Purine nucleosides protect injured neurons and stimulate neuronal regeneration by intracellular and membrane receptor-mediated mechanisms

Like adenine-based purines, extracellular nonadenine-based purines have a m ultitude of trophic effects on the growth, differentiation, and survival of target cells. The nonadenine-based purines, which include guanosine, inosi ne, and GTP, apparently exert their trophic effects by interacting with bot h intercellular targets as well as those on the cell surface. Specifically, guanosine and inosine target the protein kinase N-kinase, in promoting rem arkable nerve process extension, even in long tracts of the central nervous system after injury. In contrast, GTP may exert its effects via a cell sur face receptor coupled to the release of calcium from internal stores. In ot her cases trophic effects may be mediated by the enhancement of release of adenine-based purines by guanosine. Additionally evidence is presented for the existence of a high-affinity binding site for guanosine with receptor-l ike characteristics on the plasma membranes of astrocytes and brain tissue. This site may be C-protein-coupled and exert its effects through activatio n of the MAP kinase cascade. One effect apparently mediated through this me chanism is the production and release by astrocytes of trophic protein grow th factors such as NGF and TGF beta. These have substantial neuroprotective effects. additionally, this pathway is apparently involved in modulating t he expression of P2Y(1) and P2Y(2) receptors in response to extracellular g uanosine. Extracellular nonadenine-based purines can interact with other gr owth factors, but these interactions are not always synergistic. For exampl e, combinations of guanosine and FGF are antagonistic and reduce the growth of microvascular cells in vitro. Some of the properties of the nonadenine- based purines likely derive from their unique intracellular metabolism in w hich conversion of guanine to xanthine is the final catabolic step. This st ep is catalyzed by guanase, the activity of which varies markedly in differ ent brain regions, raising the possibility that guanine or guanosine are in volved in neurotransmission. Together these data suggest several potentiall y useful pharmacological approaches involving nonadenine-based purines to m odulate trophic effects in the central nervous system. Drug Dev. Res. 52:30 3-315, 2001. (C) 2001 Wiley-Liss, Inc.