title: Noradrenaline increases intracellular glutathione in human astrocytoma U-251 MG cells by inducing glutamate-cysteine ligase protein via β3-adrenoceptor stimulation.
abstract: 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 24h concentration-dependently increased their intracellular GSH concentration. This increase was inhibited by a non-selective β-adrenoceptor antagonist propranolol and by a selective β3-adrenoceptor antagonist SR59230A, but not by a non-selective α-adrenoceptor antagonist phenoxybenzamine, or by a selective β1-adrenoceptor antagonist atenolol or by a selective β2-adrenoceptor antagonist butoxamine. In addition, the selective β3-adrenoceptor agonist CL316243 increased the intracellular GSH in U-251 MG cells. Treatment of the cells with noradrenaline (10μM) for 24h 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 β3-adrenoceptor stimulation.
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: yoshioka@pharm.setsunan.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: 12d404kh@edu.setsunan.ac.jp.
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Kadoi
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: yamamuro@pharm.setsunan.ac.jp.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamamuro
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: ishimaru@pharm.setsunan.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishimaru
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. Electronic address: smaeda@pharm.setsunan.ac.jp.
authors.forename: Sadaaki
authors.initials: S
authors.lastname: Maeda
mesh_terms: D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D001254:Astrocytoma / Q000473:pathology*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*
chemical_list: D058673:Adrenergic beta-3 Receptor Antagonists; D022702:Receptors, Adrenergic, beta-3; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D009638:Norepinephrine
keywords: Astrocytes; Atenolol (PubChem CID: 2249); Butoxamine (PubChem CID: 134495); CL316243 (PubChem CID: 5312115); Glutamate-cysteine ligase; Glutathione; Isoproterenol (PubChem CID: 3779); Noradrenaline; Noradrenaline (PubChem CID: 439260); PD98059 (PubChem CID: 4713); Phenoxybenzamine (PubChem CID: 4768); Propranolol (PubChem CID: 4946); SP600125 (PubChem CID: 8515); SR59230A (PubChem CID: 5311452); β(3)-adrenoceptor