[reverett123]

1. J Biol Chem. 2011 May 6;286(18):16504-15. Epub 2011 Mar 18.

Alternative mitochondrial electron transfer as a novel strategy for
neuroprotection.

Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, Ju X, Liu R, Qian H, Marvin MA,
Goldberg MS, She H, Mao Z, Simpkins JW, Yang SH.

Department of Pharmacology and Neuroscience, Institute for Alzheimer's Disease
and Aging Research, University of North Texas Health Science Center, Fort Worth,
Texas 76107-2699, USA.

Neuroprotective strategies, including free radical scavengers, ion channel
modulators, and anti-inflammatory agents, have been extensively explored in the
last 2 decades for the treatment of neurological diseases. Unfortunately, none of
the neuroprotectants has been proved effective in clinical trails. In the current
study, we demonstrated that methylene blue (MB) functions as an alternative
electron carrier, which accepts electrons from NADH and transfers them to
cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB
derivative, with the redox center disabled by N-acetylation, had no effect on
mitochondrial complex activities. MB increases cellular oxygen consumption rates
and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective
against various insults in vitro at low nanomolar concentrations. Our data
indicate that MB has a unique mechanism and is fundamentally different from
traditional antioxidants. We examined the effects of MB in two animal models of
neurological diseases. MB dramatically attenuates behavioral, neurochemical, and
neuropathological impairment in a Parkinson disease model. Rotenone caused severe
dopamine depletion in the striatum, which was almost completely rescued by MB. MB
rescued the effects of rotenone on mitochondrial complex I-III inhibition and
free radical overproduction. Rotenone induced a severe loss of nigral
dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB
significantly reduced cerebral ischemia reperfusion damage in a transient focal
cerebral ischemia model. The present study indicates that rerouting mitochondrial
electron transfer by MB or similar molecules provides a novel strategy for
neuroprotection against both chronic and acute neurological diseases involving
mitochondrial dysfunction.

PMCID: PMC3091255
PMID: 21454572 [PubMed - indexed for MEDLINE]