Zeng Ju, Zhang Xiaorui, Wang Jianhui, Cheng Xiaorui, Zhang Yongxiang, Zhou Wenxia
Department of Neuroimmunopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
Front Pharmacol. 2020 Apr 28;11:350. doi: 10.3389/fphar.2020.00350. eCollection 2020.
Aging is a natural biological process associated with cognitive decline and neuroendocrine-immune system changes; the neuroendocrine-immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)-Liuwei Dihuang decoction (LW)-and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4 and CD4CD28 cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4CD28 cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8CD28 cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic.
衰老为与认知衰退和神经内分泌免疫系统变化相关的自然生物学过程；神经内分泌免疫系统在脑衰老和神经退行性变中起关键作用，基于免疫衰老来辨别延缓衰老进程的有益尝试至关重要。在本研究中，我们探究了中药六味地黄汤（LW）以及多奈哌齐、美金刚和褪黑素对衰老小鼠认知衰退的影响。衰老的SAMR1小鼠口服给予多奈哌齐（1mg/kg）、美金刚（10mg/kg）、褪黑素（10mg/kg）和LW（10g/kg），持续3个月。进行穿梭箱、莫里斯水迷宫和高架零迷宫实验以评估认知功能，并采用流式细胞术、Luminex技术和放射免疫分析法来检测淋巴细胞亚群、炎症因子和激素。我们观察到，褪黑素和LW可延长小鼠存活天数，美金刚、褪黑素和LW治疗可显著改善焦虑行为，LW、多奈哌齐和美金刚可显著改善主动回避反应，多奈哌齐可显著提高空间学习能力，LW和褪黑素对老年小鼠的空间记忆有益。对于免疫功能，LW可增加血浆中CD4和CD4CD28细胞数量，并降低TNF-α、IL-1β和G-CSF水平，还可通过调节脾脏中Th2细胞活性来促进抗炎因子IL-4、IL-5和IL-10的分泌。多奈哌齐和美金刚对衰老引起的CD4CD28细胞减少具有保护作用，并降低血浆中促炎因子TNF-α、IL-1β和G-CSF水平。褪黑素可逆转CD8CD28细胞失衡并增加B细胞数量。对于内分泌因子，LW可提高垂体中促甲状腺激素水平，褪黑素可提高血液中生长激素水平。我们的研究结果表明，LW可改善衰老小鼠的认知衰退，这可能与调节活化T细胞、下丘脑-垂体-性腺轴激素以及增加抗炎因子有关。同时，多奈哌齐和美金刚在调节适应性免疫方面具有优势，褪黑素在调节B细胞和垂体激素方面具有优势，从整体角度来看LW在神经内分泌免疫功能方面比其他药物表现出更好的效果。LW可能是一种治疗抗衰老相关综合征的潜在策略，并且它还可为临床药物联合使用或治疗提供用药指导价值。
