The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections.
It is now generally accepted that excitotoxic cell death involves bioenergetic failure resulting from the cycling of Ca2+ and the generation of reactive oxygen species (ROS) by mitochondria. Both Ca2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Deltapsi(m)) that results from the proton gradient that is generated across the inner membrane. Mitochondrial uncoupling refers to a condition in which protons cross the inner membrane back into the matrix while bypassing the ATP synthase. As a consequence of this "short-circuit," there is a reduction in Deltapsi(m). We have previously demonstrated that animals treated with the classic uncoupling agent 2,4-dinitrophenol (DNP) show significant protection against brain damage following striatal injections of the NMDA agonist quinolinic acid (QA). In an effort to elucidate the mechanism of neuroprotection, we have assessed the effects of DNP on several parameters of mitochondrial function caused by QA. The results presented herein demonstrate that treatment with DNP attenuates QA-induced increases in mitochondrial Ca2+ levels and ROS formation and also improves mitochondrial respiration. Our findings indicate that DNP may confer protection against acute brain injury involving excitotoxic pathways by mechanisms that maintain mitochondrial function.
Korde
Amit S
AS
Department of Neurology, University of Kentucky, Lexington, KY 40536-0284, USA.
Sullivan
Patrick G
PG
Maragos
William F
WF
D019297:2,4-Dinitrophenol / Q000494:pharmacology*; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage; D006706:Homeostasis / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017378:Quinolinic Acid / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D017378:Quinolinic Acid; D019297:2,4-Dinitrophenol