Protective Mechanisms of Adenosine in Neurons and Glial Cells^a

Abstract

As illustrated in Figure 1, a disturbance of the intracellular Ca2+ homeostasis is thought to be a common pathogenic factor for the generation of secondary nerve cell damage that develops after brain trauma or stroke or during the course of neurodegenerative diseases. A neuronal Ca2+ overload which may result from an excessive glutamate-evoked membrane depolarization and consecutive Ca2+ influx as well as from an activation of metabotropic receptors and consecutive intracellular Ca2+ mobilization is known to have direct toxic effects on the cytoskeleton and the cell metabolism of neurons. In addition, a Ca(2+)-dependent activation of glial cells along with the loss of physiologically required mature astrocyte functions and with the acquisition of potentially neurotoxic microglial properties, has more recently been recognized as an additive pathogenic factor. This may provide an effective target for pharmacological interference. Specifically, the reinforcement of an endogenous homeostatic regulator, which obtained its sophisticated know-how during evolution, may provide a neuroprotective therapy which can handle the complexity of the pathological process with a minor risk of pharmacological side effects. Adenosine is such an ancient molecular signal that acts on both neurons and glial cells. In neurons, adenosine activates K+ and Cl- conductances, which limits synaptically evoked depolarization, thus counteracting the Ca2+ influx through voltage-dependent and NMDA receptor-operated ion channels. This A1 receptor-mediated effect seems to be the major action by which adenosine adds directly to the protection of neurons against Ca(2+)-dependent damage. In glial cells, the prevalent effect of adenosine is its regulatory influence on the Ca2+ and cAMP-dependent molecular signaling that determines the cellular proliferation rate, the differentiation state and related functions. When mimicking the activation of metabotropic glutamate receptors in cultures of immature rat astrocytes, which largely resemble pathologically activated astrocytes, a transient Ca2+ mobilization was initiated by adenosine. This A1 receptor-mediated Ca2+ signal caused a prolonged potentiation of the A2 receptor-mediated intracellular cAMP rise. An experimentally sustained enhancement of the cAMP signaling initiated the differentiation of cultured astrocytes and the new expression of K+ and Cl- channels which are required for the physiological astrocyte function to maintain the extracellular ion homeostasis. Evidence is accumulating that a strengthening of the cAMP signaling, which can be achieved by adenosine agonists and also by the pharmacon propentofylline (an adenosine uptake blocker and phosphodiesterase inhibitor), stimulates the mRNA production of neurotrophic factors in astrocytes. In cultured microglial cells, several days' treatment with adenosine agonists or propentofylline markedly inhibited their proliferation rate, the in vitro spontaneously occurring transformation into macrophages and their particularly high formation of free oxyg...

Propentofylline reverses delayed remyelination in streptozotocin-induced diabetic rats

“…In cultured microglial cells, several days' treatment with adenosine agonists or PPF increased apoptosis in activated microglial cells and strongly inhibited the secretion of proinflammatory substances and the formation of ROS, as well as their transformation into macrophages after injury (31,32). Probably by affecting Ca ++ -and cAMPdependent molecular signaling pathways, PPF stimulates the production of trophic factors in astrocytes, apparently avoiding a harmful and secondary astrocytic activation caused by previous microglial up-regulation.…”

“…Known mechanisms of PPF include inhibition of cyclic AMP (cAMP) and cyclic GMP phosphodiesterases (PDE) and action as a reuptake inhibitor for the purine nucleoside and neurotransmitter adenosine by blocking the activity of membrane nucleoside transporters (ENTs). This leads to increased intracellular cAMP levels and greater extracellular concentrations of adenosine (16), stimulating adenosinergic neurotransmission and adenosine 2 (A2) receptor-mediated cAMP synthesis (31,32).…”

TNFα-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity?

“…The activation of TNFR1 appears to damage neurons whereas activation of TNFR2 is protective (Peschon et al, 1998;Fontaine et al, 2002;Yang et al, 2002). Furthermore, the presence or absence of compounds that modify TNFα action also greatly influences possible neuroprotective and neurotoxic effects (Schubert et al, 1997;Carlson et al, 1998).…”

Interleukin-6 Enhances Expression of Adenosine A1 Receptor mRNA and Signaling in Cultured Rat Cortical Astrocytes and Brain Slices

“…Postsynaptically, adenosine increases conductances of various K ϩ -and Cl Ϫ -channels, which hyperpolarize the membrane potential and counteract a transmitter induced depolarisation with a subsequent reduction of Ca 2 ϩ -influx and stabilization of the Mg 2 ϩ blockage of NMDA receptors (Rudolphi et al 1992a,b;Rudolphi and Schubert 1996). Most, if not all, of these actions of adenosine are mediated via the adenosine A 1 receptor, whereas the role of the other adenosine receptor subtype in neuroprotection is less clear (Schubert et al 1997;Abbracchio and Cattabeni 1999;Heurteaux et al 1995). Accordingly, upregulation of adenosine A 1 receptors by chronic treatment with A 1 -antagonists increases the neuroprotective effect of adenosine (Sutherland et al 1991; Rudolphi et al 1992a,b).…”