Enhanced parasympathetic cholinergic activity with galantamine 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 h. Outcomes were assessed at baseline, 2 and 4 h 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-h 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-h 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.

Innovative assessment of lipid‐induced oxidative stress and inflammation in harvested human endothelial cells

“…Previous work has shown that African American individuals have a greater oxidative stress response to lipid infusion at doses of 0.8 mL/m 2 /min with heparin (200 U/hrs for 4 hrs) than in Whites (Lopes et al., 2003), which is confirmed by plasma levels of the oxidative stress biomarker F2‐isoprostane (Parsa et al., 2022; Saleem et al., 2023). However, a reliable protocol to measure dynamic changes in oxidative stress responses in human endothelial cells has yet to be developed.…”

“…The differences in the results endpoints are insignificant because we are still blinded to the treatment of these participants. Considering that the patients also received galantamine, which diminishes NADPH oxidase activity and lowers oxidative stress levels (Parsa et al., 2022), galantamine may have mitigated the inflammatory and oxidative impact of lipid infusion in the patients.…”

“…3.1.1 | Use of lipid and heparin infusion to stimulate oxidative stress and inflammation Following our established protocol, we infused 20% lipids (Intralipids, Baxter Healthcare Crop. Glendale, CA) at 0.8 mL/m 2 /min for 4 h (Parsa et al, 2022). An initial heparin bolus of 1000 U was administered, followed by a 200 U/h infusion during the 4-hour period of lipid infusion to activate endothelial lipoprotein lipase on the vascular endothelium, which hydrolyzes nonesterified free fatty acids (NEFA) from triglycerides during lipid infusion.…”

Obesity Is Associated with Increased F2-Isoprostanes and IL-6 in Black Women

“…The levels of F 2 -IsoPs were measured in plasma using negative ion gas chromatographymass spectrometry by the Vanderbilt University Eicosanoid Core Laboratory as previously described [37,38]. Similarly, levels of F 2 -IsoPs in PBMCs were measured as previously described [39].…”