Therapeutic and preventive effects of methylene blue on Alzheimer's disease pathology in a transgenic mouse model

• Published in: Neuropharmacology 2014-01, Vol.76, p.68-79
• Main Authors: Paban, V., Manrique, C., Filali, M., Maunoir-Regimbal, S., Fauvelle, F., Alescio-Lautier, B.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alanine - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - prevention & control; Amyloid beta-Peptides - metabolism; Animals; APP/PS1 mice; Avoidance Learning - drug effects; Beta-amyloid; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cognitive science; Cognitive Sciences; Cortex; Discrimination (Psychology) - drug effects; Disease Models, Animal; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; HRMAS NMR; Injections, Intraperitoneal; jMRUI; Lactic Acid - metabolism; Life Sciences; Male; Memory; Methylene Blue - administration & dosage; Methylene Blue - pharmacology; Methylene Blue - therapeutic use; Mice; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - metabolism; Motor Activity - drug effects; Nesting Behavior - drug effects; Neurobiology; Neurons and Cognition; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neuroscience; Psychology; Psychology and behavior
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.06.033

Methylene blue (MB) belongs to the phenothiazinium family. It has been used to treat a variety of human conditions and has beneficial effects on the central nervous system in rodents with and without brain alteration. The present study was designed to test whether chronic MB treatment taken after (therapeutic effect) or before (preventive effect) the onset of beta-amyloid pathology influences cognition in a transgenic mouse model (APP/PS1). In addition, the present study aims at revealing whether these behavioral effects might be related to brain alteration in beta-amyloid deposition. To this end, we conducted an in vivo study and compared two routes of drug administration, drinking water versus intraperitoneal injection. Results showed that transgenic mice treated with MB orally or following intraperitoneal injection were protected from cognitive impairments in a variety of social, learning, and exploratory tasks. Immunoreactive beta-amyloid deposition was significantly reduced in the hippocampus and adjacent cortex in MB-treated transgenic mice. Interestingly, these beneficial effects were observed independently of beta-amyloid load at the time of MB treatment. This suggests that MB treatment is beneficial at both therapeutic and preventive levels. Using solid-state High Resolution Magic Angle Spinning Nuclear Magnetic Resonance (HRMAS-NMR), we showed that MB administration after the onset of amyloid pathology significantly restored the concentration of two metabolites related to mitochondrial metabolism, namely alanine and lactate. We conclude that MB might be useful for the therapy and prevention of Alzheimer's disease. This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’. •MB treatment rescued social behavior in transgenic mice.•MB alleviated the cognitive deficits in spatial and non-spatial memory.•MB treatment reduced beta-amyloid load in hippocampus and cortex.•MB administration restored the concentration of alanine and lactate.•MB treatment was beneficial at both therapeutic and preventive levels.