In a mouse model of MS, mice treated with the mitochondrial translocator protein ligand etifoxine experienced reduced symptom severity.
Upregulation of the mitochondrial translocator protein (TSPO) is associated with a number of diseases of the central nervous system, including multiple sclerosis (MS). Etifoxine is a TSPO ligand that promotes neuronal regeneration in the periphery and stimulates neural steroidogenesis.
The authors of “A TSPO Ligand Is Protective in a Mouse Model of Multiple Sclerosis,” published in EMBO Molecular Medicine, wrote that there is “substantial evidence indicating that promotion of neurosteroid synthesis may be beneficial in CNS diseases, with some studies reporting decreased neurosteroid levels in MS patients and other (mouse model) studies showing benefits from treatment with neurosteroids.
To study the effects of the TSPO ligand etifoxine on neuroinflammatory damage, the authors “used experimental autoimmune encephalomyelitis (EAE), a model of MS in mice in which an autoimmune response was induced against the myelin oligodendrocyte glycoprotein (MOG) peptide (aa 35—55).” They posited that the increase in neurosteroid levels produced by etifoxine “could lead to similar effects as direct neurosteroid treatment, along with offering the direct downregulation of immune cell activity.”
For the study, researchers induced EAE in mice and administered daily doses of etifoxine or placebo “at defined time periods during the course of EAE.” They evaluated neurological deficits and graded them on a five-point scale for 40 days. They reported that mice treated with etifoxine showed a decrease in the peak of clinical scores of EAE, as well as delayed onset of the first signs of clinical symptoms. Further, “mean body weight loss during the peak of the disease was significantly less in mice treated with etifoxine than in mice in the control group,” important because “muscle wasting due to CNS damage is a reliable indicator of EAE progression.”
In their discussion of the study results, the authors wrote that “The administration of etifoxine, through its promotion of steroidogenesis, may lead to the inhibition of infiltration of peripheral immune cells during the course of EAE. The initial onset of EAE symptoms was delayed when mice were administered etifoxine before the onset of clinical signs.”
The modulation of TSPO also showed beneficial effects after neural injury, with etifoxine promoting the retention of myelin basic protein (MBP) and the inhibition of microglia and CD4+ cells.
They concluded that these results “show that the TSPO ligand etifoxine is protective and promotes recovery in a mouse model of MS,” resulting in “less peripheral immune cell infiltration of the spinal cord, as well as increased oligodendroglial regeneration.” TSPO ligands such as etifoxine, “could have new clinical applications in the treatment of MS. Steroid administration has already been implicated as an option for treatment. Through the promotion of local steroid production, the use of clinically available TSPO ligands may be a more efficacious and safer form of treatment.”
In a news release that accompanied publication of the study results, lead author Wenbin Deng, PhD, associate professor of biochemistry and molecular medicine at UC Davis, said the team’s discovery of etifoxine's effects on an MS animal model “suggests that mitochondrial TSPO represents a potential therapeutic target for MS drug development,” and that “drugs designed to more precisely bind to mitochondrial TSPO may help repair the myelin sheath of MS patients and thereby even help restore the transmission of signals in the central nervous system that enable normal motor, sensory and cognitive functions.”