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

✍ Scribed by M.P. Rathbone; P.J. Middlemiss; J. Gysbers; J. Diamond; M. Holmes; E. Pertens; B.H. Juurlink; A. Glasky; R. Ritzmann; M. Glasky; C.E. Crocker; J.J. Ramirez; A. Lorenzen; T. Fein; E. Schulze; U. Schwabe; R. Ciccarelli; P. Di Iorio; F. Caciagli

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 315 KB
• Volume: 45
• Category: Article
• ISSN: 0272-4391
• DOI: 10.1002/(sici)1098-2299(199811/12)45:3/4<356::aid-ddr36>3.0.co;2-c

✦ Synopsis

Like their adenine-based counterparts, increasing evidence implicates extracellular nonadenine-based purines such as guanosine and GTP as trophic effector molecules, affecting the growth and differentiation of cells in the nervous system. The extracellular concentration of guanosine is higher than that of adenosine, both in physiological and pathological conditions. Extracellular guanosine and GTP stimulate the astrocyte cell division, apparently through enhancing release of their adenine-based counterparts, 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 release of NGF and S100b. As well, guanosine and GTP enhance the differentiation of PC12 cells and hippocampal neurons in vitro. Their action on PC12 cells is associated with the early synthesis of adenotin-1, a chaperone protein. A hypoxanthine analog, AIT-082, has similar activity on PC12 cells and neurons to guanosine, but is not metabolized. It enhances memory in both old memory-deficient mice and in young mice, stimulates neurotrophic factor synthesis in astrocytes in vitro and in brain in vivo, and protects hippocampal neurons in vitro from a ''dying-back'' neuropathy caused by brief exposure 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. Although AIT-082 enhances NGF synthesis, unlike exogenously administered NGF it does not produce hyperalgesia. AIT-082 may prove useful in the treatment of 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.