20 Sep 2019

A drug commonly prescribed to keep enlarged prostates in check may hold promise for Parkinson’s disease. According to a study published September 16 in the Journal of Clinical Investigation, terazosin (TZ), an α1-adrenergic receptor antagonist that moonlights as a glycolysis booster, raised ATP, upped mitochondrial numbers, and ultimately saved dopaminergic neurons from degeneration in multiple models of PD. Led by Michael Welsh at the University of Iowa in Iowa City and Lei Liu of Beijing University, the researchers claim that among men who took terazosin or related drugs to quell prostate hyperplasia, the incidence of PD was low, and symptoms of diagnosed disease were mild. 

The researchers uncovered TZ’s energy-boosting prowess serendipitously, Welsh explained. In Beijing, TZ popped up as a top hit in Liu’s screen for cell death inhibitors in fruit flies. Flies lack α1-adrenergic receptors so, probing further, Liu found that the drug activates phosphoglycerate kinase 1 (PGK1), one of two enzymes that generate ATP in the glycolysis pathway (Chen et al., 2015). Since mitochondrial malfunction and impaired bioenergetics are features of withering neurons in PD, the researchers decided to test this ATP-boosting drug in models of the disease.

First author Rong Cai and colleagues began with the MPTP injection mouse model of parkinsonism. Given daily at the time of injection of this mitochondrial toxin, TZ attenuated all core pathologies, including the drop in ATP, loss of mitochondria in the striatum, loss of dopaminergic neurons, and loss of balance. When the researchers delayed TZ treatment until seven days after MPTP injection, the drug still had beneficial effects on dopaminergic function and motor performance by day 14.

TZ similarly protected other toxin models of parkinsonism, including 6-OHDA in rats, and rotenone in flies. In the insects, knocking out PGK1 erased the benefits of TZ, bolstering the idea that the drug fends off a PD-like syndrome via this enzyme.

In genetic models of Parkinson’s, the researchers saw TZ treatment assuage motor deficits, for example in flies carrying PD mutations in PINK1 or LRRK2. In transgenic mice overexpressing wild-type α-synuclein—the primary component of the Lewy body inclusions that define the disease—treatment with TZ between three and 15 months of age partially protected against loss of balance. Finally, in induced pluripotent stem-cell-derived neurons from two PD patients who carried the G2019S mutation in the LRRK2 gene, TZ increased ATP levels and lessened accumulation of α-synuclein aggregates (see image above).

Could TZ really work for people with PD? Because the drug is commonly prescribed for benign enlargement of the prostate in men over the age of 60—an age group at risk for PD—Welsh reasoned that database sleuthing could begin to answer this question. The researchers first turned to the Parkinson’s Progression Markers Initiative database, which tracks symptom progression in people with PD. They identified seven men with PD who took TZ and 269 who did not. Men on TZ had a slower rate of motor decline. Still in the PPMI database, the researchers expanded their query to include related drugs—doxazosin (DZ) and alfuzosin (AZ)—which are also used to treat prostate enlargement and contain the same quinazoline motif shown to enhance PGK1 function. The 13 men taking TZ, DZ, or AZ had slower progression of motor decline than those not on the drugs. Crucially, 24 men with PD who took tamsulosin, another prostate drug that antagonizes α1-adrenergic receptors but does not activate PGK1, did not have this relative protection. “I just about fell off my chair when I saw those results,” Welsh said.

To expand their search to more people, the researchers accessed the IBM Watson/Truven Health Analytics MarketScan Database for insurance claims relating to PD. They identified 2,880 men with PD who took TZ, DZ, or AZ, and 15,409 men with PD who took tamsulosin. They next selected 79 diagnostic codes related to PD, such as falls, tremor, walking problems, and sleep disorders. They found that compared with men with PD who took tamsulosin, those taking TZ, DZ, or AZ had a 22 percent lower relative risk of having any of these diagnostic codes in their files, suggesting they had milder disease. They also had fewer hospital visits for motor and non-motor symptoms, as well as PD complications.

To see if the ATP-boosting drugs might delay or prevent PD, the researchers identified more than 78,000 men in the Truven database without PD who took TZ, DZ, or AZ, then tracked their files for 284 days. During that time, 118 of them were diagnosed with PD, compared with 190 age-matched men who took tamsulosin instead. This yielded a hazards ratio of 0.62, suggesting that TZ, DZ, and AZ reduce the incidence of PD.

“All of this is very encouraging, and indicates that TZ is a strong candidate for clinical trials to see if it can be repurposed for Parkinson’s,” wrote Chris Elliott of the University of York, U.K. “In this TZ joins other drugs (including UDCA and Exenatide) that affect energy metabolism.” Howeve, Elliott noted that the mechanism of TZ’s effects on neurons remains to be ironed out, and cautioned that the drug has risks. “It reduces blood pressure, which may already be low in people with Parkinson’s, and so careful evaluation of its safety is needed."

