Adenosine and adenosine receptors in metabolic imbalance-related neurological issues

Abstract

Metabolic syndromes (e.g., obesity) are characterized by insulin resistance, chronic inflammation, impaired glucose metabolism, and dyslipidemia. Recently, patients with metabolic syndromes have experienced not only metabolic problems but also neuropathological issues, including cognitive impairment. Several studies have reported blood-brain barrier (BBB) disruption and insulin resistance in the brain of patients with obesity and diabetes. Adenosine, a purine nucleoside, is known to regulate various cellular responses (e.g., the neuroinflammatory response) by binding with adenosine receptors in the central nervous system (CNS). Adenosine has four known receptors: A1R, A2AR, A2BR, and A3R. These receptors play distinct roles in various physiological and pathological processes in the brain, including endothelial cell homeostasis, insulin sensitivity, microglial activation, lipid metabolism, immune cell infiltration, and synaptic plasticity. Here, we review the recent findings on the role of adenosine receptor-mediated signaling in neuropathological issues related to metabolic imbalance. We highlight the importance of adenosine signaling in the development of therapeutic solutions for neuropathological issues in patients with metabolic syndromes.

Keywords: Adenosine; Adenosine receptors; Blood-brain barrier (BBB); Insulin resistance; Metabolic imbalance.

Fig. 1.

Schematic images of adenosine receptors in immune cells. The ectonucleotidases triphosphate diphophahydrolase-1 (CD39) metabolizes adenosine triphosphate (ATP) into adenosine monophosphate (AMP), and ecto-5′-nucleotidase (CD73) metabolizes AMP into adenosine. Adenosine is then converted to inosine by CD26-adenosine deaminase (ADA). The adenosine 2A receptor (A2A) and 2B receptor (A2B) are coupled to adenylyl cyclase (AC). AC converts AMP to cyclin AMP (cAMP), subsequently activating protein kinase A (PKA). Activated PKA leads to decreased reactive oxygen species (ROS) production, increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, reduced forkhead box O 1 (FOXO1) phosphorylation, decreased calcium secretion, and decreased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Ultimately, adenosine A2A and A2B receptor-mediated signaling inhibit inflammatory responses by suppressing the secretion of pro-inflammatory cytokines and enhancing the secretion of anti-inflammatory cytokines in immune cells such as T-cells and NK cells. TNF-α: tumor necrosis factor-α, IL-1β: interleukin 1β, IFN-γ: interferon gamma, IL-10: interleukin-10.

Fig. 2.

Schematic images of adenosine receptors in the synapse. Ecto-5′-nucleotidase (CD73) metabolizes adenosine triphosphate (ATP) into adenosine. The adenosine 1 receptor (A1R) inhibits the conversion of cyclin AMP (cAMP), thereby blocking protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling. AlR also suppresses the production of glutamate and calcium in post-synaptic neurons. The adenosine A2A receptor (A2AR) promotes cAMP-PKA-CREB signaling and enhances glutamate production in post-synaptic neurons. Equilibrative nucleoside transporter (ENT) mediates adenosine reuptake in astrocytes. LTP: long term potentiation, IP3: inositol-tri-phosphate; mGluR: metabotropic glutamate receptor of subtype, Gln: glutamine, NMDAR: N-methyl-D-aspartate receptor, AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.