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.

Cissus verticillata Extract Decreases Neuronal Damage Induced by Oxidative Stress in HT22 Cells and Ischemia in Gerbils by Reducing the Inflammation and Phosphorylation of MAPKs

“…In addition, MAPK inhibitors block inflammatory cytokine signaling [47,48] and treatment with the JNK inhibitor AS601245 protects neurons from ischemic cell death [49]. Consistent with previous studies [42,45,46], we observed significant increases in the ratios of p-JNK/JNK, p-ERK/ERK, and p-p38/p38 in the hippocampus 1 d after ischemia. Treatment with 300 mg/kg CVE significantly attenuated the increase in phosphorylation of JNK, ERK, and p38 in the hippocampus.…”

“…In addition, CVE treatment significantly reduced the ischemia-induced apoptosis and increased anti-apoptotic protein, consistent with in vitro study. To elucidate the possible mechanisms against ischemic damage in the gerbil hippocampus, we focused on oxidative stress and inflammatory responses in the hippocampus after ischemia, because several studies have demonstrated that CVE has anti-inflammatory activity [28,40], and inflammation is one of the main pathways for neuronal death after ischemia in the gerbil hippocampus [41,42]. Overexpression of ROS induced by ischemia/reperfusion causes lipid peroxidation of polyunsaturated fatty acids in the neuronal membrane and disrupts the cell membrane [43].…”

“…CVE inhibits inflammation in animal models of edema in mice [28,40] and rats [40]. Transient forebrain ischemia increases the activity of the JNK, ERK, and p38 MAPKs by phosphorylation in the gerbil hippocampus [42,45,46]. In addition, MAPK inhibitors block inflammatory cytokine signaling [47,48] and treatment with the JNK inhibitor AS601245 protects neurons from ischemic cell death [49].…”

Neuroprotective Effects of Purpurin Against Ischemic Damage via Anti-inflammatory and MAPK Pathway

“…This result is consistent with in vitro study in HT22 cells that oxidative stress induced by H 2 O 2 treatment signi cantly increased the phosphorylation of MAPKs. In addition, several studies demonstrate the increases of MAPK phosphorylation in the hippocampus after ischemia [22,44,45] and treatment with JNK blocker ameliorates the neuronal death induced by ischemia [46]. In addition, the close relationship has been reported between the cytokine-related in ammation and MAPKs [47,48].…”

Neuroprotective Effects of Purpurin Against Ischemic Damage via MAPKs, Bax, and Oxidative Stress Cascades in the Gerbil Hippocampus

“…This result is consistent with in vitro study in HT22 cells that oxidative stress induced by H 2 O 2 treatment significantly increased the phosphorylation of MAPKs. In addition, several studies demonstrate the increases of MAPK phosphorylation in the hippocampus after ischemia [ 24 , 53 , 54 ] and treatment with JNK blocker ameliorates the neuronal death induced by ischemia [ 55 ]. In addition, the close relationship has been reported between the cytokine-related inflammation and MAPKs [ 56 , 57 ].…”