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Review
.2011;11(8):1068-86.
doi: 10.2174/156802611795347609.

Modulators of nucleoside metabolism in the therapy of brain diseases

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Review

Modulators of nucleoside metabolism in the therapy of brain diseases

Detlev Boison. Curr Top Med Chem.2011.

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.

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Figure 1
Figure 1. Major pathways of adenosine metabolism
Within the central nervous system degradation of ATP constitutes the major source for synaptic adenosine, whereas thede novo synthesis plays only a minor role. In brain the major pathway for the removal of adenosine is its phosphorylation to AMP by adenosine kinase; alternatively, adenosine can be dephosphorylated by adenosine deaminase into inosine. Adenosine is a ubiquitous endproduct of transmethylation reactions. However, when adenosine levels increase the equilibrium of the s-adenosyl homocysteine (SAH) hydrolase reaction is shifted towards synthesis of SAH, resulting in the inhibition of transmethylation reactions.
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