Melatonin exhibits antioxidant properties in a mouse brain slice model of excitotoxicity

Kimberly L. Clapp-LillyInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhio

Mark A. SmithInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhio

George PerryInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhio

Peggy L. HarrisInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhio

Xiongwei ZhuInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhio

Kelly L. DrewInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhio

Lawrence K. DuffyInstitute of Arctic Biology and Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, Alaska and Institute of Pathology, Case Western Reserve University, ClevelandOhioCorrespondence[email protected]

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Abstract

Objectives. Stroke is a major cause of brain injury in Alaska. Since antioxidant levels are decreased in aged brain, the greater predisposition to neuronal death in stroke leading to subsequent neurodegeneration in aged individuals may be related to changes in oxidant balance. We studied the effect of the endogenous antioxidant melatonin on excitotoxic injury resulting from N-methyl-D-aspartate (NMDA)-induced damage by developing an organotypic mouse brain slice model. Our objective was to inhibit the effects of oxidative stress induced by NMDA in mouse brain slices, using melatonin. Methods. An organotypic mouse brain slice culture was established at PO₂ levels maintained between 80 — 100 mm Hg. NMDA, melatonin or both were added to the slices and antioxidant function was determined using the redox active iron assay as well as 8-OHG and HO-1 immunoassays. Results. This slice system allows for better regulation of both NMDA and melatonin concentrations than can be achieved by in vivo studies. Supporting an antioxidant function, melatonin (100 µM) significantly decreased redox active iron, hemexygenase (HO-1) induction and 8-hydroxyguanosine (8-OHG) following NMDA (50–100 µM) insult. However, somewhat surprisingly, high concentrations of melatonin alone (1mM), increased redox active iron levels and HO-1 induction. Conclusions. These results support the hypothesis that melatonin is a neuroprotective antioxidant. Our data also suggest that 1mM melatonin may have detrimental effects.

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Melatonin exhibits antioxidant properties in a mouse brain slice model of excitotoxicity

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Melatonin exhibits antioxidant properties in a mouse brain slice model of excitotoxicity

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