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Gernot Riedel - One of the best experts on this subject based on the ideXlab platform.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:Rationale The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. Objectives This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Methods Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15–4 mg/kg MTC; 0.1–0.5 mg/kg rivastigmine) in mono or combination treatment. Results Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. Conclusions In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine.
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15-4 mg/kg MTC; 0.1-0.5 mg/kg rivastigmine) in mono or combination treatment. Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
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P2-383: Reversal of spatial problem-solving cognitive deficit in a transgenic mouse line overexpressing the repeat domain of Tau by treatment with the Tau aggregation inhibitor Methylthioninium Chloride
Alzheimer's & Dementia, 2008Co-Authors: Valeria Melis, Serena Deiana, Charles R. Harrington, Gernot Riedel, Kwang Meng Seng, Claudia Zabke, Karsten Stamer, Franz Theuring, Claude M. WischikAbstract:ylated at several disease-relevant epitopes, leading to progressive neuronal dystrophy and formation of RIPA-insoluble tau. AD-like tau hyperphosphorylation was reduced by the tau kinase inhibitors lithium as well as SRN 003-556, but RIPA-insoluble tau accumulated regardless of reduced tau phosphorylation. Moreover, we obtained evidence that synapse pathology, assessed by two markers for synaptic vesicles, preceded axon and cell body degeneration which is in line with previous in vivo observations. Specifically SRN 003-556, a kinase inhibitor that may partially inhibit multiple tau kinases, but not lithium was able to protect hippocampal neurons from synaptic damage that was presumably caused by a toxic soluble tau fraction. Synapse protection correlated with reduced neurodegeneration observed at later stages. Conclusions: These data provide first mechanistic insights towards the functional benefits of tau kinase inhibition that have been observed in vivo. The ex vivo model system of hippocampal tau pathology described here may facilitate the identification of drug candidates, in particular kinase inhibitors, and help to identify modulators of tau toxicity in hippocampal neurons.
Serena Deiana - One of the best experts on this subject based on the ideXlab platform.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:Rationale The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. Objectives This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Methods Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15–4 mg/kg MTC; 0.1–0.5 mg/kg rivastigmine) in mono or combination treatment. Results Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. Conclusions In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine.
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15-4 mg/kg MTC; 0.1-0.5 mg/kg rivastigmine) in mono or combination treatment. Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
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P2-383: Reversal of spatial problem-solving cognitive deficit in a transgenic mouse line overexpressing the repeat domain of Tau by treatment with the Tau aggregation inhibitor Methylthioninium Chloride
Alzheimer's & Dementia, 2008Co-Authors: Valeria Melis, Serena Deiana, Charles R. Harrington, Gernot Riedel, Kwang Meng Seng, Claudia Zabke, Karsten Stamer, Franz Theuring, Claude M. WischikAbstract:ylated at several disease-relevant epitopes, leading to progressive neuronal dystrophy and formation of RIPA-insoluble tau. AD-like tau hyperphosphorylation was reduced by the tau kinase inhibitors lithium as well as SRN 003-556, but RIPA-insoluble tau accumulated regardless of reduced tau phosphorylation. Moreover, we obtained evidence that synapse pathology, assessed by two markers for synaptic vesicles, preceded axon and cell body degeneration which is in line with previous in vivo observations. Specifically SRN 003-556, a kinase inhibitor that may partially inhibit multiple tau kinases, but not lithium was able to protect hippocampal neurons from synaptic damage that was presumably caused by a toxic soluble tau fraction. Synapse protection correlated with reduced neurodegeneration observed at later stages. Conclusions: These data provide first mechanistic insights towards the functional benefits of tau kinase inhibition that have been observed in vivo. The ex vivo model system of hippocampal tau pathology described here may facilitate the identification of drug candidates, in particular kinase inhibitors, and help to identify modulators of tau toxicity in hippocampal neurons.
