Terazosin (Hytrin), a drug used to treat enlarged prostate, may also be able to slow the progression of Parkinson disease (PD), according to a study published this week in the Journal of Clinical Investigation.
The finding is the result of a collaboration involving researchers in China and at the University of Iowa (UI), combining observations from animal experiments with information from clinical databases regarding men taking the drug.
Lei Liu, PhD, at Capital Medical University in Beijing, China, found that terazosin could block cell death. Using toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, the drug increased brain adenosine triphosphate levels and slowed or prevented neuron loss if it was given before the onset of cell death. In addition, the drug could slow or stop neurodegeneration, even if treatment was delayed until after neurodegeneration had started to develop. Liu's team discovered that the cell-protective activity was due to terazosin's ability to activate phosphoglycerate kinase 1 (PGK1), an enzyme critical for cellular energy production.
Researchers then probed databases looking at patients who took terazosin and found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses.
This suggests that in patients taking terazosin and related drugs, enhanced PGK1 activity and increased glycolysis may slow neurodegeneration in PD.
"When we tested the drug in various different animal models of PD, they all got better. Both the molecular changes in the brain associated with cell death and the motor coordination in the animals improved," said Liu, a professor in the Beijing Institute for Brain Disorders, in a statement
Nandakumar Narayanan, MD, PhD, a UI neurologist, and Jordan Schultz, PharmD, UI assistant professor of psychiatry, examined the Parkinson's Progression Markers Initiative database, which is sponsored by The Michael J. Fox Foundation for Parkinson's Research. The data showed that men with PD who were taking terazosin had reduced rates of progressive motor disability compared to men with PD who were taking a different drug, tamsulosin, for enlarged prostate.
While tamsulosin is also used to treat benign prostatic hyperplasia, unlike terazosin, it does not have any effect on the PGK1 enzyme, making it a good control.
Only 13 men were identified who were taking terazosin or 1 of 2 similar drugs that also activate the PGK1 enzyme, compared with 293 men with PD who were either taking tamsulosin or were not taking any of these drugs. While the differences in motor decline between the 2 groups were statistically significant, the team looked to confirm the findings using the larger IBM Watson/Truven Health Analytics MarketScan Database, which includes de-identified records of more than 250 million people.
From there, researchers identified 2880 Parkinson's patients taking 1 of the 3 drugs that target PGK1 (terazosin, doxazosin, or alfusin) and a comparison group of 15,409 PD patients taking tamsulosin. Using medical codes to track PD-related diagnoses and hospital or clinic visits for all the patients, the data suggested that under real world conditions, terazosin and related drugs reduce the signs, symptoms, and complications of PD. Relative to patients with PD taking tamsulosin, those on terazosin or the 2 other drugs had reduced clinic and hospital visits for motor symptoms (relative risk [RR] 0.77; 95% CI, 0.70–0.84), nonmotor symptoms (RR 0.78; 95% CI, 0.73–0.83), and PD complications (RR 0.76; 95% CI, 0.71–0.82).
Patients using terazosin also had a reduced risk of a PD diagnosis, the researchers said.
Cai R, Zhang Y, Simmering JE, et al. Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases [published online September 16, 2019]. J Clin Invest
. doi: 10.1172/JCI129987.