title: Antioxidant-mediated reversal of oxidative damage in mouse modeling of complex I inhibition.
abstract: Mitochondrial dysfunction is a key component of various aging-related pathologies of the brain that result in dementia. As such, it provides an important avenue in development of therapeutic interventions for a host of neurological disorders. A requirement for functional mitochondrial respiratory chain complex I (CI), to accomplish the normal physiological processes regulating memory, seems intuitive. In the present study, a synthetic lipoylcarnitine antioxidant (PMX-500FI; 100 mg/kg/day po) was administered to female ICR mice (3-4-month old) that were subsequently treated with the mitochondrial CI inhibitor, rotenone (400 mg/kg/day). After 1 week, rotenone-induced impairment of neuronal function was evaluated in the hippocampus, a brain region that is involved in regulating memory formation. Electrophysiological recordings in live brain slices showed that long-term potentiation (LTP) was reduced by rotenone exposure (P < 0.05) while pretreatment with PMX-500FI maintained LTP similar to control levels (P > 0.05). Potentiation during theta burst stimulation (TBS) was similar among treatment groups (P > 0.05); however, neurotransmitter release, which increased in control mice after TBS, was lower in rotenone treated mice (P < 0.05), and was accompanied by reduced basal synaptic transmission (P < 0.05), increased proapoptotic signaling and decreased extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation (P < 0.05). For each of these determinations, pretreatment with PMX-500FI alleviated the harmful effects of rotenone. These results illustrate that treatment with antioxidant PMX-500FI is protective against rotenone-induced impairment of neuronal bioenergetics in the mouse hippocampus, in regard to both excitatory synaptic physiology and proapoptotic signaling. The protective effect of PMX-500FI against rotenone-induced disruption of cellular bioenergetics may have important therapeutic implications for treating aging-related dementia and other diseases related to mitochondrial dysfunction and/or oxidative damage.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Kodeeswaran
authors.initials: K
authors.lastname: Parameshwaran
authors.forename: Michael H
authors.initials: MH
authors.lastname: Irwin
authors.forename: Kosta
authors.initials: K
authors.lastname: Steliou
authors.forename: Vishnu
authors.initials: V
authors.lastname: Suppiramaniam
authors.forename: Carl A
authors.initials: CA
authors.lastname: Pinkert
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D002331:Carnitine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D055724:Electrophysiological Phenomena; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D012402:Rotenone / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; C000604151:PMX-500FI; D012402:Rotenone; D008063:Thioctic Acid; D042967:Electron Transport Complex I; D002331:Carnitine
keywords: antioxidants; complex I; hippocampus; mitochondria; rotenone; synaptic physiology