Pyrimidine and purine nucleosides and their derivatives have critical functions and pharmacological applications in the brain. Nucleosides and nucleobases are precursors of nucleotides, which serve as the energy-rich currency of intermediary metabolism and as precursors of nucleic acids. Nucleosides (e.g., adenosine) and nucleotides are key signaling molecules that modulate brain function through interaction with cell surface receptors. Brain pathologies involving nucleosides and their metabolites range from epilepsy to neurodegenerative disorders and psychiatric conditions to cerebrovascular ischemia. Nucleoside analogs are used clinically in the treatment of brain cancer and viral infections. Nucleosides are hydrophilic molecules, and transportability across cell membranes via specialized nucleoside transporter (NT) proteins is a critical determinant of their metabolism and, for nucleoside drugs, their pharmacologic actions. In mammals, there are two types of nucleoside transport process: bidirectional equilibrative processes driven by chemical gradients, and unidirectional concentrative processes driven by sodium (and proton) electrochemical gradients. In mammals, these processes, both of which are present in brain, are mediated by members of two structurally unrelated membrane protein families (ENT and CNT, respectively). In this Chapter, we review current knowledge of cellular, physiological, pathophysiological and therapeutic aspects of ENT and CNT distribution and function in the mammalian brain, including studies with NT inhibitors and new research involving NT knockout and transgenic mice. We also describe recent progress in functional and molecular studies of ENT and CNT proteins, and summarize emerging evidence of other transporter families with demonstrated or potential roles in the transport of nucleosides and their derivatives in the brain.
Adenosine is formed during conditions that deplete ATP, such as ischemia. Adenosine deaminase converts adenosine into inosine, and both adenosine and inosine can be beneficial for postischemic recovery. This study investigated adenosine and inosine release from astrocytes and neurons during chemical hypoxia or oxygen-glucose deprivation. In both cell types, 2-deoxyglucose was the most effective stimulus for depleting cellular ATP and for evoking inosine release; in contrast, oxygen-glucose deprivation evoked the greatest adenosine release. alpha,beta-Methylene ADP, an inhibitor of ecto-5'nucleotidase, significantly reduced adenosine release from astrocytes but not neurons. Dipyridamole, an inhibitor of equilibrative nucleoside transporters, inhibited both adenosine and inosine release from neurons. Erythro-9-(2-hydroxy-3-nonyl)adenine, an inhibitor of adenosine deaminase, reduced neuronal inosine release evoked by oxygen-glucose deprivation but not by 2-deoxyglucose treatment. These data indicate that (1). astrocytes release adenine nucleotides that are hydrolyzed extracellularly to adenosine, whereas neurons release adenosine per se, (2). inosine is formed intracellularly and released via nucleoside transporters, and (3). inosine is formed by an adenosine deaminase-dependent pathway during oxygen-glucose deprivation but not during 2-deoxyglucose treatment. In summary, the metabolic pathways for adenosine formation and release were cell-type dependent whereas the pathways for inosine formation were stimulus dependent.
Recently [3H]-CGS 21680 (2-[p-(2-carbonyl-ethyl)-phenylethylamino]- 5'-N-ethylcarboxamidoadenosine) has been identified as a selective adenosine A2-receptor agonist. In this study the binding of [3H]-CGS 21680 to 10 microns sections of rat neostriatum was investigated with quantitative autoradiography. Specific, saturable binding was detectable, and Scatchard analysis of saturation experiments gave estimates for KD and Bmax of 1.7 nM and 322 fmol/mg protein, respectively. The rank order of potency for inhibition of [3H]-CGS 21680 binding was 5'-N-ethylcarboxamidoadenosine (1.9 nM) greater than 2-chloroadenosine (18 nM) greater than R-N6-phenylisopropyladenosine (59 nM) greater than S-N6-phenylisopropyladenosine (460 nM) greater than 1,3-dipropyl-8-cyclopentylxanthine (700 nM). The binding of [3H]-CGS 21680 was sensitive to GTP, since 1 microM GTP reduced binding to 4.7% of control. These data support the identity of CGS 21680 as an agonist at high affinity adenosine A2-receptors and indicate these receptors in rat striatum are coupled to guanine nucleotide binding proteins.
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