Affiliation:
1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences University of Messina Messina Italy
2. Institute of Biophysics National Research Council Genova Italy
3. Institute of Pharmacology and Toxicology Paracelsus Medical University Salzburg Austria
Abstract
AbstractMelatonin 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.
Funder
Associazione Italiana per la Ricerca sul Cancro
Fondazione Telethon
Program on Negotiation
Subject
Clinical Biochemistry,Molecular Medicine,General Medicine,Biochemistry