Tohoku J. Exp. Med., 2002, 196 (3)

Effect of Phosphodiesterase Inhibitors on Nitric
Oxide Production by Glial Cells

MINKA YOSHIKAWA, AKIO SUZUMURA,¹ ATSUSHI ITO, TSUKASA TAMARU
and TETSUYA TAKAYANAGI

Department of Neurology, Nara Medical University, Shijocho, Kashihara city, Nara 634-0813, and
¹Department of Neuroimmunology, Research Institute of Eviromental Medicine, Nagoya Universiry, Chikusa, Nagoya 464-8601

Nitric oxide (NO) is considered to play a crucial role in the development of various pathological processes in the CNS, such as neuronal degeneration, inflammation and demyelination. In order to search for the agents which suppress NO production in the CNS, we examined the effects of one of the agents which elevate cyclic AMP production, phosphodiesterase inhibitors (PDEIs), on NO production by glial cells in vitro. All the types of PDEIs, from type I- to V-specific and non-specific, suppressed the production of NO by mouse microglia and astrocytes stimulated with lipopolysaccharide, in a dose-dependent manner. Suppression of inducible NO synthase by PDEIs was confirmed by the expression of mRNA by RT-PCR. Although it required 10 mM or higher concentration to effectively suppress NO production in vitro, certain combinations of three different PDEIs synergistically suppressed NO production by astrocytes at 1 mM which could be obtained in vivo at usual therapeutic doses. Similary, combinations of three PDEIs at 1 mM synergistically increased intracellular cAMP in astrocytes. The suppressive effects of PDEIs on NO production were abolished by addition of tumor necrosis factor a (TNFa). Thus, the main suppression mechanism of NO might be indirect through suppression of TNFa. Since some PDEIs are reported to pass through the blood-brain-barrier, the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis, human immunodeficiency virus-related neurological diseases and other neurodegenerative disorders in which NO may play a crucial role.

Keywords —— nitric oxide; astrocytemicroglia; tumor necrosis factor a; phosphodiesterase inhibitor

© 2002 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2002, 196, 167-177

Address for reprints: Minka Yoshikawa, Nara Prefectural Rihabilitation Center, 722 O, Tawaramotocho, Shiki-gun, Nara 634-8521, Japan.

e-mail: y_minka@mpd.biglobe.ne.jp