Charles R. Harrington - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer's Disease
Developing Therapeutics for Alzheimer's Disease, 2016Co-Authors: Claude Michel Wischik, John M. D. Storey, Damon Wischik, Charles R. HarringtonAbstract:Abstract Tau pathology in Alzheimer’s disease (AD) initiates early, before clinical symptoms are observed and before accumulation of extracellular amyloid-β. Tau aggregation is an autocatalytic process that does not depend on its phosphorylation and is highly correlated with clinical dementia. Tau aggregation inhibitors (TAIs) could provide the therapeutic means for treating AD. We have developed cell-free and cellular models and transgenic mice that model tauopathy and demonstrate the molecular basis for achieving pharmacological selectivity of TAIs. Methylthioninium Chloride, the first selective TAI identified, has demonstrated efficacy in a phase 2 trial of AD on both clinical and functional molecular neuroimaging end points. This supports the potential for use of TAIs both for prevention and for treatment of the disease. LeucoMethylthioninium is now in phase 3 trials of AD and behavioral-variant frontotemporal degeneration in order to confirm the concept of TAI therapy for these tauopathies.
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Cellular Models of Aggregation-dependent Template-directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer Disease
Journal of Biological Chemistry, 2015Co-Authors: Charles R. Harrington, John M. D. Storey, Scott Clunas, Kathleen A. Harrington, David Horsley, Ahtsham Ishaq, Steven Kemp, Christopher Paul Larch, Colin Marshall, Sarah Louise NicollAbstract:Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucoMethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of Methylthioninium Chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 μm. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 μm. These values are close to the steady state trough brain concentration of Methylthioninium ion (0.18 μm) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 μm) required to reverse behavioral deficits and pathology in Tau transgenic mice.
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Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer’s Disease
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Thomas C. Baddeley, Charles R. Harrington, John M. D. Storey, David Horsley, Jennifer Mccaffrey, J. Cheung, Valeria Melis, Claude M. WischikAbstract:Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer’s disease (AD). MT exists in equilibrium between reduced [leucoMethylthioninium (LMT)] and oxidized (MT+) forms; as a Chloride salt [Methylthioninium Chloride (MTC), “methylene blue”], it is stabilized in its MT+ form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT+ form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules.
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Tau-aggregation inhibitor therapy for Alzheimer's disease.
Biochemical Pharmacology, 2014Co-Authors: Claude M. Wischik, Charles R. Harrington, John M. D. StoreyAbstract:Abstract Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms. The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45. The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau–tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal–lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal–lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers. Methylthioninium Chloride (MTC), the first identified tau aggregation inhibitor (TAI), offers an alternative to the amyloid approach. Phase 3 trials are underway with a novel stabilized reduced form of Methylthioninium (LMTX) that has improved tolerability and absorption.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:Rationale The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. Objectives This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Methods Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15–4 mg/kg MTC; 0.1–0.5 mg/kg rivastigmine) in mono or combination treatment. Results Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. Conclusions In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
Claude M. Wischik - One of the best experts on this subject based on the ideXlab platform.
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Complex Disposition of Methylthioninium Redox Forms Determines Efficacy in Tau Aggregation Inhibitor Therapy for Alzheimer’s Disease
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Thomas C. Baddeley, Charles R. Harrington, John M. D. Storey, David Horsley, Jennifer Mccaffrey, J. Cheung, Valeria Melis, Claude M. WischikAbstract:Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer’s disease (AD). MT exists in equilibrium between reduced [leucoMethylthioninium (LMT)] and oxidized (MT+) forms; as a Chloride salt [Methylthioninium Chloride (MTC), “methylene blue”], it is stabilized in its MT+ form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT+ form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules.
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Tau-aggregation inhibitor therapy for Alzheimer's disease.
Biochemical Pharmacology, 2014Co-Authors: Claude M. Wischik, Charles R. Harrington, John M. D. StoreyAbstract:Abstract Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms. The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45. The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau–tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal–lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal–lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers. Methylthioninium Chloride (MTC), the first identified tau aggregation inhibitor (TAI), offers an alternative to the amyloid approach. Phase 3 trials are underway with a novel stabilized reduced form of Methylthioninium (LMTX) that has improved tolerability and absorption.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:Rationale The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. Objectives This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Methods Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15–4 mg/kg MTC; 0.1–0.5 mg/kg rivastigmine) in mono or combination treatment. Results Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. Conclusions In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
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Methylthioninium Chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine.
