Alternative mitochondrial electron transfer as a novel strategy for neuroprotection

J Biol Chem. 2011 May 6;286(18):16504-15. doi: 10.1074/jbc.M110.208447. Epub 2011 Mar 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Electron Transport Chain Complex Proteins / antagonists & inhibitors
  • Electron Transport Chain Complex Proteins / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Glycolysis / drug effects
  • Male
  • Methylene Blue / pharmacology*
  • Mitochondria / enzymology*
  • Neurons / enzymology
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Oxygen Consumption / drug effects
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / enzymology
  • Parkinson Disease, Secondary / pathology
  • Parkinson Disease, Secondary / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Rotenone / adverse effects
  • Rotenone / pharmacology
  • Substantia Nigra / enzymology
  • Substantia Nigra / pathology
  • Substantia Nigra / physiopathology
  • Uncoupling Agents / adverse effects
  • Uncoupling Agents / pharmacology


  • Electron Transport Chain Complex Proteins
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Uncoupling Agents
  • Rotenone
  • Methylene Blue