Area, Age and Gender Dependence of the Nucleoside System in the Brain: a Review of Current Literature

Abstract

Nucleosides, such as uridine, inosine, guanosine and adenosine, may participate in the regulation of sleep, cognition, memory and nociception, the suppression of seizures, and have also been suggested to play a role in the pathophysiology of some neurodegenerative and neuropsychiatric diseases. Under pathological conditions, levels of nucleosides change extremely in the brain, indicating their participation in the pathophysiology of disorders like Alzheimer's disease, Parkinson's disease and schizophrenia. These findings have resulted in an increasing attention to the roles of nucleosides in the central nervous system. The specific effects of nucleosides depend on the expression of their receptors and transporters in neuronal and glial cells, as well as their extracellular concentrations in the brain. A complex interlinked metabolic network and transporters of nucleosides may 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. Brain levels of nucleosides were found to vary when measured in a variety of different brain regions. In addition, nucleoside levels also depend on age and gender. Furthermore, distributions of nucleoside transporters and receptors as well as nucleoside metabolic enzyme activities demonstrate the area, age and gender dependence of the nucleoside system, suggesting different roles of nucleosides in functionally different brain areas. The aim of this review article is to summarize our present knowledge of the area-, age- and gender-dependent distribution of nucleoside levels, nucleoside metabolic enzyme activity, nucleoside receptors and nucleoside transporters in the brain.

The Antiepileptic Potential of Nucleosides

“…The metabolism of nucleosides is well understood in the brain [30,41,[71][72][73][74][75][76][77]. Purines and pyrimidines are synthesized (de novo) from precursor molecules such as carbon dioxide, aspartate, 5-phosphoribosyl-1-pyrophosphate (PRPP), glutamine, glycine and formyl groups, as well as from aspartate and carbamyl-phosphate.…”

“…The catabolism of nucleotides may occur through several different routes in the brain [30,40,41,72]. Adenosine triphosphate (ATP), Urd triphosphate (UTP) and Guo triphosphate (GTP) are degraded to their corresponding monophosphates, namely, Ado monophosphate (AMP), Urd monophosphate (UMP) and Guo monophosphate (GMP), respectively, by nucleoside di-and triphosphate phosphatases ( Fig.…”

“…For instance, Hyp and Gn may be converted to IMP and GMP by Hyp phosphoribosyltransferase (HGPRT; hypoxanthine-guanine phosphoribosyltransferase) (Fig. 1), whereas Ado, adenine (Ade) and Urd are converted to AMP and UMP by ADK, Ade phosphoribosyltransferase (APRT) and Urd-cytidine (Cyd) kinase (UCK), respectively [30,77].…”

“…Nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the synthesis of DNA and RNA and are involved in gene transcription, the storage and conversion of energy and the regulation of physiological and pathophysiological processes in the brain (e.g., sleep, memory, Parkinson's disease, psychiatric disorders and epilepsy) [23][24][25][26][27][28][29][30][31][32][33][34]. In addition, genetic disorders of purine or pyrimidine metabolism may be associated with different diseases [35][36][37][38].…”

“…roles in different brain areas and that these roles may be modulated by age and gender [30,31,[53][54][55][56][57]. Among their diverse neuromodulatory functions, nucleosides may have a role in the modulation of epileptic activity as well [27,33,[58][59][60][61][62][63][64][65][66][67][68][69].…”