Melatonin Protects Kir2.1 Function in an Oxidative Stress-Related Model of Aging Neuroglia.

Melatonin is a pleiotropic biofactor and an effective antioxidant and free radical scavenger and, as such, can be protective in oxidative stress-related brain conditions including epilepsy and aging. To test the potential protective effect of melatonin on brain homeostasis and identify the corresponding molecular targets, we established a new model of oxidative stress-related aging neuroglia represented by U-87 MG cells exposed to D-galactose (D-Gal). This model was characterized by a substantial elevation of markers of oxidative stress, lipid peroxidation, and protein oxidation. The function of the inward rectifying K+ channel Kir2.1, which was identified as the main Kir channel endogenously expressed in these cells, was dramatically impaired. Kir2.1 was unlikely a direct target of oxidative stress, but the loss of function resulted from a reduction of protein abundance, with no alterations in transcript levels and trafficking to the cell surface. Importantly, melatonin reverted these changes. All findings, including the melatonin antioxidant effect, were reproduced in heterologous expression systems. We conclude that the glial Kir2.1 can be a target of oxidative stress and further suggest that inhibition of its function might alter the extracellular K+ buffering in the brain, therefore contributing to neuronal hyperexcitability and epileptogenesis during aging. Melatonin can play a protective role in this context. The inward rectifying K+ channel Kir2.1 plays a major role in extracellular potassium buffering in the brain. Here we show that in cellular models of aging neuroglia characterized by an elevated oxidative stress, the Kir2.1-induced current is dramatically reduced. This loss of function resulted from a reduction in protein abundance, with no alterations in transcript levels and trafficking to the cell surface. Importantly, the antioxidant biofactor melatonin reverted these changes. We suggest that inhibition of Kir2.1 function by oxidative stress might alter the extracellular K+ buffering in the brain, therefore contributing to neuronal hyperexcitability and epileptogenesis during aging. Melatonin can play a protective role in this context.image