Journal
EXPERIMENTAL NEUROLOGY
Volume 251, Issue -, Pages 84-90Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2013.11.005
Keywords
Mitochondria; Seizures; Epilepsy; Kainic acid; Kv1.1 knockout mice; Kcna1-null mice; Ascorbic add; Pyruvate; Alpha-tocopherol; Mitochondrial uncoupling; Mitochondrial complex I; Paired-pulse ratios; Seizure-like events; ROS; Antioxidant; Field potentials
Categories
Funding
- Nebraska [LB692]
- Epilepsy Foundation of America
- National Institutes of Health [NS072179]
- National Center for Research Resources [G20RR024001]
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Mitochondria actively participate in neurotransmission by providing energy (ATP) and maintaining normative concentrations of reactive oxygen species (ROS) in both presynaptic and postsynaptic elements. In human and animal epilepsies, ATP-producing respiratory rates driven by mitochondrial respiratory complex (MRC) I are reduced, antioxidant systems are attenuated and oxidative damage is increased. We report that MRCI-driven respiration and functional uncoupling (an inducible antioxidant mechanism) are reduced and levels of H2O2 are elevated in mitochondria isolated from KO mice. Experimental impairment of MRCI in VVT hippocampal slices via rotenone reduces paired-pulse ratios (PPRs) at mossy fiber-CA3 synapses (resembling KO PPRs), and exacerbates seizure-like events in vitro. Daily treatment with AATP [a combination therapy composed of ascorbic acid (AA), alpha-tocopherol (T), sodium pyruvate (P) designed to synergistically target mitochondrial impairments] improved mitochondrial functions, mossy fiber PPRs, and reduced seizure burden index (SBI) scores and seizure incidence in KO mice. AATP pretreatment reduced severity of MA-induced seizures resulting in 100% protection from the severe tonic-clonic seizures in WT mice. These data suggest that restoration of bioenergetic homeostasis in the brain may represent a viable anti-seizure target for temporal lobe epilepsy. (C) 2013 Elsevier Inc All rights reserved.
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