Trophic effects of purines in neurons and glial cells

In addition to their well known roles within cells, purine nucleotides such as adenosine 5' triphosphate (ATP) and guanosine 5' triphosphate (CTP), nu cleosides such as adenosine and guanosine and bases, such as adenine and gu anine and their metabolic products xanthine and hypoxanthine are released i nto the extracellular space where they act as intercellular signaling molec ules. In the nervous system they mediate both immediate effects, such as ne urotransmission, and trophic effects which induce changes in cell metabolis m, structure and function and therefore have a longer time course. Some tro phic effects of purines are mediated via purinergic cell surface receptors, whereas others require uptake of purines by the target cells. Purine nucle osides and nucleotides, especially guanosine, ATP and GTP stimulate incorpo ration of [H-3]thymidine into DNA of astrocytes and microglia and concomita nt mitosis in vitro. High concentrations of adenosine also induce apoptosis , through both activation of cell-surface A(3) receptors and through a mech anism requiring uptake into the cells. Extracellular purines also stimulate the synthesis and release of protein trophic factors by astrocytes, includ ing bFGF (basic fibroblast growth factor), nerve growth factor (NGF), neuro trophin-3, ciliary neurotrophic factor and S-100 beta protein. In vivo infu sion into brain of adenosine analogs stimulates reactive gliosis. Purine nu cleosides and nucleotides also stimulate the differentiation and process ou tgrowth from various neurons including primary cultures of hippocampal neur ons and pheochromocytoma cells. A tonic release of ATP from neurons, its hy drolysis by ecto-nucleotidases and subsequent re-uptake by axons appears cr ucial for normal axonal growth. Guanosine and GTP, through apparently diffe rent mechanisms, are also potent stimulators of axonal growth in vitro. In vivo the extracellular concentration of purines depends on a balance bet ween the release of purines From cells and their re-uptake and extracellula r metabolism. Purine nucleosides and nucleotides are released from neurons by exocytosis and from both neurons and glia by non-exocytotic mechanisms. Nucleosides are principally released through the equilibratory nucleoside t ransmembrane transporters whereas nucleotides may be transported through th e ATP binding cassette family of proteins, including the multidrug resistan ce protein. The extracellular purine nucleotides are rapidly metabolized by ectonucleotidases. Adenosine is deaminated by adenosine deaminase (ADA) an d guanosine is converted to guanine and deaminated by guanase. Nucleosides are also removed from the extracellular space into neurons and glia by tran sporter systems. Large quantities of purines, particularly guanosine and, t o a lesser extent adenosine, are released extracellularly following ischemi a or trauma. Thus purines are likely to exert trophic effects in vivo follo wing trauma. The extracellular purine nucleotide GTP enhances the tonic rel ease of adenine nucleotides, whereas the nucleoside guanosine stimulates to nic release of adenosine and its metabolic products. The trophic effects of guanosine and GTP may depend on this process. Guanosine is likely to be an important trophic effector in vivo because high concentrations remain extr acellularly for up to a week after focal brain injury. Purine derivatives are now in clinical trials in humans as memory-enhancing agents in Alzheimer's disease. Two of these, propentofylline and AIT-082, are trophic effecters in animals, increasing production of neurotrophic fac tors in brain and spinal cord. Likely more clinical uses for purine derivat ives will be found; purines interact at the level of signal-transduction pa thways with other transmitters, for example, glutamate. They can beneficial ly modify the actions of these other transmitters. (C) 1999 Elsevier Scienc e Ltd. All rights reserved.