Striatal neuroprotection with methylene blue

Abstract

Recent literature indicates that low-dose methylene blue (MB), an autoxidizable dye with powerful antioxidant and metabolic enhancing properties, might prevent neurotoxin-induced neural damage and associated functional deficits. This study evaluated whether local MB may counteract the anatomical and functional effects of the intrastriatal infusion of the neurotoxin rotenone in the rat. To this end, stereological analyses of striatal lesion volumes were performed and changes in oxidative energy metabolism in the striatum and related motor regions were mapped using cytochrome oxidase histochemistry. The influence of MB on striatal levels of oxidative stress induced by rotenone was determined, and behavioral tests were used to investigate the effect of unilateral MB coadministration on motor asymmetry. Rotenone induced large anatomical lesions resembling "metabolic strokes", whose size was greatly reduced in MB-treated rats. Moreover, MB prevented the decrease in cytochrome oxidase activity and the perilesional increase in oxidative stress associated with rotenone infusion in the striatum. MB also prevented the indirect effects of the rotenone-induced lesion on cytochrome oxidase activity in related motor regions, such as the striatal regions rostral and caudal to the lesion, the substantia nigra compacta and reticulata, and the pedunculopontine nucleus. At a network level, MB maintained a global strengthening of functional connectivity in basal ganglia-thalamocortical motor circuits, as opposed to the functional decoupling observed in rotenone-alone subjects. Finally, MB partially prevented the behavioral sensorimotor asymmetries elicited by rotenone. These results are consistent with protective effects of MB against neurotoxic damage in the brain parenchyma. This study provides the first demonstration of the anatomical, metabolic and behavioral neuroprotective effects of MB in the striatum in vivo, and supports the notion that MB could be a valuable intervention against neural damage associated with oxidative stress and energy hypometabolism. Corresponding author: Prof. Dr. F. Gonzalez-Lima, University of Texas at Austin, 1 University Station A8000, Austin, TX 78712, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 October 20. Published in final edited form as:Neuroscience. (Bruchey and Gonzalez-Lima, 2008). MB has been widely used as a supravital stain of nervous tissue (O'Leary et al., 1968), as well as an artificial electron donor (Lindahl and Oberg, 1961, Lehninger, 1964, ...

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo

“…MB has also been shown to be neuroprotective in other animal models of degeneration. Amounts as low as 70 mg/kg have been shown to reduce lesion size and neurotoxicity in a rat model of stroke 28,42 and neuroprotective effects were also seen in an animal encephalopathy model. 43 Our data provide further in vivo support for the use of MB to protect against disease, and suggest that autophagy modulation is a valid avenue for drug development for tauopathies.…”

A Guide to Neurotoxic Animal Models of Parkinson's Disease

“…In initial studies in which high doses of rotenone were used, widespread lesions beyond the nigrostriatal system were reported Ferrante et al 1997;Rojas et al 2009). The rotenone model thus received little attention until Greenamyre and colleagues developed a chronic low-dose regimen (Betarbet et al 2000).…”

Rotenone-induced nigrostriatal toxicity is reduced by methylene blue

“…25,26,59 When infused into the rat striatum along with rotenone, methylene blue (8.8 µg) prevented a decrease in cytochrome oxidase activity and any perilesional increase in oxidative stress (dihydroethidium fluorescence). 60 In rats treated subcutaneously with rotenone 5 mg/kg for 8 days, methylene blue given at 500 µg/kg improved locomotor deficits and prevented striatal dopamine depletion. 25 In vitro, methylene blue at concentrations of 10 nM-10 µM increased the viability of murine hippocampal cells incubated with 5 µM rotenone.…”