Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stress-induced behaviours in mice.
Thiamine (vitamin B1) deficiency in the brain has been implicated in the development of dementia and symptoms of depression. Indirect evidence suggests that thiamine may contribute to these pathologies by controlling the activities of glycogen synthase kinase (GSK)-3β. While decreased GSK-3β activity appears to impair memory, increased GSK-3β activity is associated with the distressed/depressed state. However, hitherto direct evidence for the effects of thiamine on GSK-3β function has not been reported. Here, we administered thiamine or, the more bioavailable precursor, benfotiamine at 200mg/kg/day for 2weeks to C57BL/6J mice, to determine whether treatment might affect behaviours that are known to be sensitive to GSK-3β activity and whether such administration impacts on GSK-3β expression within the brain. The mice were tested in models of contextual conditioning and extinction, a 5-day rat exposure stress test, and a modified swim test with repeated testing. The tricyclic antidepressant imipramine (7.5mg/kg/day), was administered as a positive control for the effects of thiamine or benfotiamine. As for imipramine, both compounds inhibited the upregulation of GSK-3β induced by predator stress or repeated swimming, and reduced floating scores and the predator stress-induced behavioural changes in anxiety and exploration. Coincident, thiamine and benfotiamine improved learning and extinction of contextual fear, and the acquisition of the step-down avoidance task. Our data indicate that thiamine and benfotiamine have antidepressant/anti-stress effects in naïve animals that are associated with reduced GSK-3β expression and conditioning of adverse memories. Thus thiamine and benfotiamine may modulate GSK-3β functions in a manner that is dependent on whether the contextual conditioning is adaptive or maladaptive.
EURON - European Graduate School for Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severnii proezd, 1, Chernogolovka 142432, Russia; Institute of General Pathology and Pathophysiology, Baltiiskaya str, 8, Moscow 125315, Russia; I.M.Sechenov First Moscow Medical University, Moscow, Russia.
Nataliia
N
Markova
EURON - European Graduate School for Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; Institute of General Pathology and Pathophysiology, Baltiiskaya str, 8, Moscow 125315, Russia; I.M.Sechenov First Moscow Medical University, Moscow, Russia.
Nataliia
N
Bazhenova
Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK. Electronic address: daniel.anthony@pharm.ox.ac.uk.
Daniel C
DC
Anthony
EURON - European Graduate School for Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; GIGA-Neurosciences, University of Liege, 4000, Liege, Belgium.
Julie
J
Vignisse
I.M.Sechenov First Moscow Medical University, Moscow, Russia.
Andrey
A
Svistunov
EURON - European Graduate School for Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; I.M.Sechenov First Moscow Medical University, Moscow, Russia; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, Germany.
Klaus-Peter
KP
Lesch
EURON - European Graduate School for Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; GIGA-Neurosciences, University of Liege, 4000, Liege, Belgium.
Lucien
L
Bettendorff
EURON - European Graduate School for Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229 ER Maastricht, Netherlands; I.M.Sechenov First Moscow Medical University, Moscow, Russia. Electronic address: t.strekalova@maastrichtuniversity.nl.
Tatyana
T
Strekalova
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014803:Vitamin B Complex / Q000627:therapeutic use*
D012333:RNA, Messenger; D014803:Vitamin B Complex; D000071679:Glycogen Synthase Kinase 3 beta; D013831:Thiamine; C013835:benphothiamine
Animal models; Benfotiamine; Depression; Glycogene-synthase-kinase-3-beta (GSK-3β); Plasticity; Thiamine