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Adenosine A2A receptor agonist polydeoxyribonucleotide ameliorates short-term memory impairment by suppressing cerebral ischemia-induced inflammation via MAPK pathway.

ABSTRACT: Cerebral ischemia causes tissue death owing to occlusion of the cerebral blood vessels, and cerebral ischemia activates mitogen-activated protein kinase (MAPK) and induces secretion of pro-inflammatory cytokines. Adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), suppresses the secretion of pro-inflammatory cytokines and exhibits anti-inflammatory effect. In the current study, the therapeutic effect of PDRN on cerebral ischemia was evaluated using gerbils. For the induction of cerebral ischemia, the common carotid arteries were exposed, and then aneurysm clips were used to occlude the common carotid arteries bilaterally for 7 minutes. In the PDRN-treated groups, the gerbils were injected intraperitoneally with 0.3 mL of saline containing 8 mg/kg PDRN, per a day for 7 days following cerebral ischemia induction. In order to confirm the participation of the adenosine A2A receptor in the effects mediated by PDRN, 8 mg/kg 7-dimethyl-1-propargylxanthine (DMPX), adenosine A2A receptor antagonist, was treated with PDRN. In the current study, induction of ischemia enhanced the levels of pro-inflammatory cytokines and increased phosphorylation of MAPK signaling factors in the hippocampus and basolateral amygdala. However, treatment with PDRN ameliorated short-term memory impairment by suppressing the production of pro-inflammatory cytokines and inactivation of MAPK signaling factors in cerebral ischemia. Furthermore, PDRN treatment enhanced the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) as well as phosphorylation of cAMP response element-binding protein (p-CREB). Co-treatment of DMPX and PDRN attenuated the therapeutic effect of PDRN on cerebral ischemia. Based on these findings, PDRN may be developed as the primary treatment in cerebral ischemia.

SUBMITTER: Ko IG

PROVIDER: S-EPMC7971468 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Adenosine receptors and ?-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism. Recent structures of ?-adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors. Here we present two crystal structures of the thermostabilized human adenosine A(2A) receptor (A(2A)R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. 8). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand-binding pocket where it makes polar interactions with conserved residues in H7 (Ser?277(7.42) and His?278(7.43); superscripts refer to Ballesteros-Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A(2A)R with the agonist-bound structures of ?-adrenoceptors indicates that the contraction of the ligand-binding pocket caused by the inward motion of helices 3, 5 and 7 may be a common feature in the activation of all GPCRs.

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Adenosine A2A receptor agonist polydeoxyribonucleotide ameliorates short-term memory impairment by suppressing cerebral ischemia-induced inflammation via MAPK pathway.

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