Abstract
Experimental studies have shown that ligands of the 18 kDa translocator protein can reduce neuronal damage induced by traumatic brain injury by protecting mitochondria and preventing metabolic crisis. Etifoxine, an anxiolytic drug and 18 kDa translocator protein ligand, has shown beneficial effects in the models of peripheral nerve neuropathy. The present study investigates the potential effect of etifoxine as a neuroprotective agent in traumatic brain injury (TBI). For this purpose, the effect of etifoxine on lesion volume and modified neurological severity score at 4 weeks was tested in Sprague–Dawley adult male rats submitted to cortical impact contusion. Effects of etifoxine treatment on neuronal survival and apoptosis were also assessed by immune stains in the perilesional area. Etifoxine induced a significant reduction in the lesion volume compared to nontreated animals in a dose-dependent fashion with a similar effect on neurological outcome at four weeks that correlated with enhanced neuron survival and reduced apoptotic activity. These results are consistent with the neuroprotective effect of etifoxine in TBI that may justify further translational research.
Highlights
Mitochondrial permeability transition has emerged during the past two decades as a pivotal event in the process of neuronal death in a vast range of neurological pathologies including stroke, neurotrauma, as well as several neurodegenerative conditions including Parkinson’s and Alzheimer’s diseases
The cyclophilin D combines with the adenine nucleotide translocator (ANT) to form a high conductance channel, the mitochondrial permeability transition pore, across the inner mitochondrial membrane (IMM), otherwise impermeable under normal conditions, in contrast to the outer mitochondrial membrane (OMM) [1]
Since PK11195 and Ro5-4864 were initially categorized as antagonist and agonist translocator protein (TSPO) ligands [19], it may be hypothesized that Ro5-4864 and additional agonists may be of potential therapeutic interest as neuroprotective agents through inhibition of the mitochondrial permeability transition pore (mPTP)
Summary
Mitochondrial permeability transition has emerged during the past two decades as a pivotal event in the process of neuronal death in a vast range of neurological pathologies including stroke, neurotrauma, as well as several neurodegenerative conditions including Parkinson’s and Alzheimer’s diseases. Since PK11195 and Ro5-4864 were initially categorized as antagonist and agonist TSPO ligands [19], it may be hypothesized that Ro5-4864 and additional agonists may be of potential therapeutic interest as neuroprotective agents through inhibition of the mPTP This hypothesis has been supported by preliminary in vitro studies showing that addition of TSPO ligands to mitochondrial pellets resulted in a protective effect against known mitochondrial noxious agents such as, calcium and Bax, with preserved mitochondrial membrane polarization, reduced release of AIF, and decreased activation of caspase 9 [20,21]. These findings were further supported by in vivo animal studies showing that treatment with Ro5-4864 was associated with enhanced neuronal survival, improved oxidative metabolism expressed by lower lactate/pyruvate ratio, and decreased mitochondrial damage following cortical injury [21,22]
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