The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial
Journal: 2021/March - Frontiers in Immunology
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.
Keywords: autonomic modulation; cholinergic; galantamine; heart rate variability; inflammation; metabolic syndrome; oxidative stress.
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The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial

+6 authors
Click here for additional data file.(103K, TIF)
Hypertension Unit, University of São Paulo (USP), São Paulo, Brazil
Postgraduate Program in Health Science, Midwestern State University (UNICENTRO), Paraná, Brazil
Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
Biomedical Sciences Institute Department of Physiology and Biophysics, University of São Paulo (USP), São Paulo, Brazil
Laboratory of Immunobiology, Department of Medicine, Center for Bioelectronic Medicine, Karolinska Institutet, Stockholm, Sweden
The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
Edited by: Niccolo Terrando, Duke University, United States
Reviewed by: Robert A. Whittington, Columbia University, United States; Bruno Bonaz, Center Hospitalier Universitaire de Grenoble, France; Annette Bruchfeld, Karolinska Institutet (KI), Sweden
*Correspondence: Valentin A. Pavlov ude.llewhtron@volvapv
Fernanda Marciano Consolim Colombo rb.evoninu@milosnoc.adnanref
This article was submitted to Inflammation, a section of the journal Frontiers in Immunology
†These authors have contributed equally to this work
Edited by: Niccolo Terrando, Duke University, United States
Reviewed by: Robert A. Whittington, Columbia University, United States; Bruno Bonaz, Center Hospitalier Universitaire de Grenoble, France; Annette Bruchfeld, Karolinska Institutet (KI), Sweden
Received 2020 Oct 28; Accepted 2021 Feb 8.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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.

Keywords: metabolic syndrome, galantamine, cholinergic, oxidative stress, heart rate variability, autonomic modulation, inflammation
Abstract

Footnotes

Funding. This study was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and by the National Institutes of Health (NIH) Grants NIH-NIGMS: R01GM128008 to VP, and R35GM118182-01 to KT. The funders of this study had no role in study design, data collection, data analysis, data interpretation, or manuscript writing. The corresponding author had full access to all the data of the study and had the final responsibility for the manuscript submission. This manuscript has been released as a pre-print at medRxiv (70).

Footnotes
Click here for additional data file.(103K, TIF)

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