Enhanced Parasympathetic Cholinergic Activity Inhibited Lipid-induced Oxidative Stress in Obese African Americans

Abstract Background: African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress.Objective: To test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs.Methods: Proof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 hours. Outcomes were assessed at baseline, 2 and 4 hours during the infusion.Main Outcome Measures: Changes in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-hrs post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha).Results: A total of 32 obese AA women were screened and fourteen completed the study (age 37.8±10.70 years old, BMI 38.7±3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007±0.008 vs. -0.002±0.006 ng/sample, P=0.016), and plasma (0.01±0.02 vs. -0.003±0.01 ng/mL, P=0.023). Galantamine also decreased IL-6 (11.4±18.45 vs. 7.7±15.10 pg/mL, P=0.021) and TNFα levels (18.6±16.33 vs. 12.9±6.16 pg/mL, P=0.021, 4-hrs post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5±10.49 vs. 43.6±13.38 during placebo pg/uL, P=0.025).Conclusions: In this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs.Trial registration: ClinicalTrials.gov identifiers NCT02365285