The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial

Abstract

Background: 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.Trial Design and Methods: 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 (n = 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.Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39–2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34–1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46–1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 μmol/mg protein, [95% CI 0.57–1.20], P = 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.Conclusion: 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.

Oxidative Stress Biomarkers and Mitochondrial DNA Copy Number Associated with APOE4 Allele and Cholinesterase Inhibitor Therapy in Patients with Alzheimer’s Disease

“…In our study into the effects of medication on the oxidative/anti-oxidative status and mtDNA copy number, we found significant associations between AD patients using rivastigmine or galantamine and a lower serum TBARS level as well as increased mtDNA copy number. The reduction of TBARS level induced by cholinesterase inhibitors has previously been observed in both mouse and human studies; furthermore, it has been suggested that the reduction may inhibit disease progression [ 42 , 43 ]. Our study is the first to involve dementia patient observations to support this theory.…”

Exploring the vagus nerve and the inflammatory reflex for therapeutic benefit in chronic spinal cord injury

“…These beneficial effects are associated with a decrease in insulin levels and alleviated insulin resistance [72,73]. In addition, analysis of heart rate variability reveals that galantamine treatment modulates the autonomic regulation and sympathovagal balance towards lower sympathetic and higher vagal activity [72,73] (Fig. 1).…”

“…Performing a clinical trial with galantamine in people with metabolic syndrome supported by findings from animal studies and the fact that this centrally acting acetylcholinesterase inhibitor is a clinically approved drug for Alzheimer's disease [23,84]. In a randomized, double-blind, placebo-controlled trial treatments of patients with the metabolic syndrome with relatively low galantamine doses (8 mg, escalated to 16 mg daily) for 12 weeks significantly suppressed plasma TNF and leptin levels, increased plasma adiponectin levels, and ameliorates oxidative stress [72,73 ▪▪ ]. These beneficial effects are associated with a decrease in insulin levels and alleviated insulin resistance [72,73 ▪▪ ].…”

“…These observations support the possibility of performing clinical trials utilizing VNS in combination with rehabilitation approaches for functional recovery of patients with incomplete cervical SCI. In addition, considering the anti-inflammatory and beneficial metabolic efficacy of VNS [43,71] and cholinergic drugs, for example, galantamine [23,72,73], these two approaches can be evaluated in future clinical trials for alleviating the interrelated inflammatory and cardiovascular and metabolic burdens in patients with chronic SCI (Fig. 1).…”

Galantamine as a Treatment Option for Nicotine Addiction

“…However, there is no caution in place for the use of galantamine in people having mental health problems [ 12 ]. A randomized trial by Sangaleti et al [ 13 ] found that galantamine treatment reduces oxidative stress by increasing antioxidant enzyme activities which includes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase [ 13 ]. Moreover, galantamine significantly alleviates insulin resistance reducing the risk of metabolic syndrome and cardiovascular diseases [ 13 ].…”