title: Protection by an antioxidant of rotenone-induced neuromotor decline, reactive oxygen species generation and cellular stress in mouse brain.
abstract: Exposure to environmental toxins, including rotenone, results in central nervous system and systemic toxicity. Rotenone is a widely used pesticide and a mitochondrial complex I (CI) inhibitor. This study reports effectiveness of a synthetic lipoylcarnitine antioxidant compound, lipoylcarnitine methyl ester iodide (PMX-500F), for treatment of chronic rotenone induced neurological deficits in mice. Mice (C57BL/6NTac; two months of age) received oral administration of rotenone (30 mg/kg/day) or vehicle, preceded by intraperitoneal injection of PMX-500F (19 mg/kg) or vehicle for four weeks. In the Rota-rod test, rotenone treatment had no effect (P>0.05); however, PMX-500F treatment improved locomotor coordination and endurance (latency to fall time; P<0.05). For neuromuscular strength (wire hang test), rotenone treated mice showed reduced latency to fall compared to control mice (P<0.05). PMX-500F treatment improved the outcome in both control and rotenone exposed mice (P<0.05). Rotenone administration increased ROS generation in the forebrain and midbrain regions, but not in the cerebellum (P<0.05). Co-treatment with PMX-500F normalized the ROS in forebrain and midbrain regions to that of the control concentrations. In rotenone administered mice, activated stress-activated protein kinase/c-Jun NH2-terminal kinase (pSAPK/JNK) was higher in forebrain and midbrain lysates than in control mice (P<0.05) and treatment with PMX-500F reduced pSAPK/JNK to control levels. The pSAPK/JNK levels in the cerebellum were similar in all four groups (P>0.05). Total SAPK/JNK was not altered by either rotenone or PMX-500F treatment (P>0.05). These results illustrate that an antioxidant, here PMX-500F, provides protection against rotenone induced decline in neuromotor function, reactive oxygen species (ROS) generation and cellular stress.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849, United States. paramko@auburn.edu
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: Carl A
authors.initials: CA
authors.lastname: Pinkert
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D015386:Hazardous Substances / Q000633:toxicity; D007306:Insecticides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity*; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000975:Antioxidants; D015386:Hazardous Substances; D007306:Insecticides; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D012402:Rotenone; D042967:Electron Transport Complex I