title: Modulators of nucleoside metabolism in the therapy of brain diseases.
abstract: Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the "soft and smart" therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed.
authors.affiliation: RS Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Ave, Portland, OR 97232, USA. dboison@DowNeurobiology.org
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000502:physiology; D001927:Brain Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D012893:Sleep Wake Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D000248:Adenosine Kinase; D000241:Adenosine