Abstract
In view of the increasing evidence that a pathological glial activation plays a significant role in the development of neurodegenerative diseases, we investigated the underlying molecular signaling as a possible target for a pharmacological therapy. Here, we are particularly focusing on the endogenous modulation of the Ca2+ and cyclic nucleotide-dependent signaling by the nucleoside adenosine and its reinforcement by the xanthine derivative propentofylline (PPF). As an experimental model, we used cultured rat microglial cells and astrocytes that are immature, show a high proliferation rate, and resemble in several aspects pathologically activated glial cells. A prolonged increase of the cellular cAMP level favored the differentiation of cultured astrocytes and associated properties required for the physiological nerve cell function. On the other hand, a strengthening of the cyclic nucleotide-dependent signaling inhibited potentially neurotoxic properties of cultured microglial cells. Similar effects were obtained by treatment with propentofylline, which mimicked modulatory adenosine effects and increased the intracellular level of cAMP and cGMP. Such a pharmacological glial cell conditioning, obtained by modifying the strength and the timing of these second messengers, may provide a therapy of neurodegenerative diseases in which a pathological activation of microglial cells and astrocytes is discussed to play a pathogenic role.
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References
Banati R. B., Gehrmann J., Schubert P., and Kreutzberg G. W. (1993) Cytotoxicity of microglia.Glia 7, 111–118.
Banati R. B., Schubert P., Rothe G., Gehrmann J., Rudolphi K., Valet G., and Kreutzberg G. W. (1994) Modulation of intracellular formation of reactive oxygen intermediates in peritoneal macrophages and microglia/brain macrophages by propentofylline.J. Cerebr. Blood Flow Cell. Metab. 14, 145–149.
DeLeo J., Töth L., Schubert P., Rudolphi K., and Kreutzberg G. W. (1987) Ischemia-induced neuronal cell death, calcium accumulation and glial response in the hippocampus of the Mongolian gerbil and protection by the xanthine derivative HWA 285.J. Cerebr. Blood Flow Cell Metab. 7, 745–752.
Dyrcks T., Dyrcks E., Masters C. L., and Beyreuther K. (1993) Amyloidogenicity of rodent and human β A4 sequences.FEBS Lett. 324, 231–236.
Ferroni S., Marchini C., Schubert P., and Rapisarda C. (1995) Two distinct inward rectifying conductances are expressed in cultured rat cortical astrocytes after long-term dibutyryl-cyclic-AMP treatment.FEBS Lett. 267, 219–325.
Guilian D., Baker T. J., Shih L. C. N., and Lachman L. B. (1986) Interleukin-1 of the central nervous system is produced by ameboid microglia.J. Exp. Med. 164, 594–604.
McRae A., Gilland E., Bona E., and Hagberg H. (1995) Microglia activation after neonatal hypoxic ischemia.Developmental Brain Research 34, 245–252.
McRae A., Keil M., and Rudolphi K. (1993) Forebrain ischemia in mongolian gerbil: a model to investigate Alzheimer disease microglial antibodies and amyloid.Soc. Neurosci. Abstr. 19, 623.
McRae A., Rudolphi K., and Schubert P. (1994) Propentofylline depresses amyloid and Alzheimer's CSF microglial antigens after ischemia.NeuroReport 5, 1193–1196.
Meskini N., Nëmoz G., Okyayuz-Bakiouti I., Lagard M., and Prigent A. F. (1994) Phosphodiesterase inhibitory profile of some related xanthine derivatives pharmacologically active on peripheral microcirculation.Biochem. Pharmacol. 47, 781–788.
Nishizuka Y. (1986) Studies and perspectives of protein kinase C.Science 233, 305–312.
Ogata T., Nakamura Y., Tsuji K., Shibata T, Kataoka K., and Schubert P. (1994) Adenosine enhances intracellular Ca2+ mobilization in conjunction with metabotropic glutamate receptor activation by t-ACPD in cultured hippocampal astrocytes.Neurosci. Lett. 170, 5–8.
Ogata T., Nakamura Y., and Schubert P. (1996) Potentiated cAMP rise in metabotropically stimulated rat cultured astrocytes by a Ca2+-related A1/A2 receptor cooperation.Eur. J. Neurosci. in press.
Parkinson F. E. and Fredholm B. B. (1991) Effects of propentofylline on adenosine A1 and A2 receptors and nitrobenzylthioinosine-sensitive nucleoside transporters: quantitative autoradiographic analysis.Eur. J. Pharmacol. 202, 361–366.
Schubert P., Banati R., Dux E., Gehrmann J., Rudolphi K., and Kreutzberg G. W. (1992) Reactive oxygen intermediates in microglial cells differentiating into brain macrophages: depression by propentofylline and relation to adenosine action, inPharmacology of Cerebral Ischemia (Krieglstein J. and Oberpichler H., eds.), pp. 461–467, Wiss. Verl. Ges., Stuttgart.
Schubert P., Rudolphi K., Fredholm F., and Nakamura Y. (1994) Modulation of nerve and glial cell function by adenosine—Role in the development of ischemic brain damage.Int. J. Biochem. 26, 1227–1236.
Shinoda J., Furukawa Y., and Furukawa S. (1990) Stimulation of nerve growth factor synthesis/secretion by propentofylline in cultured mouse astroglial cells.Biochem. Pharmacol. 39, 1813–1816.
Si Q., Nakamura Y., Schubert P., Rudolphi K., and Kataoka K. (1996) Adenosine and propentofylline inhibit phorbol ester-induced proliferation of cultured microglial cells.Exp. Neurol. (in press).
Stefanovich V. (1985) Effect of propentofylline on cerebral metabolism of rats.Drug. Dev. Res. 6, 327–338.
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Schubert, P., Ogata, T., Ferroni, S. et al. Modulation of glial cell signaling by adenosine and pharmacological reinforcement. Molecular and Chemical Neuropathology 28, 185–190 (1996). https://doi.org/10.1007/BF02815221
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DOI: https://doi.org/10.1007/BF02815221