Division of Paediatric Intensive Care Unit, Department of Paediatrics, Ataturk University Faculty of Medicine, Erzurum, Turkey.
Division of Paediatric Neurology, Department of Paediatrics, Ataturk University Faculty of Medicine, Erzurum, Turkey.
Clin Exp Pharmacol Physiol. 2021 Aug;48(8):1103-1110. doi: 10.1111/1440-1681.13493. Epub 2021 May 10.
This study aims to investigate the protective effect of roflumilast, a phosphodiesterase (PDE)-4 enzyme inhibitor, and demonstrate its possible role in the development prevention of cerebral ischemia/reperfusion injury (CI/RI) after stroke induced by carotid artery ligation in juvenile rats. The rats were randomly divided into five groups: healthy group without any treatment, healthy group administered with 1 mg/kg roflumilast, CI group not administered with roflumilast, CI group administered with 0.5 mg/kg roflumilast, and CI group administered with 1 mg/kg roflumilast. In the CI groups, reperfusion was achieved 2h after ischemia induction; in the roflumilast groups, this drug was intraperitoneally administered immediately after reperfusion and at the 12 hour. At the end of 24h, the rats were sacrificed and their brain tissues removed for examination. The mRNA expressions obtained with real-time PCR of IL-1β, TNF-α, and NLRP3 significantly increased in the CI/RI-induced groups compared with the control group, and this increase was significantly lower in the groups administered with roflumilast compared with the CI/RI-induced groups. Moreover, ELISA revealed that both IL-1 β and IL-6 brain levels were significantly higher in the CI/RI-induced groups than in the controls. This increase was significantly lower in the groups administered with roflumilast compared with the CI/RI-induced groups. Histopathological studies revealed that the values closest to those of the healthy group were obtained from the roflumilast groups. Nissl staining revealed that the Nissl bodies manifested normal density in the healthy and roflumilast-administered healthy groups, but were rare in the CI/RI-induced groups. Roflumilast treatment increased these decreased Nissl bodies with increasing doses. Observations indicated that the Nissl body density was close to the value in the healthy group in the CI/RI-induced group administered with 1 mg/kg roflumilast. Overall, roflumilast reduced cellular damage caused by CI/RI in juvenile rats, and this effect may be mediated by NLRP3.
本研究旨在探讨磷酸二酯酶（PDE）-4 酶抑制剂罗氟司特对脑缺血/再灌注损伤（CI/RI）的保护作用，并证明其在幼鼠颈总动脉结扎诱导的中风后可能具有预防作用。将大鼠随机分为五组：无任何处理的健康组、给予 1mg/kg 罗氟司特的健康组、未给予罗氟司特的 CI 组、给予 0.5mg/kg 罗氟司特的 CI 组和给予 1mg/kg 罗氟司特的 CI 组。在 CI 组中，缺血诱导后 2 小时进行再灌注；在罗氟司特组中，该药物在再灌注后立即和 12 小时时腹腔内给药。在 24 小时结束时，处死大鼠并取出脑组织进行检查。实时 PCR 检测的 IL-1β、TNF-α 和 NLRP3 的 mRNA 表达在 CI/RI 诱导组中明显高于对照组，而在给予罗氟司特的组中明显低于 CI/RI 诱导组。此外，ELISA 显示，在 CI/RI 诱导组中，IL-1β 和 IL-6 的脑水平明显高于对照组。在给予罗氟司特的组中明显低于 CI/RI 诱导组。组织病理学研究表明，罗氟司特组最接近健康组。Nissl 染色显示，在健康和给予罗氟司特的健康组中，Nissl 体表现出正常的密度，但在 CI/RI 诱导组中则很少见。罗氟司特治疗增加了这些减少的 Nissl 体，剂量增加。观察表明，在给予 1mg/kg 罗氟司特的 CI/RI 诱导组中，Nissl 体密度接近健康组的值。总的来说，罗氟司特减轻了幼鼠 CI/RI 引起的细胞损伤，这种作用可能是通过 NLRP3 介导的。
