Trends in Pharmacological Sciences
Adenosine receptor signaling in the brain immune system
Section snippets
Adenosine regulates brain function in health and disease
The purine nucleoside adenosine is a modulatory substance that is studied by researchers from different biomedical areas because of the plethora of its actions on organs and tissues. Probably one of the most widely recognized effects of adenosine is its ability to control CNS functions in both physiological and pathophysiological conditions. Adenosine interacts with four receptors (A1, A2A, A2B and A3 receptors) 1, 2, which are seven-membrane-spanning proteins that couple to heterotrimeric G
Adenosine metabolism in the CNS
Physiological actions of adenosine result almost exclusively from activation of cell-surface adenosine receptors and the stimulation of downstream intracellular pathways. Processes that are related to the generation, release, cellular uptake and metabolism of adenosine determine its bioavailability at receptor sites 1, 2. There are two sources of extracellular adenosine: release of adenosine from the intracellular space via specialized transporters; and extracellular conversion of released
Adenosine modulates the development of a neuroprotective astrocyte phenotype
Astrocytes are the major population of glial cells in the CNS and they have several important physiological properties that are related to CNS homeostasis. In response to noxious stimuli to the CNS, astrocytes undergo a process of proliferation, morphological change (hypertrophy of cell bodies, thickening and elongation of astrocytic processes) and increase the expression of glial fibrillary acidic protein [29]. This process, which is termed astrogliosis, is associated with enhanced release of
Regulation of the function of resident microglia by adenosine
Resident microglia constitute ∼10% of the cells in the CNS [47]. These cells are the intrinsic macrophages of the CNS and, although microglia and infiltrating macrophages have similar functions, they can be distinguished immunohistochemically [48]. Microglia respond rapidly and relatively uniformly to several kinds of injury with characteristic morphological changes, proliferation, upregulation of cell-surface molecules and production of soluble mediators. Most neurological disorders involve
Adenosine receptors on infiltrating immune cells regulate inflammatory processes in the brain
Focal ischemia in the CNS is associated with the infiltration of several types of hematogenous cells, including granulocytes, macrophages and T cells [56]. Bacterial meningitis is characterized by pleocytosis of neutrophils into the cerebrospinal fluid [57]. Infiltration of monocytes and/or macrophages into the CNS is also an early feature of HIV-1 infection, and later recruitment of macrophages might be a key step in the development of HIV-1-associated dementia [58]. Although these
Future perspectives and therapeutic implications
A large body of evidence supports the view that adenosine receptors might be targets for drug development in several disease states that affect the CNS 1, 2, 3, 5, 6, 7. However, with a few exceptions, there is no direct evidence that the beneficial effects are caused by interfering with the immune system of the brain. Based on the fact that A1 receptor deficiency aggravates experimental allergic encephalomyelitis [59], A1 receptor agonists might be worthy of evaluation for the therapy of
Acknowledgements
This work was supported by National Institutes of Health Grant GM66189 and Hungarian Research Fund OTKA (T 049537) in addition to the Intramural Research Program of NIH, NIAAA.
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