Etifoxine improves sensorimotor deficits and reduces glial activation, neuronal degeneration, and neuroinflammation in a rat model of traumatic brain injury

Abstract

BackgroundTraumatic brain injury (TBI) results in important neurological impairments which occur through a cascade of deleterious physiological events over time. There are currently no effective treatments to prevent these consequences. TBI is followed not only by an inflammatory response but also by a profound reorganization of the GABAergic system and a dysregulation of translocator protein 18 kDa (TSPO). Etifoxine is an anxiolytic compound that belongs to the benzoxazine family. It potentiates GABAergic neurotransmission, either through a positive allosteric effect or indirectly, involving the activation of TSPO that leads to an increase in neurosteroids synthesis. In several models of peripheral nerve injury, etifoxine has been demonstrated to display potent regenerative and anti-inflammatory properties and to promote functional recovery. Prior study also showed etifoxine efficacy in reducing brain edema in rats. In light of these positive results, we used a rat model of TBI to explore etifoxine treatment effects in a central nervous system injury, from functional outcomes to the underlying mechanisms.MethodsMale Sprague-Dawley rats received contusion (n = 18) or sham (n = 19) injuries centered laterally to bregma over the left sensorimotor cortex. They were treated with etifoxine (50 mg/kg, i.p.) or its vehicle 30 min following injury and every day during 7 days. Rats underwent behavioral testing to assess sensorimotor function. In another experiment, injured rats (n = 10) or sham rats (n = 10) received etifoxine (EFX) (50 mg/kg, i.p.) or its vehicle 30 min post-surgery. Brains were then dissected for analysis of neuroinflammation markers, glial activation, and neuronal degeneration.ResultsBrain-injured rats exhibited significant sensorimotor function deficits compared to sham-injured rats in the bilateral tactile adhesive removal test, the beam walking test, and the limb-use asymmetry test. After 2 days of etifoxine treatment, behavioral impairments were significantly reduced. Etifoxine treatment reduced pro-inflammatory cytokines levels without affecting anti-inflammatory cytokines levels in injured rats, reduced macrophages and glial activation, and reduced neuronal degeneration.ConclusionsOur results showed that post-injury treatment with etifoxine improved functional recovery and reduced neuroinflammation in a rat model of TBI. These findings suggest that etifoxine may have a therapeutic potential in the treatment of TBI.

Neurodegeneration and Sensorimotor Deficits in the Mouse Model of Traumatic Brain Injury

“…Traumatic brain injury is frequently associated with secondary neurodegeneration that leads to impairment in sensory motor functions [35][36][37]. Our result agrees with previous studies that demonstrates progressive brain atrophy and sensorimotor deficits in rodent model of traumatic brain injury [38][39][40][41].…”

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

“…Ultimately, this manifested in the recovery of sensory and motor functions [106]. Etifoxine administration has also been found to improve scores in behavioural testing and rescues from neuronal degeneration in a rat model of traumatic brain injury, accompanied by reduced microglial activation and reduced cortical concentrations of IL-1α, IL-1β, IL-6, CCL2 and TNF-α [107]. In an Alzheimer's disease mouse model, application of Ro5-4864 attenuated the accumulation of amyloid beta plaques in the hippocampus and decreased microglial activation.…”

A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury

“…Etifoxine is a clinically available, high-affinity TSPO agonist [ 4 ]. Previous studies have shown beneficial effects of etifoxine and other TSPO ligands to modulate the microglial response and promote neural survival after several types of central nervous system (CNS) insults [ 10 , 13 – 15 ]. To further determine the potential neuroprotective and anti-inflammatory effects of etifoxine treatment on ischemic brain injury, we examined the efficacy and mechanisms of action by etifoxine in mice subjected to middle cerebral artery occlusion (MCAO) and reperfusion.…”