TY - JOUR
T1 - The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections
AU - Korde, Amit S.
AU - Sullivan, Patrick G.
AU - Maragos, William F.
PY - 2005/10
Y1 - 2005/10
N2 - 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 Ca 2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Δψm) 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 Δψm. 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.
AB - 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 Ca 2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Δψm) 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 Δψm. 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.
KW - Acute injury
KW - Calcium
KW - Mitochondrial uncoupling
KW - Oxymetry
KW - Reactive oxygen species
KW - Respiratory control ratio
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U2 - 10.1089/neu.2005.22.1142
DO - 10.1089/neu.2005.22.1142
M3 - Article
C2 - 16238490
AN - SCOPUS:27444431612
SN - 0897-7151
VL - 22
SP - 1142
EP - 1149
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
IS - 10
ER -