A Breakthrough in Preclinical Research
In a landmark 2017 study, researchers at the University of Aberdeen reported that the drug trodusquemine, originally developed for cancer and diabetes, had a profound effect on atherosclerosis in mice. Specifically, a single dose was shown to “completely reverse” the effects of fatty plaque build-up in the arteries of mice with established atherosclerosis. The findings were considered highly impressive and offered a tantalizing glimpse into a new therapeutic strategy for cardiovascular disease, which is a leading cause of mortality worldwide. At the time, researchers noted that the next logical step was to test the drug's ability to improve outcomes in human patients.
The research was based on earlier observations that the drug's target, the enzyme Protein Tyrosine Phosphatase 1B (PTP1B), was overactive in people with obesity and diabetes, conditions strongly linked to accelerated atherosclerosis. The study’s success in animal models provided a strong proof-of-concept that inhibiting this specific enzyme could yield significant anti-atherosclerotic benefits.
The Dual-Action Mechanism of Trodusquemine
Understanding how trodusquemine works offers insight into its potential for reversing plaque formation. The drug's mechanism of action is primarily centered on its ability to inhibit the PTP1B enzyme while also activating another key protein, AMPK.
PTP1B Inhibition and Anti-Inflammatory Effects
Protein Tyrosine Phosphatase 1B (PTP1B) plays a major role in regulating cell function and is often over-expressed in individuals with obesity and insulin resistance. PTP1B can contribute to inflammation, a key component of atherosclerosis, by prompting macrophages (white blood cells) to take up oxidized cholesterol and become 'foam cells'. Trodusquemine's inhibition of PTP1B blocks this process, preventing the transformation of macrophages and reducing inflammation within the arterial walls. This mechanism explains the reduction in fatty deposits seen in the mouse studies.
AMPK Activation and Metabolic Benefits
In addition to blocking PTP1B, trodusquemine also activates the protein AMPK (adenosine monophosphate-activated protein kinase). This protein is known for its role in cellular energy balance and is stimulated during exercise. The activation of AMPK by trodusquemine helps to reduce chronic inflammation and improve lipid metabolism, contributing to lower levels of total cholesterol and triglycerides, which are key risk factors for atherosclerosis. By mimicking the effects of exercise, trodusquemine tackles the metabolic underpinnings of cardiovascular disease.
Advancements Toward Human Trials
Following the promising preclinical mouse studies, researchers at the University of Aberdeen continued their work to validate the drug's effects in humans at a cellular level. In a 2023 update, they announced successful follow-up tests on white blood cells taken from both healthy volunteers and individuals with coronary artery disease.
This research confirmed that the same biochemical changes observed in the mice—the inhibition of PTP1B and a reduction in 'bad' (LDL) cholesterol—occurred in human cells. The feasibility study provided the necessary proof-of-principle data to justify moving toward full human clinical trials. However, translating these findings into an approved, widely available medication has proven challenging.
The Path to Clinical Evaluation
- Initial trials: Trodusquemine was initially advanced into Phase I clinical trials for diabetes and obesity, where it demonstrated good tolerability.
- Financial setback: Subsequent planned Phase II trials for those indications were unfortunately halted due to financial difficulties experienced by the drug's original developer.
- Pending trials: As of late 2023, human trials specifically investigating trodusquemine's efficacy for atherosclerosis were still in the planning stages and had not commenced.
Comparison: Trodusquemine vs. Current Treatments
To put trodusquemine's potential into context, it is helpful to compare its proposed mechanism and effects with the current standard of care for atherosclerosis, primarily statin medications.
| Feature | Trodusquemine (Preclinical Data) | Standard Treatments (e.g., Statins) |
|---|---|---|
| Mechanism of Action | Inhibits PTP1B, activates AMPK, reduces inflammation | Primarily inhibits HMG-CoA reductase to lower cholesterol production |
| Plaque Reversal | Demonstrated reversal in mouse models | Primarily slows progression, minimal regression |
| Inflammation | Directly reduces chronic inflammation via PTP1B/AMPK | Modestly reduces inflammation secondary to cholesterol reduction |
| Metabolic Effect | Improves lipid metabolism, lowers cholesterol and triglycerides | Primarily targets LDL-C levels, other lipid effects vary |
| Clinical Status | Preclinical and early human cell studies completed; human trials pending | Approved, widely used, extensive clinical trial data |
Broader Potential and Future Outlook
Beyond reversing plaque buildup, trodusquemine has shown potential for a range of other age-related conditions, suggesting it could be a novel geroprotector. Research has indicated it may also prevent vascular calcification, a separate but related issue in cardiovascular disease, by improving mitochondrial health. Its ability to target multiple pathways simultaneously differentiates it from more narrowly focused drugs like statins.
The future of trodusquemine hinges on securing new investment to fund the necessary human clinical trials for atherosclerosis. The positive results from the 2023 human cell study provide a compelling case for investment. If successful in human trials, a therapy like trodusquemine could offer a new paradigm in cardiovascular medicine, moving beyond just managing risk factors to actively reversing the disease process. Interested readers can explore a broader review of the aminosterol's anti-aging properties in the journal Nature.
Conclusion
While the preclinical data suggesting trodusquemine can reverse atherosclerosis are highly promising, the journey from mouse to human medicine is long and complex. The encouraging human cell study in 2023 reinforced the potential of PTP1B inhibition as a therapeutic target for reversing plaque formation. However, significant financial and logistical hurdles remain before this promising treatment can be confirmed safe and effective in people. Further research and successful human clinical trials are essential to determine if trodusquemine will one day be a key medication in the fight against cardiovascular disease.
