Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea.
Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea.
PLoS One. 2021 Mar 18;16(3):e0248689. doi: 10.1371/journal.pone.0248689. eCollection 2021.
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.
脑缺血是由于脑血管阻塞导致组织死亡，脑缺血激活丝裂原活化蛋白激酶（MAPK）并诱导促炎细胞因子的分泌。腺嘌呤 A2A 受体激动剂，聚脱氧核糖核苷酸（PDRN），抑制促炎细胞因子的分泌并表现出抗炎作用。在本研究中，使用沙鼠评估了 PDRN 对脑缺血的治疗作用。为了诱导脑缺血，暴露颈总动脉，然后使用动脉瘤夹将颈总动脉双侧闭塞 7 分钟。在 PDRN 治疗组中，沙鼠在脑缺血诱导后每天腹腔内注射含有 8mg/kg PDRN 的 0.3mL 生理盐水。为了确认腺苷 A2A 受体在 PDRN 介导的作用中的参与，用 8mg/kg 7-二甲基-1-丙炔基黄嘌呤（DMPX），腺苷 A2A 受体拮抗剂处理 PDRN。在本研究中，诱导缺血增强了海马和基底外侧杏仁核中促炎细胞因子的水平，并增加了 MAPK 信号转导因子的磷酸化。然而，PDRN 治疗通过抑制脑缺血中促炎细胞因子的产生和 MAPK 信号转导因子的失活，改善了短期记忆障碍。此外，PDRN 治疗增强了环磷酸腺苷（cAMP）的浓度以及 cAMP 反应元件结合蛋白（p-CREB）的磷酸化。DMPX 和 PDRN 的共同处理减弱了 PDRN 对脑缺血的治疗作用。基于这些发现，PDRN 可能被开发为脑缺血的主要治疗方法。
