Hypertension Unit, University of São Paulo (USP), São Paulo, Brazil.
Postgraduate Program in Health Science, Midwestern State University (UNICENTRO), Paraná, Brazil.
Front Immunol. 2021 Mar 11;12:613979. doi: 10.3389/fimmu.2021.613979. eCollection 2021.
The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS. The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS ( = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment. Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39-2.92], = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34-1.51], = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46-1.07], = 0.05], and systemic nitrite levels [log scale 0.83 μmol/mg protein, [95% CI 0.57-1.20], = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment. Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.
代谢综合征（MetS）是一种与肥胖相关的疾病，其流行程度和治疗选择有限。氧化应激、低度炎症和神经自主调节改变是发病机制的重要组成部分和驱动因素。加兰他敏是一种乙酰胆碱酯酶抑制剂和胆碱能药物，已被临床批准用于治疗阿尔茨海默病，它与几种免疫和代谢紊乱的疾病中的炎症的神经胆碱能调节有关。在这里，我们研究了加兰他敏对氧化应激的影响，并与代谢综合征患者的炎症和心血管代谢参数进行了平行研究。在随机分配的代谢综合征患者（每组 22 人）中，研究了加兰他敏治疗（每天 8 毫克，持续 4 周，然后每天 16 毫克，持续 8 周）和安慰剂的效果。研究了氧化应激标志物，包括超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶活性、脂质和蛋白质过氧化、亚硝酸盐水平，在治疗前和治疗结束时进行了分析。此外，还分析了血浆细胞因子和脂肪因子水平、胰岛素抵抗（HOMA-IR）和其他相关心血管代谢指标。在治疗前和治疗的每 4 周，还通过心率变异性（HRV）检查自主神经调节。加兰他敏治疗显著增加了抗氧化酶的活性，包括 SOD[+1.65 USOD/mg 蛋白，[95%置信区间 0.39-2.92]，=0.004]和 CAT[+0.93 nmol/mg，[95%置信区间 0.34-1.51]，=0.01]，降低了脂质过氧化[硫代巴比妥酸反应物质[log 标度 0.72 pmol/mg，[95%置信区间 0.46-1.07]，=0.05]和全身亚硝酸盐水平[log 标度 0.83 μmol/mg 蛋白，[95%置信区间 0.57-1.20]，=0.04]与安慰剂相比。此外，加兰他敏治疗 8 周和 12 周后，还显著减轻了炎症状态和胰岛素抵抗，并降低了 HRV 的低频/高频比值。小剂量加兰他敏可减轻代谢综合征患者的氧化应激，同时具有有益的抗炎和代谢作用，并调节神经自主调节。这些发现对于进一步研究胆碱能药物加兰他敏改善代谢综合征具有重要意义。
