Mitochondrial oxidative stress and epilepsy in SOD2 deficient mice: attenuation by a lipophilic metalloporphyrin.

Abstract

Epileptic seizures are a common feature associated with inherited mitochondrial diseases. This study investigated the role of mitochondrial oxidative stress in epilepsy resulting from mitochondrial dysfunction using cross-bred mutant mice lacking mitochondrial manganese superoxide dismutase (MnSOD or SOD2) and a lipophilic metalloporphyrin catalytic antioxidant. Video-EEG monitoring revealed that in the second to third week of postnatal life (P14-P21) B6D2F2 Sod2(-/-) mice exhibited frequent spontaneous motor seizures providing evidence that oxidative stress-induced mitochondrial dysfunction may contribute to epileptic seizures. To confirm the role of mitochondrial oxidative stress in epilepsy a newly developed lipophilic metalloporphyrin, AEOL 11207, with high potency for catalytic removal of endogenously generated reactive oxygen species was utilized. AEOL 11207-treated Sod2(-/-) mice showed a significant decrease in both the frequency and duration of spontaneous seizures but no effect on seizure severity. A significant increase in the average lifespan of AEOL 11207-treated Sod2(-/-) mice compared to vehicle-treated Sod2(-/-) mice was also observed. Indices of mitochondrial oxidative stress and damage (aconitase inactivation, 3-nitrotyrosine formation, and depletion of reduced coenzyme A) and ATP levels affecting neuronal excitability were significantly attenuated in the brains of AEOL 11207-treated Sod2(-/-) mice compared to vehicle-treated Sod2(-/-) mice. The occurrence of epileptic seizures in Sod2(-/-) mice and the ability of catalytic antioxidant therapy to attenuate seizure activity, mitochondrial dysfunction, and ATP levels suggest that ongoing mitochondrial oxidative stress can contribute to epilepsy associated with mitochondrial dysfunction and disease.

• Authors: Li-Ping Liang, Simon Waldbaum, Shane Rowley, Ting-Ting Huang, Brian J Day, Manisha Patel
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 45 Issue 3 Pg. 1068-76 (Mar 2012) ISSN: 1095-953X [Electronic] United States
• PMID: 22200564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Video-Audio Media)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• AEOL 11207
• Adenine Nucleotides
• Anticonvulsants
• Metalloporphyrins
• NAD
• 3-nitrotyrosine
• Tyrosine
• Superoxide Dismutase
• superoxide dismutase 2
• Fumarate Hydratase
• Aconitate Hydratase
• Glutathione
• Coenzyme A
• Glutathione Disulfide

Topics

• Aconitate Hydratase (metabolism)
• Adenine Nucleotides (metabolism)
• Analysis of Variance
• Animals
• Animals, Newborn
• Anticonvulsants (therapeutic use)
• Cerebral Cortex (pathology, ultrastructure)
• Chromatography, High Pressure Liquid
• Coenzyme A (metabolism)
• Disease Models, Animal
• Electroencephalography
• Epilepsy (drug therapy, genetics, pathology)
• Fumarate Hydratase (metabolism)
• Glutathione (metabolism)
• Glutathione Disulfide (metabolism)
• Metalloporphyrins (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (drug effects)
• NAD (metabolism)
• Oxidative Stress (drug effects, genetics)
• Superoxide Dismutase (deficiency)
• Tyrosine (analogs & derivatives, metabolism)