目的: 探究山茱萸总苷(total glycosides from cornus officinalis, TGCO)是否通过调节胆碱能抗炎通路(cholinergic anti-inflammatory pathway, CAP)改善甲状腺功能减退所致认知功能障碍。方法: 将60只成年雄性SD大鼠随机分为模型组、空白对照组、TGCO低剂量组(3 g/kg·d)、TGCO中剂量组(6 g/kg·d)、TGCO高剂量组(12 g/kg·d)及阳性对照组(优甲乐)。采用0.1%丙硫氧嘧啶溶液灌胃30 d制备甲状腺功能减退大鼠模型,造模成功后分别给予各给药组相应剂量的TGCO连续灌胃21 d。通过Morris水迷宫测试学习认知功能,ELISA法测定血清甲状腺激素及相关神经递质水平,Western blot检测脑内炎症因子、神经递质合成酶及相关信号通路蛋白表达。结果: 与模型组相比,TGCO各剂量组逃避潜伏期逐渐缩短,目标象限停留时间和穿越平台次数逐渐增加,且高剂量组效果最为显著(P＜0.05);与模型组相比,高剂量TGCO处理组大鼠血清中三碘甲腺原氨酸(triiodothyronine, T3)、四碘甲腺原氨酸(tetraiodothyronine, T4)水平升高,促甲状腺激素(thyroid stimulating hormone, TSH)水平降低(P＜0.05);同时,高剂量TGCO处理组大鼠血清中乙酰胆碱(acetylcholine, Ach)、多巴胺(dopamine, DA)水平上升(P＜0.05),5-羟色胺(5-hydroxytryptamine,5-HT)水平降低(P＜0.05);与模型组相比,TGCO各剂量组肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)、白细胞介素-1β(interleukin-1β, IL-1β)、白细胞介素-6(interleukin-6, IL-6)表达逐渐降低(P＜0.05),胆碱乙酰转移酶(choline acetyltransferase, ChAT)、酪氨酸羟化酶(tyrosine hydroxylase, TH)表达逐渐升高(P＜0.05),呈剂量依赖性。结论: TGCO可有效改善甲状腺功能减退所致认知功能障碍,其机制可能与调节神经递质、抑制炎症反应及调控相关信号通路有关,为临床治疗提供了新的理论依据。
Objective: To investigate whether total glycosides from cornus officinalis (TGCO) can improve cognitive dysfunction caused by hypothyroidism via regulating cholinergic anti-inflammatory pathway (CAP). Methods: Sixty adult male SD rats were randomly divided into model group, blank control group, TGCO low-dose group (3 g/kg·d), TGCO medium-dose group (6 g/kg·d), TGCO high-dose group (12 g/kg·d) and positive control group (Euthyrox). The rat model of hypothyroidism was prepared by intragastric administration of 0.1% propylthiouracil solution for 30 days. After successful modeling, the corresponding doses of TGCO were given to each administration group for 21 days. The learning and cognitive function was tested by Morris water maze. The levels of serum thyroid hormones and related neurotransmitters were measured by ELISA. The expression of inflammatory factors, neurotransmitter synthase and related signaling pathway proteins in the brain were detected by Western blot. Results: Compared with the model group, the escape latency of each TGCO dose group was gradually shortened, the target quadrant residence time and the number of crossing the platform were gradually increased, and the effect of the high dose group was the most significant (P＜0.05). Compared with the model group, the levels of triiodothyronine (T3) and tetraiodothyronine (T4) in the serum of rats in the TGCO high-dose group were increased, and the levels of thyroid stimulating hormone (TSH) were decreased (P＜0.05). At the same time, the levels of acetylcholine (Ach) and dopamine (DA) in the serum of rats in the TGCO high-dose group were increased (P＜0.05), and the level of 5-hydroxytryptamine (5-HT) was decreased (P＜0.05). Compared with the model group, the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in each TGCO dose group were decreased gradually (P＜0.05). The expression of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) were increased gradually in a dose-dependent manner (P＜0.05). Conclusion: TGCO can effectively improve cognitive dysfunction caused by hypothyroidism, and its mechanism may be related to regulating neurotransmitters, inhibiting inflammatory response and regulating related signaling pathways, which provides a new theoretical basis for clinical treatment.
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