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Antioxidant‐Mediated Reversal of Oxidative Damage in Mouse Modeling of Complex I Inhibition
Author(s) -
Parameshwaran Kodeeswaran,
Irwin Michael H.,
Steliou Kosta,
Suppiramaniam Vishnu,
Pinkert Carl A.
Publication year - 2015
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21242
Subject(s) - oxidative damage , antioxidant , oxidative phosphorylation , oxidative stress , chemistry , mechanism (biology) , pharmacology , biophysics , biochemistry , biology , philosophy , epistemology
Preclinical ResearchMitochondrial 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. Drug Dev Res 76 : 8272–81, 2015. © 2015 Wiley Periodicals, Inc.