Hot Topic: Functions and Metabolism of Brain Nucleosides and their Metabolites

What is it about?

In the present issue, first the metabolic network of nucleosides under normoxic and anoxic/ischemic conditions is described by Ipata et al. Nucleosides are converted to nucleotides, which are required by various biochemical pathways and for building nucleic acids. Because the capacity of de novo purine and pyrimidine synthesis is limited in the brain, salvage pathways are necessary for the proper functioning of the brain and for maintaining qualitative and quantitative balance of intracellular brain nucleoside triphosphates. The importance of cross talk between extra- and intracellular nucleoside metabolism, nucleoside interconversion, 5-phosphoribosyl-1-pyrophosphate synthesis and energy repletion are also emphasized by the authors. Given the importance of nucleosides in a number of biochemical reactions in the brain, it is not surprising that neurological symptoms result from defects in a number of nucleoside metabolism enzymes, including, for example, hypoxanthine-guanine phosphoribosyltransferase and different nucleoside and nucleotide kinases and phosphorylases. The known inborn errors of purine and pyrimidine metabolism, their neurological syndromes and the possible links between specific enzymatic alterations and brain damage are summarized by Micheli et al. Parkinson et al. describe recent advances in the field of nucleoside transport. It has long been established by physiological studies that concentrative as well as equilibrative transporters contribute to the uptake of nucleosides. Relatively recently, four genes encoding the equilibrative and three genes encoding the Na+-dependent concentrative nucleoside transporters have been identified in several species. Furthermore, additional nucleobase transporters have recently been discovered. The identification of these transporters allowed for the individual examination of their transport characteristics, cellular distributions, and physiological functions. Potential therapeutic uses of drugs affecting nucleoside transporters for treatment of cerebral ischemia, epilepsy, neurodegenerative diseases, cancer and viral infections are also described. Purine receptors are grouped as P1 (or A) adenosine receptor and P2 adenine nucleotide receptors. Currently, A1, A2A, A2B, and A3 receptors for adenosine are known. These receptors are all G-protein coupled receptors. P2 receptors are further divided into ion channels (P2X), and G-protein coupled nucleotide receptors (P2Y). In addition to ATP, some of the nucleotide receptors recognize ADP, UTP, UDP, and UDP-glucose. These receptors have diverse signal transduction pathways and participate in a number of neural functions. The development of selective agonists and antagonists is in progress, suggesting that there may be pharmaceutical uses for drugs acting on these novel targets. Novel developments in this field and the role of different types of nucleoside and nucleotide receptors in CNS diseases such as neurodegenerative diseases, epilepsy and neuropsychiatric disorders are described by Burnstock et al. Transporters of nucleosides and a complex interlinked metabolic network balance nucleoside levels in the brain tissue under normal conditions and enable the fine modulation of neuronal and glial processes via nucleoside receptor signaling mechanisms. Normal brain levels of nucleosides were found to differ when measured in a variety of brain regions. The distributions of nucleoside transporters and receptors as well as nucleoside metabolic enzyme activities also demonstrate regional differences, suggesting different roles for nucleosides in different brain areas. Recent advances in this research area are described by Kovács et al. These authors also describe and discuss age- and gender-dependant alterations in brain nucleoside levels. The concentrations of adenosine and ATP in the neuronal extracellular space are not constant but increase in response to, e.g., increased neuronal activity, depolarization, or ischemia. ATP, and possibly other nucleotides, are actively transported into synaptic vesicles, are stored in them either alone or together with other neurotransmitters, and are released in a calcium-dependent way from presynaptic terminals. They may also be released by other mechanisms, for example, cell damage. These molecules can bind to plasma membrane receptors or can be degraded by extracellular nucleotidases to nucleosides. In addition, adenosine, and possibly other nucleosides as well, can be released by reversed action of nucleoside transporters. Sperlágh and Vizi describe the actions of adenosine in the hippocampus and basal ganglia and the pharmacological and clinical aspects of these adenosine actions. It has been suggested that the direct action of adenosine on its receptors is involved in a number of neuronal functions. One of the first of these hypotheses was that adenosine connects neuronal activity and energy metabolism. Through its inhibitory action, adenosine may also have a neuroprotective function. A large body of evidence suggests that adenosine may also be involved in the regulation of the sleep-wakefulness cycle because it mediates sleepiness following prolonged wakefulness. This potential function of adenosine is described by Huang et al.. Although adenosine is the most studied nucleoside, evidence suggests that other nucleosides such as guanosine, inosine and uridine may also have considerable effects in the CNS, including trophic actions. The roles and mechanisms of actions of these non-adenosine nucleosides are exciting fields for future investigation. Dobolyi et al. summarize the data in the literature that supports the involvement of uridine in the sleep-wakefulness cycle, epilepsy, regulation of mood and memory, and neuronal plasticity. Potential mechanisms, including effects on membrane formation, uridine nucleotide formation, and receptor actions are also described. Proteins related to nucleosides represent a great number of drug targets that can be utilized for therapeutic purposes. A number of drugs acting on nucleoside metabolic enzymes, transporters, and receptors are being tested for their therapeutic potential in stroke, epilepsy, pain management, Alzheimer’s disease, Parkinson’s disease and schizophrenia. In his review, Detlev Boison highlights the role of nucleoside function and dysfunction in physiological and pathophysiological conditions with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. He also covers pharmacological approaches to the use inhibitors of nucleoside metabolism, with particular emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, he discusses novel gene-based and focal treatment therapeutic strategies to augment nucleoside function. The review by Lopes et al. covers recent studies, undertaken mostly in humans, revealing the actions of adenosine and related drugs in cognition and memory as well as in several pathological situations such as psychiatric disorders, drug addiction and neurodegenerative disorders. The actual use of adenosine or adenosine receptor ligands in ongoing clinical trials for the treatment of schizophrenia, panic disorder and anxiety, cocaine dependence and Parkinson’s disease is discussed. The evidence highlights the promising potential of adenosine or adenosine receptor ligands as therapeutic agents in several brain disorders. Overall, the research discussed in this issue supports the conclusion that the analysis and clarification of the role of nucleosides and their transporters and receptors in the brain will lead to a better understanding of the nucleoside system, which in turn will contribute to the design of more effective and selective drugs to potentially treat a wide range of central nervous system diseases.

