Summary
Microglial cells are believed to play an active role in most inflammatory and degenerative brain diseases. Many of the effects of microglial cells can be ascribed to the numerous substances that these cells can synthesize and release upon activation by a variety of stimuli, including cytokines, pro-inflammatory substances, neurotransmitters and viral proteins.
Cyclic AMP (cAMP) is one of the major second messengers and is known to regulate several properties of activated microglia. Interestingly, elevations of cAMP levels can elicit neuroprotective processes in vivo and in vitro, which could be in part related to a controlled microglial activation. It is therefore important on one hand to understand the factors regulating the synthesis of cAMP, and on the other hand to elucidate how cAMP can regulate microglial functions related to brain inflammation, degeneration and repair. In cultured microglia, at least three types of receptors linked to adenylyl cyclase through a stimulatory G protein have been described: the β-adrenergic, the adenosine A2a and the Prostaglandin (PG) EP2 receptors. The microglial synthesis of cAMP can be depressed by a variety of pathophysiological Stimuli that can act at different levels in the cAMP cascade. For example, bacterial lipopolysaccharide and interferon-y have been shown to lower cAMP levels by stimulating type IV Phosphodiesterase activity. Acute Stimulation of protein kinase C led to a depression of PGE2-induced cAMP synthesis by interfering with EP2/EP4 receptors, whereas inactivation or inhibition of protein kinase C reduced the synthesis of the second messenger by inhibiting adenylyl cyclase activity. The human immunodeficiency virus protein gp 120 inhibited β-adrenergic-mediated cAMP synthesis but not the synthesis induced by direct activation of adenylyl cyclase, whereas the viral regulatory protein tat inhibited cAMP synthesis in both conditions. In lipopolysaccharide- activated microglial cells, the effects of cAMP were tested by different authors using one or more of the following tools: receptor agonists (isoproterenol, PGE2, 11-deoxy-16,16-dm-PGE2, adenosine agonists), adenylyl cyclase activators or inhibitors, Inhibitors of protein kinase A, cAMP analogs. cAMP analogs and cAMP-elevating agents (including PGE2) depressed the production of substances and/or expression of molecules potentially involved in the establishment of brain damage (nitrogen and oxygen radicals) or in the amplification of inflammation and immune responses (tumor necrosis factor, interleukin-1, interleukin-12 and co-stimulatory molecules) while enhancing that of potentially neuroprotective or immunodepressive substances (interleukin-10, PGE2).
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Levi, G. (2000). Regulation of Cyclic AMP Synthesis in Microglial Cells and Possible Role of Cyclic AMP in Neuroprotection. In: Patterson, P., Kordon, C., Christen, Y. (eds) Neuro-Immune Interactions in Neurologic and Psychiatric Disorders. Research and Perspectives in Neurosciences. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59643-8_11
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DOI: https://doi.org/10.1007/978-3-642-59643-8_11
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