title: Targeting deficiencies in mitochondrial respiratory complex I and functional uncoupling exerts anti-seizure effects in a genetic model of temporal lobe epilepsy and in a model of acute temporal lobe seizures.
abstract: 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 WT 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 KA-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.
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Simeone
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Matthews
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Kaeli K
authors.initials: KK
authors.lastname: Samson
authors.affiliation: Pharmacology Department, Creighton University School of Medicine, Omaha, NE 68178, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Simeone
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D001205:Ascorbic Acid / Q000627:therapeutic use; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004569:Electroencephalography; D042967:Electron Transport Complex I / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D051662:Kv1.1 Potassium Channel / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019289:Pyruvic Acid / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D012119:Respiration / Q000187:drug effects / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control / Q000628:therapy; D024502:alpha-Tocopherol / Q000627:therapeutic use
chemical_list: C118392:4-adeninyl-2-(hydroxymethyl)-2-butenyl triphosphate; C496947:Kcna1 protein, mouse; D017382:Reactive Oxygen Species; D051662:Kv1.1 Potassium Channel; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I; D024502:alpha-Tocopherol; D001205:Ascorbic Acid; D007608:Kainic Acid
keywords: AATP; ADP; ATP; Alpha-tocopherol; Antioxidant; Ascorbic acid; Epilepsy; FA; FCCP; Field potentials; KA; KO; Kainic acid; Kcna1-null mice; Kv1.1 knockout mice; MRC; Mitochondria; Mitochondrial complex I; Mitochondrial uncoupling; Oligo; P; PM; PPR; Paired-pulse ratios; Pyruvate; ROS; Rot; SBI; SLE; Seizure-like events; Seizures; TCA; UCP2; WT; adenosine diphosphate; adenosine triphosphate; ascorbic acid, alpha-tocopherol, pyrvate; fatty acid; kainic acid; mitochondrial respiratory complex; oligomycin; p-triflourometh-oxyphenylhydrazone; paired pulse ratios; postnatal day; pyruvate and malate; reactive oxygen species; rotenone; seizure burden index; seizure-like event; tricarboxylic acid; uncoupling protein 2; wild-type