In FUS[1-359]-tg mice O,S-dibenzoyl thiamine reduces muscle atrophy, decreases glycogen synthase kinase 3 beta, and normalizes the metabolome.

Autor: Probert F; Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK; Department of Chemistry, Oxford University, Mansfield Road, OX1 3TA Oxford, UK. Electronic address: fay.probert@chem.ox.ac.uk., Gorlova A; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia; Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Baltiyskaya str. 8, 125315 Moscow, Russia. Electronic address: anna.gorlova204@gmail.com., Deikin A; Joint Center for Genetic Technologies and Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Pobedy str. 85, 308015 Belgorod, Russia. Electronic address: alexei@deikin.ru., Bettendorff L; Laboratory of Neurophysiology, GIGA-Neurosciences, University of Liège, av Hippocrate 1, 13-4000 Liège, Belgium. Electronic address: L.Bettendorff@uliege.be., Veniaminova E; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia. Electronic address: katya.veniaminova@gmail.com., Nedorubov A; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia. Electronic address: nedorubov.ras@gmail.com., Chaprov KD; Joint Center for Genetic Technologies and Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, Pobedy str. 85, 308015 Belgorod, Russia; Institute of Physiologically Active Compounds RAS, Severniy pr. 1, 142432 Chernogolovka, Russia. Electronic address: chapkir@gmail.com., Ivanova TA; Institute of Physiologically Active Compounds RAS, Severniy pr. 1, 142432 Chernogolovka, Russia. Electronic address: tamar-ivanova@yandex.ru., Anthony DC; Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK. Electronic address: daniel.anthony@pharm.ox.ac.uk., Strekalova T; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russia; Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Baltiyskaya str. 8, 125315 Moscow, Russia; Maastricht University, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Universiteitssingel 40, NL 6229 Maastricht, the Netherlands. Electronic address: t.strekalova@maastrichtuniversity.nl.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 Dec; Vol. 156, pp. 113986. Date of Electronic Publication: 2022 Nov 08.
DOI: 10.1016/j.biopha.2022.113986
Abstrakt: Mutations in the gene encoding the RNA/DNA-binding protein Fused in Sarcoma (FUS) have been detected in familial amyotrophic lateral sclerosis (ALS) patients. FUS has been found to be a critical component of the oxidative damage repair complex that might explain its role in neurodegeneration. Here, we examined what impact antioxidant treatment with thiamine (vitamine B1), or its more bioavailable derivative O,S-dibenzoylthiamine (DBT), would have on the hallmarks of pathology in the FUS[1-359]-transgenic mouse model of ALS. From 8-weeks old, in the pre-symptomatic phase of disease, animals received either thiamine, DBT (200 mg/kg/day), or vehicle for 6 weeks. We examined physiological, behavioral, molecular and histological outcomes, as well as the serum metabolome using nuclear magnetic resonance (NMR). The DBT-treated mice displayed improvements in physiological outcomes, motor function and muscle atrophy compared to vehicle, and the treatment normalized levels of brain glycogen synthase kinase-3β (GSK-3β), GSK-3β mRNA and IL-1β mRNA in the spinal cord. Analysis of the metabolome revealed an increase in the levels of choline and lactate in the vehicle-treated FUS mutants alone, which is also elevated in the cerebrospinal fluid of ALS patients, and reduced glucose and lipoprotein concentrations in the FUS[1-359]-tg mice, which were not the case in the DBT-treated mutants. The administration of thiamine had little impact on the outcome measures, but it did normalize circulating HDL levels. Thus, our study shows that DBT therapy in FUS mutants is more effective than thiamine and highlights how metabolomics may be used to evaluate therapy in this model.
Competing Interests: Conflict of interest statement Here, we declare that none of the authors involved in the work have any competing interest. We confirm that founding bodies had no role in the data collection, manuscript preparation and decision to publish the results.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: