Qiao Ou, Zhang Xinyu, Zhang Yi, Ji Haixia, Li Zhi, Han Xiaoying, Wang Wenzhe, Li Xia, Wang Juan, Liu Changxiao, Gao Wenyuan
Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin, 300072, China.
The State Key Laboratories of Pharmacodynamics and Pharmacokinetics, Tianjin, 300193, China.
Chin Med. 2021 Jun 28;16(1):47. doi: 10.1186/s13020-021-00456-9.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Current drugs can only relieve symptoms, but cannot really cure AD. Cerebralcare Granule® (CG) is a Traditional Chinese medicine (TCM) containing a variety of biologically active compounds. In our previous studies, CG has shown a beneficial effect against memory impairment in mice caused by D-galactose. However, whether CG can be used as a complementary medicine for the treatment of AD remains unexplored. Here, we use a combination of CG and memantine hydrochloride (Mm) to treat Alzheimer-like pathology and investigate the effects and mechanisms in vivo.
The histology of brain was examined with Hematoxylin-eosin (HE) staining, Golgi staining and Thioflavin S staining. ELISA was applied to assess the expression levels or activities of CAT, SOD, GSH-Px, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) in serum, as well as the levels of IL-6, IL-1β, and TNF-α in the mice brain. Western blotting was used to assess the expression of β-secretase (BACE1), amyloid precursor protein (APP), APPβ, APPα, synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95).
In the present study, the combination group (CG + Mm) significantly attenuated Alzheimer-like behavior without adverse effects in APP/PS1 mice, indicating its high degree of safety and efficacy after long-term treatment. CG + Mm reduced AD pathological biomarker Aβ plaque accumulation by inhibiting BACE1 and APP expression (P < 0.05 or P < 0.001). Besides, the combination group markedly inhibited the levels of IL-1β, IL-6, and TNF-α in hippocampus (P < 0.001), as well as activities of SOD, CAT, and GSH-Px in serum (P < 0.001). By contrast, the combination group improved synaptic plasticity by enhancing SYN, PSD95, and GAP43 expression.
Taken together, these data supported the notion that CG combined with Mm might ameliorate the cognitive impairment through multiple pathways, suggesting that CG could play a role as complementary medicine to increase anti-AD effect of chemical drugs by reducing Aβ deposition, neuroinflammation, oxidative damage, and improving synaptic plasticity.
阿尔茨海默病（AD）是一种以记忆缺陷和认知衰退为特征的进行性神经退行性疾病。目前的药物只能缓解症状，无法真正治愈AD。脑复康颗粒（CG）是一种含有多种生物活性化合物的中药。在我们之前的研究中，CG已显示出对D-半乳糖诱导的小鼠记忆损伤具有有益作用。然而，CG是否可作为治疗AD的辅助药物仍未得到探索。在此，我们使用CG与盐酸美金刚（Mm）联合治疗阿尔茨海默样病理，并在体内研究其作用效果及机制。
采用苏木精-伊红（HE）染色、高尔基染色和硫黄素S染色检查脑组织学情况。应用酶联免疫吸附测定（ELISA）评估血清中过氧化氢酶（CAT）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、丙二醛（MDA）、谷丙转氨酶（ALT）、谷草转氨酶（AST）、碱性磷酸酶（ALP）、总胆红素（TBIL）的表达水平或活性，以及小鼠脑中白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的水平。采用蛋白质免疫印迹法评估β-分泌酶（BACE1）、淀粉样前体蛋白（APP）、APPβ、APPα、突触素（SYN）、生长相关蛋白43（GAP43）和突触后致密蛋白95（PSD95）的表达。
在本研究中，联合治疗组（CG + Mm）在APP/PS1小鼠中显著减轻了阿尔茨海默样行为且无不良反应，表明其长期治疗后具有高度的安全性和有效性。CG + Mm通过抑制BACE1和APP表达减少了AD病理生物标志物Aβ斑块的积累（P < 0.05或P < 0.001）。此外，联合治疗组显著抑制了海马中IL-1β、IL-6和TNF-α水平（P < 0.001），以及血清中SOD、CAT和GSH-Px的活性（P < 0.001）。相比之下,联合治疗组通过增强SYN、PSD95和GAP43表达改善了突触可塑性。
综上所述，这些数据支持CG与Mm联合可能通过多种途径改善认知障碍的观点，表明CG可作为辅助药物，通过减少Aβ沉积、神经炎症、氧化损伤及改善突触可塑性来增强化学药物的抗AD作用。
