title: Differential efficacy of the TSPO ligands etifoxine and XBD-173 in two rodent models of Multiple Sclerosis.
abstract: Neurosteroids such as progesterone and allopregnanolone have been shown to exert neuroprotective effects under a variety of pathological or insult conditions, and there is evidence that the neurosteroid system is perturbed in Multiple Sclerosis (MS) patients. Neurosteroids are synthesized in the central nervous system (CNS) through a series of metabolic transformations, beginning with a rate-limiting step of cholesterol transport through the outer mitochondrial membrane via the transporter translocator protein (TSPO). We examined the effects of etifoxine and XBD-173, two different brain penetrant TSPO agonists, for their ability to ameliorate clinical signs in two different experimental autoimmune encephalitis (EAE) models. Etifoxine, as previously reported, was efficacious in EAE, while XBD-173 was not. Surprisingly, XBD-173, but not etifoxine elevated relevant neurosteroids in brain of female rats and differed in its ability to exert anti-inflammatory and direct neuroprotective effects in vitro as compared to etifoxine. We conclude that the neurosteroid elevations produced in brain by XBD-173 are not sufficient to ameliorate EAE and suggest that etifoxine may have additional mechanisms of action that provide therapeutic benefit in this model system.
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
authors.forename: Brinda
authors.initials: B
authors.lastname: Ravikumar
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Crawford
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Dellovade
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
authors.forename: Anneli
authors.initials: A
authors.lastname: Savinainen
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Graham
authors.affiliation: U1195 Inserm & University Paris-Sud, 80, rue du Général Leclerc, 94276 Kremlin-Bicetre, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.affiliation: U1195 Inserm & University Paris-Sud, 80, rue du Général Leclerc, 94276 Kremlin-Bicetre, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Oudinet
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Webb
authors.affiliation: EMD Serono Research and Development Institute, Billerica, MA 01821, USA. Electronic address: heike1001@yahoo.com.
authors.forename: Heike
authors.initials: H
authors.lastname: Hering
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism* / Q000627:therapeutic use; D011687:Purines / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: C463819:Bzrp protein, mouse; D008024:Ligands; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D010078:Oxazines; D011687:Purines; D018079:Receptors, GABA; C002125:etifoxine
keywords: Darkagouti rat; EAE; TSPO; XBD–173; agonist; allopregnanolone; etifoxine; neuroprotection; neurosteroid; pharmacology