Physiology and pharmacology of natural and synthetic nonadenine-based purines in the nervous system

Like their adenine-based counterparts, increasing evidence implicates extra cellular nonadenine-based purines such as guanosine and GTP as trophic effe ctor molecules, affecting the growth and differentiation of cells in the ne rvous system. The extracellular concentration of guanosine is higher than t hat of adenosine, both in physiological and pathological conditions. Extrac ellular guanosine and GTP stimulate the astrocyte cell division, apparently through enhancing release of their adenine-based counter-parts, which act in an autocrine fashion. Guanosine and GTP also stimulate the synthesis by astrocytes of several neurotrophic factors, e.g., NGF, and bFGF, and the re lease of NGF and S100 beta. As well, guanosine and CTP enhance the differen tiation of PC12 cells and hippocampal neurons in vitro. Their action on PC1 2 cells is associated with the early synthesis of adenotin-1, a chaperone p rotein. A hypoxanthine analog, AlT-082, has similar activity on PC12 cells and neurons to guanosine, but is not metabolized. It enhances memory in bot h old memory-deficient mice and in young mice, stimulates neurotrophic fact or synthesis in astrocytes in vitro and in brain in vivo, and protects hipp ocampal neurons in vitro from a "dying-back" neuropathy caused by brief exp osure to high concentrations of glutamate. Given systemically, it protects neurons from NMDA-induced toxicity. Its neuroprotective effects may partly be related to its ability to stimulate release of NGF from astrocytes. Alth ough AlT-082 enhances NGF synthesis, unlike exogenously administered NGF it does not produce hyperalgesia. AlT-082 may prove useful in the treatment o f Alzheimer's disease, for which it is in Phase II trials, and also in the treatment of acute neuronal injuries due, e.g., to trauma and stroke. Drug Dev. Res. 45:356-372, 1998. (C) 1998 Wiley-Liss. Inc.