Support of homeostatic glial cell signaling: a novel therapeutic approach by propentofylline

A pathological glial cell activation, which forces microglia to transform into immunocompetent cells with cytotoxic properties and astrocytes to "de-differentiate," presumably adds to neurodegenerative diseases. We examined the modulatory effect of adenosine on the Ca2+ and cAMP-dependent regulation of such reactive glial cell properties in culture and tested possibilities of pharmacologic reinforcement. A strengthening of the cAMP-signaling, as could be achieved by adenosine agonists via a Ca(2+)-dependent action, favored the differentiation of proliferating astrocytes and associated neuroprotective properties (ion homeostasis, formation of trophic factors). But potentially neurotoxic properties of microglial cells were inhibited. Adenosine depressed their proliferation rate and transformation into macrophages, their particularly high formation of reactive oxygen intermediates and the release of the cytokine TNF-alpha. Similar effects were obtained with propentofylline, which acts as selective cAMP/cGMP phosphodiesterase inhibitor and also increases the effective concentration of adenosine by blocking its cellular reuptake. The recently observed induction of microglial apoptosis by elevated extracellular adenosine levels may further contribute to limit secondary nerve cell damage related to a pathological glial cell activation.