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Cascading Glia Reactions: a Common Pathomechanism and Its Differentiated Control by Cyclic Nucleotide Signaling
Author(s) -
SCHUBERT PETER,
MORINO TADAO,
MIYAZAKI HIROFUMI,
OGATA TADANORI,
NAKAMURA YOICHI,
MARCHINI CRISTINA,
FERRONI STEFANO
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb06346.x
Subject(s) - extracellular , microbiology and biotechnology , signal transduction , adenosine , cyclic adenosine monophosphate , chemistry , cyclic guanosine monophosphate , endocrinology , nitric oxide , microglia , medicine , biology , receptor , biochemistry , inflammation , immunology
A bstract : A pathological glia activation, stimulated by inflammatory proteins, β‐amyloid, or brain ischemia, is discussed as a common pathogenic factor for progressive nerve cell damage in vascular and Alzheimer dementia. A critical point seems to be reached, if the cytokine‐controlled microglial upregulation causes a secondary activation of astrocytes which loose the negative feedback control, are forced to give up their physiological buffering function, and may add to neuronal damage by the release of nitric oxide (NO) and by promoting toxic β‐amyloid formation. A strengthening of the cyclic adenosine‐5′,3′‐monophosphate (cAMP) signaling exerted a differential inhibition of the stimulatory cytokines tumor necrosis factor‐α (TNF‐α and interleukin‐1β (IL‐1β) released from cultured rat microglia, but maintained the negative feedback signal IL‐6; cAMP inhibited also the release of free oxygen radicals (OR) but not of NO. Reinforcement of the NO‐induced cyclic guanosine monophosphate (cGMP) increase by blockade of the phosphodiesterase (PDE) subtype‐5 with propentofylline counterbalanced the toxic NO action that causes with OR neuronal damage by peroxynitrate formation. In rat cultured astrocytes, a prolonged cAMP elevation favored cell differentiation, the expression of a mature ion channel patter, and an improvement of the extracellular glutamate uptake. Cyclic AMP signaling could be strengthened by PDE blockade and by raising extracellular adenosine, which stimulates A 2 receptor‐mediated cAMP synthesis. Via an A 1 receptor‐mediated effect, elevated adenosine was found to overcome a deficient intracellular calcium mobilization resulting from an impaired muscarinic signaling at pathologically decreased acetylcholine concentrations. We suggest that pharmaca, which elevate extracellular adenosine and/or block the degradation of cyclic nucleotides, may be used to counteract glia‐related neuronal damage in dementing processes.