessed by rotarod. In contrast, etifoxine resulted in a significant improvement of cognitive functions expressed by faster recovery in Morris water maze testing. The present findings show a significant neuroprotective effect of etifoxine in TBI through restoration of oxidative phosphorylation capacity associated with improved behavioral and cognitive outcomes. Since etifoxine is a registered drug used in common clinical practice, implementation in a phase II study may represent a reasonable step forward.

Highlights

Traumatic brain injury (TBI) represents the leading cause of mortality and permanent disability in people under 45 years of age in western industrialized countries [1,2].Following traumatic brain injury (TBI), injured cells are threatened by a complex chain of interconnected events eventually leading to the death of potentially viable cells
A substantial and significant decrease (24.3%) in oxidative phosphorylation capacity (OXPHOS) capacity could be observed in comparison with intact mitochondria (Figures 1 and 2C, control vs. calcium group Tukey-Kramer p < 0.05), despite the relatively short time of exposure of mitochondria to calcium until the addition of pyruvate
In a cohort of 36 severe TBI patients who underwent decompressive craniectomy for uncontrolled intracranial pressure (ICP) elevation, we were able to show a beneficial impact of ICP relief on the odds of survival and to provide evidence that brain decompression was associated with improvement of cerebral blood flow (CBF), though oxidative metabolism was left unaffected by surgery [14]

Summary

Introduction

Following TBI, injured cells are threatened by a complex chain of interconnected events eventually leading to the death of potentially viable cells The magnitude of this phenomenon, known as secondary brain damage, has been stressed long ago by Reilly et al, who showed that the primary injury does not intimately correlate with final outcome, emphasizing the impact of the secondary brain injury on the fate of injured cells [3]. This observation, in turn, was the trigger for initiation of a vast and multidisciplinary research effort for a better understanding of the underlying mechanisms leading to secondary cell death and the development of novel therapeutic strategies. The high expectations generated by encouraging laboratory data were not met by the deceiving results of subsequent clinical trials, making the pharmaceutical industry more reluctant to support expensive and adventurous research [4,5,6]

Objectives

Methods

Results

Discussion

Conclusion