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) phosphorylatio...
Source: Drug Development Research - Category: Drugs & Pharmacology Authors: Tags: Research Article Source Type: research