Noradrenaline increases intracellular glutathione in human astrocytoma U-251 MG cells by inducing glutamate-cysteine ligase protein via β3-adrenoceptor stimulation

Glutathione (GSH) plays a critical role in protecting cells from oxidative damage. Since neurons rely on the supply of GSH from astrocytes to maintain optimal intracellular GSH concentrations, the GSH concentration of astrocytes is important for the survival of neighboring neurons against oxidative stress. The neurotransmitter noradrenaline is known to modulate the functions of astrocytes and has been suggested to have neuroprotective properties in neurodegenerative diseases. To elucidate the mechanisms underlying the neuroprotective properties of noradrenaline, in this study, we investigated the effect of noradrenaline on the concentrations of intracellular GSH in human U-251 malignant glioma (MG; astrocytoma) cells. Treatment of the cells with noradrenaline for 24 h concentration-dependently increased their intracellular GSH concentration. This increase was inhibited by a non-selective beta-adrenoceptor antagonist propranolol and by a selective beta(3)-adrenoceptor antagonist SR59230A, but not by a nonselective oc-adrenoceptor antagonist phenoxybenzamine, or by a selective beta(1)-adrenoceptor antagonist atenolol or by a selective beta(2)-adrenoceptor antagonist butoxamine. In addition, the selective beta 3-adrenoceptor agonist CL316243 increased the intracellular GSH in U-251 MG cells. Treatment of the cells with noradrenaline (10 mu M) for 24 h increased the protein level of the catalytic subunit of glutamate-cysteine ligase (GCLc), the rate-limiting enzyme of GSH synthesis; and this increase was inhibited by SR59230A. These results thus suggest that noradrenaline increased the GSH concentration in astrocytes by inducing GCLc protein in them via beta 3-adrenoceptor stimulation. (C) 2015 Elsevier B.V. All rights reserved.