Modulation of nerve and glial function by adenosine—role in the development of ischemic damage

Abstract

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A₁ receptor enhances the K⁺ and Cl conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca²⁺ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A₁ receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca²⁺ channels. The A₁ and A₂ receptors, coupled to G₁/G_o and G_s proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A₁ receptor may mimic metabotropic receptor stimulation in activating intracellular Ca²⁺ mobilization and PKC. A₂ receptor mediated cAMP formation is depressed by high intracellular Ca²⁺ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A₁ and A₂. receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.