Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China.
Department of Pathophysiology, Chinese PLA General Hospital, Beijing 100853, China.
J Ethnopharmacol. 2018 Aug 10;222:229-238. doi: 10.1016/j.jep.2018.03.015. Epub 2018 Mar 13.
Vascular dementia (VaD) is the common cognitive disorder derived mainly from lacunar stroke (LS). The oxidative stress induced neurovascular coupling (NVC) dysfunction involves in the pathogenesis of VaD. Currently, there is no specific drug for VaD. Ling-Yang-Gou-Teng -Decoction (LG), a well-known traditional Chinese formula, has been used for preventing VaD in clinic.
In this study, we aimed to investigate the underlying mechanism of LG on VaD in rats.
VaD was replicated with autologous micro-thrombi against the background of hypercholesterolemia induced with high fatty diet. PTX (68.90 mg/kg/day), LG with three dosages (2.58, 8.14, 25.80 g/kg/day) was orally administrated to VaD rats, respectively. The NVC sensitivity was defined as the ratio of the microcirculative cerebral blood velocity (CBV) to the electroencephalograph (EEG) before and after penicillin stimulation. Behavioral performance, pathological changes of brain and oxidation related molecules were detected to assess the effects of LG on VaD.
LG exhibited beneficial effects on the VaD, which was demonstrated as improved exploratory, learning and memory abilities, relieved vascular or neural pathological changes in cerebral cortex or hippocampus. LG maintained NVC sensitivity, which was confirmed as significantly increased ΔCBV and the elevated ratio of ΔCBV/ΔqEEG. The underlying mechanisms of LG was associated with antioxidant effects, which was confirmed as significantly decreased nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression, and increased superoxide dismutase 3 (SOD3) expression. LG also reduced iNOS, increased nNOS and eNOS expression to restore NO bioavailability.
The results suggested that LG prevented VaD may associate with inhibiting oxidative stress, protecting NO bioavailability, and then maintaining NVC sensitivity.
血管性痴呆（VaD）是主要由腔隙性卒中（LS）引起的常见认知障碍。氧化应激诱导的神经血管耦联（NVC）功能障碍与 VaD 的发病机制有关。目前，尚无针对 VaD 的特定药物。灵羊钩藤汤（LG）是一种著名的中药方剂，已在临床上用于预防 VaD。
本研究旨在探讨 LG 对大鼠 VaD 的作用机制。
采用高脂饮食诱导高胆固醇血症联合自体微血栓复制 VaD 模型。PTX（68.90mg/kg/d）、LG（2.58、8.14、25.80g/kg/d）分别灌胃 VaD 大鼠。NVC 敏感性定义为青霉素刺激前后脑微循环血流速度（CBV）与脑电图（EEG）的比值。通过行为学、脑病理变化及氧化相关分子检测评估 LG 对 VaD 的作用。
LG 对 VaD 具有有益作用，表现为改善探索、学习和记忆能力，减轻大脑皮质或海马的血管或神经病理变化。LG 维持了 NVC 敏感性，表现为 CBV 的Δ显著增加和ΔCBV/ΔqEEG 的比值升高。LG 的作用机制与抗氧化作用有关，表现为 NADPH 氧化酶 2（NOX2）表达显著降低，超氧化物歧化酶 3（SOD3）表达升高。LG 还降低 iNOS、增加 nNOS 和 eNOS 表达以恢复 NO 的生物利用度。
研究结果表明，LG 预防 VaD 可能与抑制氧化应激、保护 NO 生物利用度以及维持 NVC 敏感性有关。
