National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China.
Eur J Pharmacol. 2022 Jun 15;925:174987. doi: 10.1016/j.ejphar.2022.174987. Epub 2022 Apr 28.
Ischemic stroke is one of the leading causes of mortality worldwide. The available treatments are not effective. Phosphodiesterase 9A (PDE9A) is an intracellular cyclic guanosine monophosphate (cGMP) hydrolase considered to be a promising therapeutic target for brain diseases. This study explored neuroprotective effects and the underlying mechanism of LW33, a novel PDE9A inhibitor, on ischemic stroke in vitro and in vivo.
A middle cerebral artery occlusion (MCAO) model was established in adult male Sprague-Dawley rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in human SH-SY5Y cells to mimic ischemia-reperfusion injury in vitro.
LW33 increased cell viability, reduced lactate dehydrogenase activity, and OGD/R-induced apoptosis of SH-SY5Y cells. The protective effects of LW33 against stroke occurred in the recovery phase. LW33 administration significantly reduced cerebral infarction volume in MCAO rats, without causing significant deformation or necrosis of neurons in the cortex. LW33 also improved learning and cognitive dysfunction and reduced other pathological changes in MCAO rats in the recovery period. Moreover, LW33 stimulated the cGMP/PKG/CREB pathway and up-regulated the expression of the apoptosis-related proteins, and this effect was reversed by KT5823 treatment.
LW33 inhibited cell apoptosis and promoted neuronal repair to alleviate OGD/R and MCAO induced pathological alterations via the cGMP/PKG/CREB pathway, indicating that LW33 may be a promising therapeutic target for ischemic stroke.
缺血性中风是全球范围内导致死亡的主要原因之一。现有的治疗方法并不有效。磷酸二酯酶 9A（PDE9A）是一种细胞内环鸟苷酸单磷酸（cGMP）水解酶，被认为是治疗脑部疾病的有前途的治疗靶点。本研究探讨了新型 PDE9A 抑制剂 LW33 对体外和体内缺血性中风的神经保护作用及其潜在机制。
建立成年雄性 Sprague-Dawley 大鼠大脑中动脉闭塞（MCAO）模型和人 SH-SY5Y 细胞氧葡萄糖剥夺/再氧合（OGD/R）模型，模拟体外缺血再灌注损伤。
LW33 增加了 SH-SY5Y 细胞的活力，降低了乳酸脱氢酶的活性和 OGD/R 诱导的细胞凋亡。LW33 对中风的保护作用发生在恢复期。LW33 给药可显著减少 MCAO 大鼠的脑梗死体积，而不会导致皮质神经元明显变形或坏死。LW33 还改善了 MCAO 大鼠在恢复期的学习和认知功能障碍，并减少了其他病理变化。此外，LW33 刺激 cGMP/PKG/CREB 通路并上调凋亡相关蛋白的表达，而 KT5823 处理则逆转了这一效应。
LW33 通过 cGMP/PKG/CREB 通路抑制细胞凋亡和促进神经元修复，减轻 OGD/R 和 MCAO 诱导的病理改变，表明 LW33 可能是缺血性中风的有希望的治疗靶点。
