title: Alternative mitochondrial electron transfer as a novel strategy for neuroprotection.
abstract: 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.
authors: 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.
authors: Yi
authors: Y
authors: Wen
authors: Wenjun
authors: W
authors: Li
authors: Ethan C
authors: EC
authors: Poteet
authors: Luokun
authors: L
authors: Xie
authors: Cong
authors: C
authors: Tan
authors: Liang-Jun
authors: LJ
authors: Yan
authors: Xiaohua
authors: X
authors: Ju
authors: Ran
authors: R
authors: Liu
authors: Hai
authors: H
authors: Qian
authors: Marian A
authors: MA
authors: Marvin
authors: Matthew S
authors: MS
authors: Goldberg
authors: Hua
authors: H
authors: She
authors: Zixu
authors: Z
authors: Mao
authors: James W
authors: JW
authors: Simpkins
authors: Shao-Hua
authors: SH
authors: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000009:adverse effects / Q000494:pharmacology; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D014475:Uncoupling Agents / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D014475:Uncoupling Agents; D012402:Rotenone; D008751:Methylene Blue