Antioxidant-Mediated Reversal of Oxidative Damage in Mouse Modeling of Complex I Inhibition

作者：Parameshwaran Kodeeswaran; Irwin Michael H; Steliou Kosta; Suppiramaniam Vishnu; Pinkert Carl A^*

来源：Drug Development Research, 2015, 76(2): 72-81.

DOI：10.1002/ddr.21242

• synaptic physiology
• hippocampus
• antioxidants
• mitochondria
• rotenone
• complex I

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. Drug Dev Res 76 : 8272-81, 2015.

• 出版日期2015-3