Effect of Phosphodiesterase Inhibitors on Nitric Oxide Production by Glial Cells.

Abstract

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 microM or higher concentration to effectively suppress NO production in vitro, certain combinations of three different PDEIs synergistically suppressed NO production by astrocytes at 1 microM which could be obtained in vivo at usual therapeutic doses. Similary, combinations of three PDEIs at 1 microM synergistically increased intracellular cAMP in astrocytes. The suppressive effects of PDEIs on NO production were abolished by addition of tumor necrosis factor alpha (TNFalpha). Thus, the main suppression mechanism of NO might be indirect through suppression of TNFalpha. 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.

Influence of dipyridamole and its combination with NO donor or NO synthase inhibitor on adjuvant arthritis

“…In our experiment, the antiinflammatory and anti-arthritic actions of dipyridamole were amplified markedly by L-NMMA, a non-specific NOs inhibitor. These results are in markedly good agreement with those studies that provide evidence of the involvement of inhibition of NO production in the anti-inflammatory and anti-arthritic effects of PDE inhibitors [29][30][31]. Our present results support the studies suggested that inhibition of NO synthase are potentially beneficial in treatment of condition associated with an overproduction of NO as neurodegenerative disorders and inflammation [32,33].…”

Sildenafil attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-κB signaling pathways in N9 microglia

“…Especially, at a concentration of 100 μM, the percentage suppression of sildenafil on LPS-induced NO production are 53% and 75% in N9 microglia and primary rat microglia respectively, while that of dipyridamole is about 90% in primary mouse microglia [39]. These may be correlated with some important factors, such as different structures of these two compounds, different cell lines used and different time of treatment with LPS.…”

Untitled

“…NOS2 expression was reduced by cAMP analogs in microglia [42]; by PGE2 (as well as FSK and dbcAMP) in enriched microglia [43,44]; and in mixed neuron:microglial co-cultures [36]. Microglial NOS2 was also reduced by treatment with phosphodiesterase (PDE) inhibitors [38,42-45]; as well as other agents which increase cAMP, including melanocortin peptides [46], and conditioned media from T. gondii infected astrocytes [48]. However, NOS2 is not always suppressed by elevated cAMP, and there are several studies showing that in contrast to being inhibitory, cAMP potentiates NOS2 expression [15].…”