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

Valeria Melis, Mandy Magbagbeolu, Janet E Rickard, David Horsley, Kathleen Davidson, Kathleen A Harrington, Keith Goatman, Elizabeth A Goatman, Serena Deiana, Steve P Close, Claudia Zabke, Karsten Stamer, Silke Dietze, Karima Schwab, John M D Storey, Charles R Harrington, Claude M Wischik, Franz Theuring, Gernot Riedel

Research output: Contribution to journalArticle

35 Citations (Scopus)
9 Downloads (Pure)

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 data establish that diaminophenothiazine compounds, like MT, can reverse both spatial and motor learning deficits and reduce the underlying tau pathology, and therefore offer the potential for treatment of tauopathies.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

Original languageEnglish
Pages (from-to)353-368
Number of pages16
JournalBehavioural Pharmacology
Volume26
Issue number4
DOIs
Publication statusPublished - Jun 2015

Fingerprint

Tauopathies
Methylene Blue
Transgenic Mice
Licensure
Brain
Learning
Entorhinal Cortex
Water
Proxy
Amyloid
Oral Administration
Hippocampus
Alzheimer Disease
Therapeutics
Salts
Pathology
Neurons
Pharmaceutical Preparations

Keywords

  • animal models
  • learning and memory
  • leucomethylithioninium
  • methylene blue
  • rat
  • RotaRod
  • taupathies
  • water maze

Cite this

Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. / Melis, Valeria; Magbagbeolu, Mandy; Rickard, Janet E; Horsley, David; Davidson, Kathleen; Harrington, Kathleen A; Goatman, Keith; Goatman, Elizabeth A; Deiana, Serena; Close, Steve P; Zabke, Claudia; Stamer, Karsten; Dietze, Silke; Schwab, Karima; Storey, John M D; Harrington, Charles R; Wischik, Claude M; Theuring, Franz; Riedel, Gernot.

In: Behavioural Pharmacology, Vol. 26, No. 4, 06.2015, p. 353-368.

Research output: Contribution to journalArticle

Melis, Valeria ; Magbagbeolu, Mandy ; Rickard, Janet E ; Horsley, David ; Davidson, Kathleen ; Harrington, Kathleen A ; Goatman, Keith ; Goatman, Elizabeth A ; Deiana, Serena ; Close, Steve P ; Zabke, Claudia ; Stamer, Karsten ; Dietze, Silke ; Schwab, Karima ; Storey, John M D ; Harrington, Charles R ; Wischik, Claude M ; Theuring, Franz ; Riedel, Gernot. / Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. In: Behavioural Pharmacology. 2015 ; Vol. 26, No. 4. pp. 353-368.
@article{1971241602764aeeb751318801c69c61,
title = "Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models",
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 data establish that diaminophenothiazine compounds, like MT, can reverse both spatial and motor learning deficits and reduce the underlying tau pathology, and therefore offer the potential for treatment of tauopathies.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.",
keywords = "animal models, learning and memory, leucomethylithioninium, methylene blue, rat, RotaRod, taupathies, water maze",
author = "Valeria Melis and Mandy Magbagbeolu and Rickard, {Janet E} and David Horsley and Kathleen Davidson and Harrington, {Kathleen A} and Keith Goatman and Goatman, {Elizabeth A} and Serena Deiana and Close, {Steve P} and Claudia Zabke and Karsten Stamer and Silke Dietze and Karima Schwab and Storey, {John M D} and Harrington, {Charles R} and Wischik, {Claude M} and Franz Theuring and Gernot Riedel",
note = "Acknowledgements The authors acknowledge the contributions of Bettina Seelhorst (histological analysis), Anna Thoma (animal care), Marlene Arthur (animal dosing) and Pierre-Henri Moreau (experimental discussions). This work was supported by TauRx Therapeutics Ltd., Singapore.",
year = "2015",
month = "6",
doi = "10.1097/FBP.0000000000000133",
language = "English",
volume = "26",
pages = "353--368",
journal = "Behavioural Pharmacology",
issn = "0955-8810",
publisher = "Lippincott Williams & Wilkins",
number = "4",

}

TY - JOUR

T1 - Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models

AU - Melis, Valeria

AU - Magbagbeolu, Mandy

AU - Rickard, Janet E

AU - Horsley, David

AU - Davidson, Kathleen

AU - Harrington, Kathleen A

AU - Goatman, Keith

AU - Goatman, Elizabeth A

AU - Deiana, Serena

AU - Close, Steve P

AU - Zabke, Claudia

AU - Stamer, Karsten

AU - Dietze, Silke

AU - Schwab, Karima

AU - Storey, John M D

AU - Harrington, Charles R

AU - Wischik, Claude M

AU - Theuring, Franz

AU - Riedel, Gernot

N1 - Acknowledgements The authors acknowledge the contributions of Bettina Seelhorst (histological analysis), Anna Thoma (animal care), Marlene Arthur (animal dosing) and Pierre-Henri Moreau (experimental discussions). This work was supported by TauRx Therapeutics Ltd., Singapore.

PY - 2015/6

Y1 - 2015/6

N2 - 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 data establish that diaminophenothiazine compounds, like MT, can reverse both spatial and motor learning deficits and reduce the underlying tau pathology, and therefore offer the potential for treatment of tauopathies.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

AB - 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 data establish that diaminophenothiazine compounds, like MT, can reverse both spatial and motor learning deficits and reduce the underlying tau pathology, and therefore offer the potential for treatment of tauopathies.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

KW - animal models

KW - learning and memory

KW - leucomethylithioninium

KW - methylene blue

KW - rat

KW - RotaRod

KW - taupathies

KW - water maze

U2 - 10.1097/FBP.0000000000000133

DO - 10.1097/FBP.0000000000000133

M3 - Article

VL - 26

SP - 353

EP - 368

JO - Behavioural Pharmacology

JF - Behavioural Pharmacology

SN - 0955-8810

IS - 4

ER -