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Enhanced parasympathetic cholinergic activity with galantamine inhibited lipid-induced oxidative stress in obese
Dena Parsa1, Luul A Aden1, Ashley Pitzer1
1Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 506 Robinson Research Building, Nashville, TN, 37232, USA.
Insights
African Americans with obesity experience higher cardiovascular disease risk. This study found that galantamine, by enhancing parasympathetic activity, reduced oxidative stress and inflammation in obese African Americans, offering a potential therapeutic avenue.
Area of Science:
- Cardiovascular Disease Research
- Neuroscience
- Pharmacology
Background:
- African Americans (AAs) face a disproportionately high risk of cardiovascular disease (CVD), with a 20% higher mortality rate compared to White individuals.
- Chronic inflammation and oxidative stress are key contributors to CVD development in AAs.
- Reduced parasympathetic nervous system (PNS) activity in AAs, compared to Whites, suggests a potential target for intervention.
Purpose of the Study:
- To investigate the efficacy of galantamine, an acetylcholinesterase (AChE) inhibitor, in mitigating lipid-induced oxidative stress in obese African Americans.
- To test the hypothesis that stimulating PNS cholinergic activity with galantamine can prevent oxidative stress associated with lipid infusion.
Main Methods:
- A proof-of-concept, double-blind, randomized, placebo-controlled, crossover study was conducted.
- Fourteen obese AA women received a single 16 mg dose of galantamine or placebo, followed by a 4-hour intralipid infusion.
- Outcomes, including F2-isoprostanes (oxidative stress marker) and inflammatory cytokines, were measured at baseline, 2, and 4 hours post-infusion.
Main Results:
- Galantamine significantly inhibited the rise of F2-isoprostanes in both peripheral blood mononuclear cells (PBMC) and plasma compared to placebo.
- Treatment with galantamine led to a significant reduction in IL-6 and TNF-alpha inflammatory cytokine levels.
- These beneficial effects were correlated with increased plasma acetylcholine levels following galantamine administration.
Conclusions:
- This pilot study demonstrates that enhancing PNS cholinergic activity with galantamine effectively inhibits lipid-induced oxidative stress and inflammation in obese African Americans.
- Galantamine presents a promising therapeutic strategy for managing oxidative stress and inflammation in this high-risk population.
- Further research is warranted to explore the long-term cardiovascular benefits of galantamine in obese AAs.
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.
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