Psychopharmacology, 2008Co-Authors: Serena Deiana, Charles R. Harrington, Claude M. Wischik, Gernot RiedelAbstract:The cholinergic system is involved in cognition as well as in age-related cognitive decline and Alzheimer disease (AD). Cholinergic enhancers ameliorate AD symptoms and represent the main current therapy for AD. MTC (Methylthioninium Chloride), an antioxidant with metabolism-enhancing properties may be a novel candidate with pro-cognitive capacities. This study was performed: (1) to assess the pro-cognitive efficacy of MTC and establish its dose-response; (2) to compare the efficacy of MTC with rivastigmine and (3) to determine the potential for combination therapy by co-administration of MTC and rivastigmine. Spatial cognition of female NMRI mice was tested in a reference memory water maze task. Subjects received intra-peritoneal injections of scopolamine (0.5 mg/kg) followed by vehicle, and/or MTC and/or rivastigmine (0.15-4 mg/kg MTC; 0.1-0.5 mg/kg rivastigmine) in mono or combination treatment. Scopolamine treatment prevented spatial learning in NMRI female mice and the deficit was reversed by both rivastigmine and MTC in a dose-dependent manner. Mono-therapy with high doses of rivastigmine (>0.5 mg/kg) caused severe side effects but MTC was safe up to 4 mg/kg. Co-administration of sub-effective doses of both drugs acted synergistically in reversing learning deficits and scopolamine-induced memory impairments. In our model, MTC reversed the spatial learning impairment. When combined with the ChEI rivastigmine, the effect of MTC appeared to be amplified indicating that combination therapy could potentially improve not only symptoms but also contribute beneficially to neuronal metabolism by minimising side effects at lower doses.
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P4-347: Tau aggregation inhibitor (TAI) therapy with rember™ arrests the trajectory of rCBF decline in brain regions affected by Tau pathology in mild and moderate Alzheimer's disease (AD)
Alzheimer's & Dementia, 2008Co-Authors: Roger T. Staff, Trevor S. Ahearn, Alison D. Murray, Peter Bentham, Kwang Meng Seng, Claude M. WischikAbstract:Background: Neurofibrillary degeneration is a hallmark pathology that defines AD and is correlated with clinical dementia. rember (Methylthioninium Chloride) dissolves Tau protein polymers (Paired Helical Filaments) isolated from human AD brain, and prevents Tau aggregation in cell models at the nanomolar range (0.15 0.58 M). MTC has efficacy in Tau transgenic animal models, reversing cognitive and other behavioural defects, and reverses Tau pathology in the brain. Methods: As part of an exploratory, dose-range finding, parallel design, double-blind, randomised, placebo-controlled trial of rember monotherapy in 332 subjects meeting NINCDS-ADRDA for probable AD stratified by CDR, 138 were imaged at baseline and approximately 24 weeks later using Tc HMPAO SPECT imaging at 9 sites in the UK. Of 135 suitable for analysis, 52, 15, 32 and 36 received placebo, 30mg, 60mg and 100mg tid respectively. Both ROI (region of interest) and SPM (statistical parametric mapping) image analyses were performed. Results: Both ROI and SPM analyses showed, as expected, that those receiving placebo had significant reduction in rCBF over a 24 weeks. Although subjects who were CDR-mild at baseline showed no clinical decline over 24 weeks, SPECT scan confirmed significant decline in rCBF in this group, suggesting that a masking of decline by cognitive reserve in mild AD may confound clinical outcome analysis. Those receiving rember showed no significant reduction in rCBF regardless of baseline clinical severity. Comparing the groups indicated that rember significantly (p .05 FDR corrected) reduced the rate of rCBF decline particularly in the hippocampal, medial temporal, and temporal regions (See Figure). The 60 mg dose produced the largest effect.
Karen Duff - One of the best experts on this subject based on the ideXlab platform.
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Methylthioninium Chloride methylene blue induces autophagy and attenuates tauopathy in vitro and in vivo
Autophagy, 2012Co-Authors: Erin E Congdon, Jessica W Wu, Natura Myeku, Yvette H Figueroa, Mathieu Herman, Paul S Marinec, Jason E Gestwicki, Chad A Dickey, Haung W Yu, Karen DuffAbstract:More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubule-binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium Chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, BECN1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases.