Neuromodulatory Effects of Guanine-Based Purines in Health and Disease

Abstract

The function of guanine-based purines (GBPs) is mostly attributed to the intracellular modulation of heteromeric and monomeric G proteins. However, extracellular effects of guanine derivatives have also been recognized. Thus, in the central nervous system (CNS), a guanine-based purinergic system that exerts neuromodulator effects, has been postulated. The thesis that GBPs are neuromodulators emerged from in vivo and in vitro studies, in which neurotrophic and neuroprotective effects of these kinds of molecules (i.e., guanosine) were demonstrated. GBPs induce several important biological effects in rodent models and have been shown to reduce seizures and pain, stabilize mood disorder behavior and protect against gliomas and diseases related with aging, such as ischemia or Parkinson and Alzheimer diseases. In vitro studies to evaluate the protective and trophic effects of guanosine, and of the nitrogenous base guanine, have been fundamental for understanding the mechanisms of action of GBPs, as well as the signaling pathways involved in their biological roles. Conversely, although selective binding sites for guanosine have been identified in the rat brain, GBP receptors have not been still described. In addition, GBP neuromodulation may depend on the capacity of GBPs to interact with well-known membrane proteins in glutamatergic and adenosinergic systems. Overall, in this review article, we present up-to-date GBP biology, focusing mainly on the mechanisms of action that may lead to the neuromodulator role of GBPs observed in neurological disorders.

Keywords: Alzheimer’s disease; Parkinson’s disease; glutamatergic system; guanosine; neuromodulation; purinergic system.

Figure 1

Purine metabolism. The guanine nucleotides guanosine-5′-triphosphate (GTP), guanosine-5′-diphosphate (GDP) and guanosine-5′-monophosphate (GMP) are sequentially dephosphorylated by ecto-nucleotidases (i.e., Ecto-NTPDase and Ecto-5’-nucleotidase), thus generating guanosine. Guanosine is hydrolyzed by PNP generating the purine base guanine. By action of a guanine deaminase (GDA), guanine is converted into xanthine and subsequently to uric acid by the action of a xanthine oxidase. Adenine nucleotides are also hydrolyzed forming the nucleosides adenosine and inosine. The following nitrogenous bases, hypoxanthine, xanthine and uric acid, are formed intracellularly. Ecto-NTPDase, ecto-nucleotide diphosphohydrolase or apyrase; ADA, adenosine deaminase; AdoK, adenosine kinase; APRT, adenine phosphoribosyl transferase; HGPRT, hypoxanthine-guanine phosphoribosyl transferase; PNP, purine nucleoside phosphorylase. APRT and HGPRT are mainly involved in the intracellular salvage purines pathway.

Figure 2

Guanine-based purinergic signaling. This cartoon presents an overview of the main mechanisms involved in the neuroprotective effects of guanosine. The release of guanine nucleotides (i.e., GTP) from synaptic vesicles or astrocytes produces extracellular guanosine (Guo) following hydrolysis by ecto-nucleotidases. Guanine may also be formed by PNP activity on guanosine (not represented). A specific binding site for Guo has not been disclosed yet (i.e., guanosine receptor, GuoR), but guanosine effects through calcium-dependent (big) conductance potassium (BK) channels, A₁R and A_2AR adenosine receptors, and glutamatergic N-methyl-D-aspartate receptors (NMDARs) has been described. Guanosine promotes neuroprotection through an anti-inflammatory effect of inhibiting nuclear factor kappa B (NF-κB) activation via MAPK/ERK. Additionally, guanosine presents antioxidant effects, as reducing the reactive oxygen species (ROS) generation, preventing inducible nitric oxide synthase (iNOS) expression, and by increasing antioxidant defenses, as Heme-oxygenase-1 (HO-1) levels. Activation of PI3K/Akt, protein kinase C (PKC) and MAPK/ERK by guanosine leads to stimulation of excitatory amino acid transporters (EAATs) activity. Guo also increases glutamine (Gln) synthetase (GS) activity, thus reducing extracellular levels of glutamate (Glu) and protecting from glutamate excitotoxicity. Figure designed using image templates from Servier Medical Art https://smart.servier.com/image-set-download/.