Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Abstract

The role of adenosine A 3 receptors in synaptic transmission under severe (7 min) and shorter (2-5 min) ischemic conditions, obtained by oxygen and glucose deprivation (OGD), was investigated in rat hippocampal slices. The effects of selective A 3 agonists or antagonists were examined on field excitatory postsynaptic potentials (fEPSPs) extracellularly recorded at the dendritic level of the CA1 pyramidal region. The novel, selective A 3 antagonist LJ1251 ((2R,3R,4S)-2-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol, 0.1-10 nM) protected hippocampal slices from irreversible fEPSP depression induced by severe OGD and prevented or delayed the appearance of anoxic depolarization. Similar results were obtained when severe OGD was carried out with a long, receptor-desensitizing exposure to various selective A 3 agonists: 5′-Nmethylcarboxamidoadenosine derivatives Cl-IB-MECA (N 6 -(3-iodobenzyl)-2-chloro), VT72 (N 6 -methoxy-2-phenylethynyl), VT158 (N 6 -methoxy-2-phenylethynyl), VT160 (N 6 -methoxy-2-(2-pyridinyl)-ethynyl), and VT163 (N 6 -methoxy-2-p-acetylphenylethynyl) and AR132 (N 6 -methyl-2-phenylethynyladenosine).The selective A 3 antagonist MRS1523 (3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine carboxylate, 100 nM) reduced fEPSP depression evoked by 2-min OGD and induced a faster recovery of fEPSP amplitude after 5-min OGD. Similar results were obtained for 2-or 5-min OGD applied in the presence of each of the A 3 agonists tested. Shorter exposure to A 3 agonists significantly delayed the recovery of fEPSP amplitude after 5-min OGD.This indicates that A 3 receptors, stimulated by selective A 3 agonists, undergo desensitization during OGD. It is inferred that CA1 hippocampal A 3 receptors stimulated by adenosine released during brief ischemia (2 and 5 min) might exert A 1 -like protective effects on neurotransmission. Severe ischemia would transform the A 3 receptor-mediated effects from protective to injurious.

Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

“…These findings will be discussed in turn. The role of adenosine in neuroprotection is very well established: experimental evidence indicates that activation of A 1 R or inhibition of A 2A R improves neuronal recovery on brain injury (Cunha, 2005), whereas the role played by A 3 R and A 2B R in neuroprotection is less clear cut (Michel et al, 1999;Fedorova et al, 2003;Chen et al, 2006;Pugliese et al, 2007). In the present experimental conditions, we did not observe any clear effect of eliminating A 2A receptors.…”

The adenosine kinase hypothesis of epileptogenesis

“…Recent findings suggest that the physiological consequences of A 3 receptor activation show dose-dependent effects: While CA1 hippocampal A 3 receptors stimulated by adenosine released during brief ischemia might exert A 1 receptor-like protective effects on neurotransmission, severe ischemia (i.e. higher dose of adenosine) would transform the A 3 receptor-mediated effects from protective to injurious (Maria Pugliese et al, 2007). In line with this notion, activation of A 3 receptors led to heterologous desensitization of A 1 receptors (Dunwiddie et al, 1997), and activation of A 2A and A 3 receptors by endogenous adenosine aggravated epileptic activity in slice cultures (Etherington and Frenguelli, 2004).…”

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A3 Adenosine Receptor Antagonists

“…ARTICLE AR subtype of all of the compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) reported in this work.…”

“…Interest for this new series was driven by the structural similarity between the PHTZ skeleton and both the 2-aryl-1,2,4-triazolo [4,3-a]quinoxalin-1-one (TQX) and the 4-carboxamido-quinazoline (QZ) scaffolds extensively investigated in our previously reported studies. Our attention was focused at position 4 of the phthalazine nucleus where different amido and ureido moieties were introduced (compounds [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Some of the new PHTZ compounds showed high hA 3 AR affinity and selectivity, the 2,5-dimethoxyphenylphthalazin-1(2H)-one 18 being the most potent and selective hA 3 AR antagonist among this series (K i = 0.776 nM; hA 1 / hA 3 and hA 2A /hA 3 > 12000).…”

“…9 Thus, numerous A 3 AR agonists and antagonists have been investigated for their potential therapeutic applications 7,[9][10][11][12][14][15][16][17] and to shed light on which could be the best choice for a given disease. It is easy to understand why we have directed our efforts in this intriguing direction and why, in the past few years, our attention has been focused on the development of adenosine A 3 receptor antagonists.…”