Influence of Guanine-Based Purines on the Oxidoreductive Reactions Involved in Normal or Altered Brain Functions

Abstract

The production of reactive oxygen species (ROS) in the brain is homeostatically controlled and contributes to normal neural functions. Inefficiency of control mechanisms in brain aging or pathological conditions leads to ROS overproduction with oxidative neural cell damage and degeneration. Among the compounds showing therapeutic potential against neuro-dysfunctions induced by oxidative stress are the guanine-based purines (GBPs), of which the most characterized are the nucleoside guanosine (GUO) and the nucleobase guanine (GUA), which act differently. Indeed, the administration of GUO to in vitro or in vivo models of acute brain injury (ischemia/hypoxia or trauma) or chronic neurological/neurodegenerative disorders, exerts neuroprotective and anti-inflammatory effects, decreasing the production of reactive radicals and improving mitochondrial function via multiple molecular signals. However, GUO administration to rodents also causes an amnesic effect. In contrast, the metabolite, GUA, could be effective in memory-related disorders by transiently increasing ROS production and stimulating the nitric oxide/soluble guanylate cyclase/cGMP/protein kinase G cascade, which has long been recognized as beneficial for cognitive function. Thus, it is worth pursuing further studies to ascertain the therapeutic role of GUO and GUA and to evaluate the pathological brain conditions in which these compounds could be more usefully used.

Keywords: eustress and oxidative stress; guanine (GUA); guanosine (GUO); memory decay; mitochondrial metabolism; nitric oxide (NO); nitric oxide synthase (NOS); reactive oxygen species (ROS).

Figure 1

Intra- and extra-cellular metabolism of guanine-base purines. Guanosine (GUO) and GUA (guanine), which are formed in the extracellular fluid are mostly regained inside the cells by specific transporters (equilibrative nucleoside transporter 2, ENT-2) [38] and recycled in the purine salvage pathway to reconstitute the intracellular nucleotide pool thanks to the activity of specific kinases such as guanylate kinase (GMPK) and nucleotide diphosphokinase (NDPK) converting GMP into GDP and GDP into GTP, respectively [24,25]. GTP can be released from neurons by exocytosis [34,35] and in large amount from glial cells [36]. Other abbreviations: cN-II, cytosolic nucleotidase II; GDA, guanine deaminase; GTP, GDP, GMP, guanosine tri-, di-, monophosphate; HGPRT, hypoxanthine-guanine phosphoribosyl transferase; NTPDase, nucleotide triphosphate diphosphohydrolase; PNP, purine nucleoside phosphorylase; UA, uric acid; XAN, xanthine; XO, xanthine oxidase.

Figure 2

Scheme of the molecular pathways activated by SH-SY5Y neuroblastoma cell exposure to GUA, as reported in [39]. Abbreviations: cGMP, cyclic GMP; GDA, guanine deaminase; GUA, guanine; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; NO, nitric oxide; NOS, nitric oxide synthase; p-ASK1, phosphorylated apoptosis signal-regulating kinase 1; p-JNK, phosphorylated c-Jun N-terminal kinase; p-p38, phosphorylated p38 kinase; p-PKB, phosphorylated protein kinase B; PI3K, phosphoinositide-3 kinase; PKC, protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; XAN, xanthine.