Forodesine Hydrochloride

Astrocytes contain a high concentration of adenosine triphosphate (ATP) that enables these cells to perform their physiological functions in brain. To investigate the mechanisms involved in astrocytic ATP restoration, the ATP content of cultured primary rat astrocytes was first depleted by a preincubation with the mitochondrial uncoupler BAM15 before extracellular substrates and their combinations were applied to foster ATP restoration. To test for the contribution of the purine salvage pathway to synthesize new adenosine monophosphate (AMP) for ATP restoration, several purine nucleosides and purine bases as well as their combinations were applied. In the absence of glucose, partial ATP restoration was found for incubations with inosine and guanosine that was lowered by forodesine, an inhibitor of purine nucleoside phosphorylase. In glucose-fed cells, the coapplication of micromolar concentrations of adenine with inosine or guanosine, but not with ribose, accelerated ATP restoration in a concentration-dependent manner. By such treatments, 80% of the initial ATP content were restored within 40 min. The supporting effects of inosine and guanosine on ATP restoration were prevented by the presence of forodesine, demonstrating the contribution of purine nucleoside phosphorylase in the ATP restoration observed. These data demonstrate that ATP-deprived astrocytes need for rapid ATP restoration - in addition to glucose as energy substrate - an adenine source and inosine or guanosine as precursor for the ribose phosphate moiety of ATP.