The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia

J Neurochem. 2005 Sep;94(6):1676-84. doi: 10.1111/j.1471-4159.2005.03328.x. Epub 2005 Jul 25.

Abstract

Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.

Publication types

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

MeSH terms

  • 2,4-Dinitrophenol / pharmacology*
  • Animals
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Cerebral Infarction / drug therapy*
  • Cerebral Infarction / physiopathology
  • Cerebral Infarction / prevention & control
  • Cytochromes c / metabolism
  • Cytoprotection / drug effects
  • Cytoprotection / physiology
  • Disease Models, Animal
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Ischemic Attack, Transient / drug therapy*
  • Ischemic Attack, Transient / metabolism
  • Ischemic Attack, Transient / physiopathology
  • Male
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Uncoupling Agents / pharmacology

Substances

  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Uncoupling Agents
  • Cytochromes c
  • 2,4-Dinitrophenol