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The Journal of Neuroscience, December 15, 2000, 20(24):8980-8986

Nitric Oxide Modulation of Interleukin-1-Evoked Intracellular Ca²⁺ Release in Human Astrocytoma U-373 MG Cells and Brain Striatal Slices

Antonella Meini¹, Alberto Benocci¹, Maria Frosini¹, Gianpietro Sgaragli¹, Gianpaolo Pessina², Carlo Aldinucci², Gisèle Tchuisseu Youmbi¹, and Mitri Palmi¹

¹ Istituto di Scienze Farmacologiche and ² Istituto di Fisiologia, Università di Siena, 53100 Siena, Italy

Intracellular Ca²⁺ mobilization and release into mammal CSF plays a fundamental role in the etiogenesis of fever induced by the proinflammatory cytokine interleukin-1 (IL-1) and other pyrogens. The source and mechanism of IL-1-induced intracellular Ca²⁺ mobilization was investigated using two experimental models. IL-1 (10 ng/ml) treatment of rat striatal slices preloaded with ⁴⁵Ca²⁺ elicited a delayed (30 min) and sustained increase (125-150%) in spontaneous ⁴⁵Ca²⁺ release that was potentiated by L-arginine (300 µM) and counteracted by N--nitro-L-arginine methyl ester (L-NAME) (1 and 3 mM). The nitric oxide (NO) donors diethylamine/NO complex (sodium salt) (0.3 and 1 mM) and spermine/NO (0.1 and 0.3 mM) mimicked the effect of IL-1 on Ca²⁺ release. IL-1 stimulated tissue cGMP concentration, and dibutyryl cGMP enhanced Ca²⁺ release. The guanyl cyclase inhibitors 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (100 µM) and 6-[phenylamino]-5,8 quinolinedione (50 µM) counteracted Ca²⁺ release induced by 2.5 but not 10 ng/ml IL-1. Ruthenium red (50 µM) and, to a lesser extent, heparin (3 mg/ml) antagonized IL-1-induced Ca²⁺ release, and both compounds administered together completely abolished this response. Similar results were obtained in human astrocytoma cells in which IL-1 elicited a delayed (30 min) increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) (402 ± 71.2% of baseline), which was abolished by 1 mM L-NAME. These data indicate that the NO/cGMP-signaling pathway is part of the intracellular mechanism transducing IL-1-evoked Ca²⁺ mobilization in glial and striatal cells and that the ryanodine and the inositol-(1,4,5)-trisphosphate-sensitive Ca²⁺ stores are involved.

Key words: interleukin-1; nitric oxide; Ca²⁺ release; human astrocytoma cells; rat striatum; cGMP; Ca²⁺ stores; fever; neurotoxicity

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20248980-07$05.00/0

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