Behavioral effects of methylene blue on an animal model of sodium azide-induced metabolic deficits
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In some neurodegenerative diseases, the activity of cytochrome c oxidase, an enzyme necessary for aerobic energy production, is decreased. Sodium azide, reversibly inhibits cytochrome c oxidase in the electron-transport chain. Behavioral deficits produced by sodium azide in animal models are similar to those found in neurodegenerative diseases in humans. In the experiments described here, sodium azide was systemically infused via an osmotic pump implanted during surgery in Sprague Dawley rats. They were assessed in an open field test, Morris water maze, and a spontaneous alternation test. Histochemical analysis of cytochrome c oxidase activity was conducted on brain, skeletal muscle, and cardiac muscle sections. The sodium azide group showed significant decreases in spontaneous activity in the open field test, decreased learning and memory retention in the Morris water maze, but no differences in the spontaneous alternation test. Pharmacological intervention that could compensate for the reduction of cytochrome c oxidase activity in neurons may be beneficial in the treatment of neurodegenerative diseases. One such candidate, methylene blue was administered to Sprague-Dawley rats after training, in the memory consolidation period, and its effects assessed in a probe test for memory retention in a baited holeboard maze. The percentage of visits to baited holes compared to all hole-visits was significantly higher in the methylene blue group. In the final experiment, Sprague-Dawley rats were assigned to one of three treatment groups: sodium azide, sodium azide plus methylene blue, and control. They were assessed in a probe test for memory retention in a baited holeboard maze. Methylene blue was successful in restoring memory retention inhibited by the sodium azide. The memory score for the sodium azide group was significantly less than the control and methylene blue group. In vitro studies have shown that methylene blue can accept electrons in the electron-transport chain in mitochondria. Methylene blue may compensate for decreased cytochrome c oxidase activity by accepting electrons upstream from cytochrome c oxidase and shuttling electrons to molecular oxygen, a step necessary for oxidative phosphorylation. Compensating for impaired mitochondrial respiration makes methylene blue a candidate for further study as a treatment in neurodegenerative diseases.