Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine.
BACKGROUND
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.


OBJECTIVE
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.
Deiana
Serena
S
School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, Scotland.
Harrington
Charles R
CR
Wischik
Claude M
CM
Riedel
Gernot
G
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008751:Methylene Blue / Q000494:pharmacology*; D051379:Mice; D018727:Muscarinic Antagonists; D018697:Nootropic Agents / Q000494:pharmacology*; D048448:Phenylcarbamates / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D000068836:Rivastigmine; D012601:Scopolamine; D013028:Space Perception / Q000187:drug effects; D013550:Swimming / Q000502:physiology
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D048448:Phenylcarbamates; D012601:Scopolamine; D000068836:Rivastigmine; D008751:Methylene Blue