Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models

Behavioural Pharmacology
Valeria MelisG Riedel

Abstract

Given the repeated failure of amyloid-based approaches in Alzheimer's disease, there is increasing interest in tau-based therapeutics. Although methylthioninium (MT) treatment was found to be beneficial in tau transgenic models, the brain concentrations required to inhibit tau aggregation in vivo are unknown. The comparative efficacy of methylthioninium chloride (MTC) and leucomethylthioninium salts (LMTX; 5-75 mg/kg; oral administration for 3-8 weeks) was assessed in two novel transgenic tau mouse lines. Behavioural (spatial water maze, RotaRod motor performance) and histopathological (tau load per brain region) proxies were applied. Both MTC and LMTX dose-dependently rescued the learning impairment and restored behavioural flexibility in a spatial problem-solving water maze task in Line 1 (minimum effective dose: 35 mg MT/kg for MTC, 9 mg MT/kg for LMTX) and corrected motor learning in Line 66 (effective doses: 4 mg MT/kg). Simultaneously, both drugs reduced the number of tau-reactive neurons, particularly in the hippocampus and entorhinal cortex in Line 1 and in a more widespread manner in Line 66. MT levels in the brain followed a sigmoidal concentration-response relationship over a 10-fold range (0.13-1.38 μmol/l). These d...Continue Reading

References

Jan 1, 1991·Acta Neuropathologica·H Braak, E Braak
Jul 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·C R HarringtonC M Wischik
Oct 1, 1996·Proceedings of the National Academy of Sciences of the United States of America·C M WischikC R Harrington
Jul 21, 1997·FEBS Letters·T M VisariusB H Lauterburg
Aug 22, 2000·European Journal of Clinical Pharmacology·C PeterB H Lauterburg
Feb 20, 2004·American Journal of Physiology. Cell Physiology·James M MayCharles E Cobb
Mar 14, 2009·The Journal of Biological Chemistry·Bess FrostMarc I Diamond
Jan 4, 2013·PloS One·Masato HosokawaMasato Hasegawa
Apr 20, 2013·JAMA Neurology·Lary C WalkerBradley T Hyman
Dec 24, 2013·Biochemical Pharmacology·Claude M WischikJohn M D Storey

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Citations

Jan 6, 2016·Drugs·Lidia Bakota, Roland Brandt
Jul 20, 2016·BioMed Research International·Francesco PanzaGiancarlo Logroscino
Aug 23, 2016·BioMed Research International·J Mendiola-PrecomaG Garcia-Alcocer
Aug 4, 2016·Immunotherapy·Francesco PanzaGiancarlo Logroscino
Jan 30, 2016·Expert Review of Neurotherapeutics·Davide SeripaFrancesco Panza
Jan 27, 2016·Expert Opinion on Pharmacotherapy·Francesco PanzaGiancarlo Logroscino
Dec 13, 2016·Cold Spring Harbor Perspectives in Medicine·Jennifer N RauchJason E Gestwicki
Dec 12, 2017·Journal of Alzheimer's Disease : JAD·Claude M WischikCharles R Harrington
Aug 26, 2017·Molecular Neurobiology·Donovan TuckerQuanguang Zhang
Aug 2, 2017·Metabolic Brain Disease·Anzelle DelportJacobus P Petzer
Apr 1, 2018·Expert Opinion on Investigational Drugs·Ali ShoeibiIrene Litvan
Mar 3, 2020·Expert Opinion on Therapeutic Targets·Elisabetta Lauretti, Domenico Praticò
Apr 15, 2020·Current Pharmaceutical Design·Kadja Luana Chagas MonteiroEdeildo Ferreira da Silva-Júnior
Sep 10, 2018·Molecular Neurobiology·Ghulam Jeelani PirYipeng Wang
Mar 16, 2019·Inflammopharmacology·Darshpreet KaurRahul Deshmukh
Feb 11, 2020·Expert Opinion on Pharmacotherapy·Nader Nael HashwehGeorge T Grossberg
Nov 19, 2020·Scientific Reports·Katy L H Marshall-PhelpsMarta Woloszynowska-Fraser
Dec 8, 2020·Frontiers in Neurology·Sebastian S OakleyLouise C Serpell
Mar 7, 2021·International Journal of Molecular Sciences·Luis O Soto-RojasJosé Luna-Muñoz
Apr 9, 2021·Acta Neuropathologica·Jaime Vaquer-AliceaLukasz A Joachimiak
Apr 4, 2021·Current Opinion in Chemical Biology·Mateusz BiesagaXavier Salvatella
Apr 21, 2019·International Journal of Biological Macromolecules·Anuradha Venkatramani, Dulal Panda
Oct 16, 2021·Der Nervenarzt·Gesine RespondekGünter U Höglinger

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Methods Mentioned

BETA
transgenic
light microscopy
dissection

Software Mentioned

R Development Core Team
Ethovision Pro
GraphPad
GraphPad QuickCalcs
R
GraphPad Prism
RotaRod

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