Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, 111, Geonjae-ro, Naju-si, Jeollanam-do, 58245, Republic of Korea.
Department of Oriental Medicine, College of Oriental Medicine, Dongshin University, 120-9, Dongsindae-gil, Naju-si, Jeollanam-do, 58245, Republic of Korea.
J Ethnopharmacol. 2022 Oct 5;296:115451. doi: 10.1016/j.jep.2022.115451. Epub 2022 Jun 17.
Patients with dementia are diagnosed with deficiency patterns and interior patterns in traditional Chinese medicine due to decreased physical strength, mental atrophy including cognitive function, and decreased motor function in the gastrointestinal tract. Since "greater yin symptom" in Shanghanlun has been interpreted as interior, deficiency, and cold pattern in traditional Chinese medicine, it is necessary to determine whether Geijigadaehwang-tang (GDT) has therapeutic effects on neurodegenerative diseases and the underlying mechanism if it has such effects.
Trimethyltin (TMT), a neurotoxic organotin compound, has been used to induce several neurodegenerative diseases, including epilepsy and Alzheimer's disease. This study aimed to evaluate the therapeutic efficacy of GDT for TMT-induced hippocampal neurodegeneration and seizures and to determine the mechanisms involved at the molecular level.
The main components of GDT were analyzed using ultra-performance liquid chromatography. TMT was used to induce neurotoxicity in microglial BV-2 cells and C57BL6 mice. GDT was administered at various doses to determine its neuroprotective and seizure inhibition effects. The inhibitory effects of GDT on TMT-induced apoptosis, inflammatory pathways, and oxidative stress pathways were determined in the mouse hippocampal tissues.
GDT contained emodin, chrysophanol, albiflorin, paeoniflorin, 6-gingerol, and liquiritin apioside. In microglial BV-2 cells treated with TMT, GDT showed dose-dependent neuroprotective effects. Oral administration of GDT five times for 2.5 days before and after TMT injection inhibited seizures at doses of 180 and 540 mg/kg and inhibited neuronal death in the hippocampus. In hippocampal tissues extracted from mice, GDT inhibited the protein expression of ionized calcium binding adaptor molecule 1, glial fibrillary acidic protein, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3, and phosphorylated nuclear factor (NF)-κB/total-NFκB ratio. Additionally, GDT inhibited the messenger RNA levels of tumor necrosis factor-α, inducible nitric oxide synthase, apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, interleukin-1β, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1.
This study's results imply that GDT might have neuroprotective potential in neurodegenerative diseases through neuronal death inhibition and anti-inflammatory and antioxidant mechanisms.
由于体力下降、精神萎缩（包括认知功能）和胃肠道运动功能下降，患有痴呆症的患者被诊断为中医的虚证和里证。由于《伤寒论》中的“大阴证”被解释为中医的里证、虚证和寒证，因此有必要确定枳实大黄汤（GDT）是否对神经退行性疾病具有治疗作用，如果有，其作用机制是什么。
三甲基锡（TMT）是一种神经毒性有机锡化合物，已被用于诱导多种神经退行性疾病，包括癫痫和阿尔茨海默病。本研究旨在评估 GDT 对 TMT 诱导的海马神经退行性变和癫痫发作的治疗效果，并在分子水平上确定涉及的机制。
使用超高效液相色谱法分析 GDT 的主要成分。使用 TMT 诱导小胶质细胞 BV-2 细胞和 C57BL6 小鼠的神经毒性。以不同剂量给予 GDT，以确定其神经保护和抑制癫痫发作的作用。在小鼠海马组织中测定 GDT 对 TMT 诱导的细胞凋亡、炎症途径和氧化应激途径的抑制作用。
GDT 含有大黄素、大黄酸、白芍苷、丹皮酚、6-姜辣素和甘草苷。在 TMT 处理的小胶质细胞 BV-2 细胞中，GDT 表现出剂量依赖性的神经保护作用。在 TMT 注射前 2.5 天和后 5 天每天口服 GDT 180 和 540mg/kg 可抑制癫痫发作，并抑制海马神经元死亡。从小鼠海马组织中提取的 GDT 抑制了离子钙结合接头分子 1、胶质纤维酸性蛋白、核苷酸结合寡聚化结构域样受体家族富含亮氨酸重复序列蛋白 3 和磷酸化核因子（NF）-κB/总 NFκB 比值的蛋白表达。此外，GDT 抑制了肿瘤坏死因子-α、诱导型一氧化氮合酶、凋亡相关斑点样蛋白含有半胱氨酸蛋白酶募集域、半胱天冬酶-1、白细胞介素-1β、红细胞衍生 2 相关因子 2 和血红素加氧酶-1 的信使 RNA 水平。
本研究结果表明，GDT 通过抑制神经元死亡和抗炎抗氧化机制，可能具有神经退行性疾病的神经保护潜力。
