The trophic effects of purines and purinergic signaling in pathologic reactions of astrocytes

This article reviews the effects of extracellular purine bases, nucleosides, and nucleotides as intracellular signaling molecules with trophic effects on cells after insults to the brain and spinal cord. Astrocytes are the principal source of extracellular purines in brain after injury, ischemia, or trauma. In vitro and in vivo extracellular purines have both immediate and long-term trophic effects, including stimulation of astrocyte and neuronal differentiation, mitosis, morphogenesis, apoptosis, and stimulation of growth and trophic factor synthesis. The effects of the nucleoside adenosine and the nucleotide adenosine triphosphate (ATP) are mediated principally via specific receptors on the cell surface coupled to a series of signaling cascades. Unlike adenosine and ATP, guanosine and guanosine triphosphate (GTP) do not act at classical purine receptors. However, they exert similar effects on astrocytes, apparently by causing the astrocytes to release large amounts of adenosine and ATP over prolonged periods. The release of adenosine and ATP may be related to the effects of guanosine on the purine nucleoside transporters in the cell membrane, whereas the release of ATP may be due to the effects of GTP on the ATP-binding cassette (ABC) proteins. Physiologically, the effects of guanosine are important because this nucleoside, unlike adenosine, remains elevated for prolonged periods after brain injury.