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Why is it important?

Nucleosides are metabolic intermediates of the synthesis of nucleotides, which are in turn the building blocks of nucleic acids and which participate in a number of fundamental biochemical reactions. In particular, ATP is the major energy transfer molecule, and among the nucleotides, its additional extracellular signaling role was the first to be suggested. Its corresponding nucleoside, adenosine, has also been demonstrated to be a neuromodulator substance. It has now been over 35 years since purinergic signal transmission in the nervous system has been suggested. Since that time, various requirements for classification as a neurotransmitter have been demonstrated for adenine nucleotides and adenosine including regulated release, elimination from the extracellular space, action on neuronal activity, and the existence and pharmacological characterization of receptors. In addition, a large body of evidence derived from human disorders also supports the conclusion that nucleosides have a crucial role in neural function. Anti-cancer and anti-viral drugs that affect nucleoside metabolism have neurological side effects. Some metabolic disorders have also been shown to originate from defects in nucleoside metabolism. In the 1960s, the enzyme deficit underlying Lesch-Nyhan syndrome, a relatively frequent disorder of nucleoside metabolism with peculiar neurological symptoms, was identified as a deficiency of hypoxanthine-guanine phosphoribosyltransferase. Since then, a number of other disorders that cause mental retardation or other neurological symptoms have been attributed to deficits in nucleoside metabolism. The accumulating knowledge in the field of nucleoside and nucleotide metabolism and pharmacology in the nervous system led to the possibility of developing novel therapeutic approaches to treat major neurological disorders.

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