Antioxidant-mediated reversal of oxidative damage in mouse modeling of complex I inhibition
Irwin, Michael H.
Pinkert, Carl A.
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Citation (published version)Kodeeswaran Parameshwaran, Michael H Irwin, Kosta Steliou, Vishnu Suppiramaniam, Carl A Pinkert. 2015. "Antioxidant-mediated reversal of oxidative damage in mouse modeling of complex I inhibition." Drug Development Research, Volume 76, Issue 2, pp. 72 - 81. https://doi.org/10.1002/ddr.21242
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),in order to accomplish the normal physiological processes regulating memory,seems intuitive. In this study, a synthetic lipoylcarnitine antioxidant (PMX-500FI; 100 mg/kg/day) was administered by oral gavage to female ICR mice (3-4 month-old) that were subsequently treated with the mitochondrial complex I inhibitor rotenone (400 mg/kg/day). After one week, rotenone-induced impairment of neuronal function was evaluated in the hippocampus, a region of the brain that functions primarily 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 pre-treatment 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 pro-apoptotic signaling and decreased extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation (P<0.05). For each of these determinations, pre-treatment 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 pro-apoptotic 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.