학술논문
Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis.
Document Type
Academic Journal
Author
Oxombre B; U1172-LilNCog-Lille Neurosciences & Cognition, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; Madouri F; U1172-LilNCog-Lille Neurosciences & Cognition, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; SATT Nord, F-59800 Lille, France.; Journé AS; U1172-LilNCog-Lille Neurosciences & Cognition, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; SATT Nord, F-59800 Lille, France.; Ravez S; U1172-LilNCog-Lille Neurosciences & Cognition, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; Woitrain E; U1011-Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; Odou P; ULR 7365-GRITA-Groupe de Recherche sur les Formes Injectables et les Technologies Associées, Université de Lille, CHU Lille, F-59006 Lille, France.; Duhal N; CUMA-Centre Universitaire de Mesures et d'Analyses, Université de Lille, F-59000 Lille, France.; Ninni S; U1011-Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; Montaigne D; U1011-Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; Delhem N; CHU Lille, UMR 1189-OncoThAI (Thérapies Assistées par Lasers et Immunothérapies pour l'Oncologie), Université de Lille, Inserm, F-59000 Lille, France.; Immune Insight, Institut de Virologie de Lille, F-59021 Lille, France.; Vermersch P; U1172-LilNCog-Lille Neurosciences & Cognition, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.; Melnyk P; U1172-LilNCog-Lille Neurosciences & Cognition, Université de Lille, Inserm, CHU Lille, F-59000 Lille, France.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS.