September 17, 2019 -- Collaborative research from the University of Iowa and researchers in China and Spain, show evidence that a current drug used to treat prostate cancer may improve Parkinson's disease (PD) symptoms by slow neurodegeneration. The results from experimental models and clinical database analysis were published on September 16, in the Journal of Clinical Investigation.
Parkinson's disease is a common neurogenerative disease that affects over 6 million people worldwide. Hallmark features of PD include loss and impaired function of dopamine neurons leading to motor abnormalities. There are currently treatments available to only relive PD symptoms, but none to prevent neurodegeneration. Aging, environmental toxins, and genetic mutations are all risk factors. Previous research suggests that PD pathogenesis includes impaired bioenergetics and reduced ATP levels. The research team hypothesized that increasing glycolysis in vivo might slow or prevent the apoptotic neurodegeneration of PD.
The current research is built upon the findings of a team member, Lei Liu, PhD, at Capital Medical University in Beijing, China who found that terazosin, a drug for treating enlarged prostate, or benign prostatic hyperplasia, could also block cell death. She found that terazosin binds and activates phosphoglycerate kinase 1 (PKG1), the first ATP-generating enzyme in glycolysis. The drug elicited beneficial effects for PD by enhancing PGK1 activity independent of α1-adrenergic antagonism (pathway utilized for treating prostate conditions).
"I'm really excited about this finding because I think it has the opportunity to change the lives of people with Parkinson's disease (and possibly other types of neurodegenerative disease.)" says Michael Welsh, MD, UI professor of internal medicine, a Howard Hughes Medical Institute investigator, and director of the Pappajohn Biomedical Institute at the UI.
Studying PD using animal models
Initially, researchers at the University of Iowa used PD flies, mice, rats, and human cells to test their hypothesis. The crystal structure of terazosin with PKG1 reveals a binding motif adjacent to ADP/ATP binding sites and in cultured cells terazosin enhanced PGK1 activity. These studies suggest that terazosin had the potential to increase ATP levels and inhibit cell death, thereby slowing neurodegeneration in animal models. While these results were encouraging, the research team cautioned that results in animals do not necessarily predict similar outcomes in people.
Studying PD using clinical data
PD is more common in men over the age of 60 than women. Also, terazosin is often prescribed to older men to treat prostate disease. Therefore, the team including Jordan Schultz, PharmD, University of Iowa assistant professor of psychiatry, interrogated the Parkinson's Progression Markers Imitative (PPMI) database, sponsored by the Michael J. Fox Foundation for Parkinson's Research. This small clinical database uniquely assesses motor progression among PD patients. From this analysis, it was determined that men with PD who took terazosin (n=7) had reduced rates of progressive motor loss compared to men with PD who were taking an alternative drug, tamsulosin (does not affect PGK1).
Because of the small sample size of the PPMI database, the research team sought to evaluate a larger dataset to confirm their findings. Therefore, the team next interrogated the IBM Watson/ Truven Health Analytics MarketScan Database, which collected data from 2011 to 2016. The data was analyzed in collaboration with Jacob Simmering, PhD, University of Iowa assistant professor of internal medicine, and Phillip Polgreen, MD, University of Iowa professor of internal medicine and epidemiology. In this dataset, there were 2,880 PD patients taking a combination of drugs (including terazosin) which increases glycolysis and slows the progression of motor disability. There were 15,409 PD patients taking tamsulosin. Using predictive modeling, the relative risk for 79 clinically relevant diagnostic codes (including motor, nonmotor, and complications indicators). The data suggests that under real-world conditions, terazosin enhances PGK1 activity and reduces signs, symptoms, and complications in PD patients.
"What is particularly exciting is that terazosin is a 'repurposed drug'. So, we have a lot of safety data already from its clinical use to treat enlarged prostate," says Nandakumar Narayanan, MD, PhD, University of Iowa neurologist, and co-author. The research team is currently planning phase I clinical trials to access if the treatment will work for PD patients.
There were several limitations in the current research including analysis of human databases was limited to men, data from humans are retrospective, and the analysis of the PPMI and Truven databases compared patients on combination (with terazosin) with those on tamsulosin.
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