Effect of Metformin on Spontaneous Calcium Signaling in Cultured Astrocytes during Normoxic and Hypoxic Conditions

Abstract

Astrocyte function is controlled by intracellular Ca2+ signaling. On the other hand, hypoxia influences calcium dynamics and its homeostatic range because of reduction of ATP synthesis, which inhibits ATP dependent processes. By using Ca2+ sensitive fluorescence dye, we studied how metformin changed spontaneous oscillating Ca2+ signals in soma of astrocytes from 5–7-day-old rats grown under normoxic and mild-hypoxic (2% O2) conditions. Mild hypoxic conditions applied for 24 h did not change astrocyte viability; however, it reduced the relative amplitude of Ca2+ signals, slowed the decay of the signals, and increased the period of spontaneous oscillations. Lower concentrations of metformin, 0,25 or 0,5 mM, applied before hypoxia reduced this detrimental influence by partially restoring the amplitude, fastening the decay, and reducing the period of Ca2+ signaling. In contrast, higher concentration, 1mM, of metformin exaggerated the effects of hypoxia by reducing signals, slowing their decay and prolonged the period between signals. Unexpectedly, in astrocytes grown under normoxic conditions all concentrations of metformin after several hours of application had detrimental effects for Ca2+ signaling. Low concentration of metformin under mild hypoxic conditions helps to rescue the functioning of astrocytes by conditioning the cells to prolonged hypoxic influence.