'Semantic similarity' leads to novel drug candidates for Parkinson's disease (Probucol)

Medical Xpress / Public Library of Science / PLoS Biology ^ | Feb. 2, 2023 | Angus McQuibban et al

[ConservativeMind]

The words that researchers use to describe their results can be harnessed to discover potential new treatments for Parkinson's disease, according to a new study. The study employed an artificial intelligence (AI) system to identify an existing anti-cholesterol drug that has the ability to promote disposal of mitochondria, energy-making components of the cell which are damaged in the disease.

The full pathogenic pathway leading to Parkinson's disease (PD) is unknown, but one clear contributor is mitochondrial dysfunction and the inability to dispose of defective mitochondria, a process called mitophagy. At least five genes implicated in PD are linked to impaired mitophagy, either directly or indirectly, and so the authors sought compounds that could enhance the mitophagy process.

The top 79 candidates were screened in cell culture against a mitochondrial poison. The three top candidates from that assay were then tested on several other mitophagy assays, which identified probucol, a cholesterol-lowering drug, as the compound with the best combination of effectiveness and likely safety. Probucol was also found to improve motor function, survival, and neuron loss in two different animal models of Parkinson's disease.

Probucol's effect on mitophagy required the formation and action of lipid droplets, transient cell structures that help maintain mitochondrial integrity during stress, and that accumulate abnormally in Parkinson's disease. Probucol is known to target ABCA1, a protein involved in lipid transport, and reduction in levels of ABCA1 reduced probucol's ability to promote mitophagy, suggesting that ABCA1 is a likely mediator of the role of lipid droplets in mitophagy.

"Our study showcased a dual in silico/cell-based screening methodology that identified known and new mechanisms leading to mitophagy enhancement," McQuibban said. "Given the linkage between lipid droplet accumulation and ABCA1, it seems likely that probucol enhances mitophagy through mobilization of lipid droplets. Targeting this mechanism may be advantageous."

[ConservativeMind]

This drug is no longer available in the US, it is elsewhere, including Canada.

There are other substances that induce mitophagy, such as Urolithin A, but this hit a nice spot within their analysis.

[ConservativeMind]

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[Blood of Tyrants]

Thanks for the article.