Clemens Scherzer of Brigham and Women’s Hospital in Boston noted that defective bioenergetics is a key pathway in Parkinson's, and that the study points at potential tool compounds to correct these defects. “The quinazoline α1 adrenoreceptor blockers, which are used for benign prostatic hyperplastia, could be repurposed for clinical trials in PD or chemically tweaked to develop brain-optimized, new bioenergetics drugs for PD,” Scherzer told Alzforum. He added that rigorous population-wide cohort studies and clinical studies will be needed.

Welsh told Alzforum that it is unclear exactly how TZ and related drugs might counteract PD. He noted that recent studies indicate that ATP itself interferes with α-synuclein aggregation and liquid phase separation (Patel et al., 2017; Hayes et al., 2018). ATP could also reduce protein aggregation by bolstering the activity of myriad enzymes, including heat-shock proteins, he added. Of course, ATP might enhance all manner of neuronal functions by supplying cells with more energy. Welsh is investigating whether the drugs affect progression or incidence of other neurodegenerative proteinopathies, including AD.

Welsh has initiated a small trial to test TZ in PD patients at Iowa University, and has applied for funding to get multicenter trials up and running. He is starting by dosing patients with 5 mg—as prescribed for prostate enlargement—but said dose-finding studies are needed. Complicating matters, the drug had a biphasic dose response on its PGK1 target in cultured cells and in mice, meaning that at higher concentrations, it no longer elevates ATP. Welsh also noted that though the primary use of the drug is for prostate enlargement, it was also briefly used to treat hypertension, and was tested in women as well as men for that indication. He plans to include both men and women with PD in trials.—Jessica Shugart

Comments

1. • Chris Elliott
     University of York
   • Posted: 27 Sep 2019

   The main claim of this paper is that a drug used to treat prostate overgrowth, terazosin (TZ), may benefit people with Parkinson’s. In particular it may reduce the risk of Parkinson’s, and/or slow its progression. Such a “disease-modifying therapy” would be very valuable, since most of the currently approved drugs reduce the symptoms, but do not slow the course of Parkinson’s. Since TZ is already approved for human use, it could be quickly repurposed for people with Parkinson’s. This drug would not be without risk, as it also reduces blood pressure, which may already be low in people with Parkinson’s, so careful evaluation of its safety is needed.

   TZ is usually defined as an α1-adrenergic receptor antagonist—this means it acts on the cell surface, interacting with specific receptors for adrenaline, the flight-or-fight hormone. This effect of TZ is to relax blood vessels—but Cai et al. propose a second mechanism. They propose that TZ also acts on an enzyme inside the cell called phosphoglycerate kinase 1 (PGK1). The proposed interaction between TZ and PGK1 would increase the synthesis of ATP, the main source of energy in the cells. Lack of ATP production is a common feature of Parkinson’s, Alzheimer’s, and other neurodegenerative conditions.

   The main strength of this paper is that it shows that TZ alleviates the progression of Parkinson’s-like effects in a range of living animal models—both genetic and environmental. TZ improves motor performance in each model, mediated (at least in part) by the dopaminergic neurons. Indeed, in the fly model, the availability of a very specific genetic manipulation shows convincingly that the TZ—PGK1 interaction is dopaminergic.

   Additionally, the paper finds—from medical databases—that people taking TZ (or related compounds) had a lower risk of Parkinson’s than the general population.

   The main weakness of the paper is that the mechanism of TZ—PGK1 interaction is not fully explored. How does the TZ get into the cell and bind to PGK1? Does it directly affect ATP production? There is little attempt to show that the effects are not due to the well-characterised adrenergic mechanisms, perhaps because these experiments are technically difficult. However, the fact that TZ benefits fly models of Parkinson’s as well as rodent models supports the idea that TZ is not acting by an adrenergic receptor mechanism, since flies have no adrenaline.

   All of this is very encouraging, and indicates that TZ is a strong candidate for clinical trials to see if it can be repurposed for Parkinson’s. In this TZ joins other drugs (including UDCA and Exenatide) that affect energy metabolism. Additionally, other adrenergic drugs have been thought to be beneficial to people with Parkinson’s, e.g. salbutamol (Mittal et al., 2017), though their proposed mechanism did not involve PGK1.

   References:

   Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Science. 2017 Sep 1;357(6354):891-898. PubMed.

   View all comments by Chris Elliott

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References

Paper Citations

1. Chen X, Zhao C, Li X, Wang T, Li Y, Cao C, Ding Y, Dong M, Finci L, Wang JH, Li X, Liu L. Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat Chem Biol. 2015 Jan;11(1):19-25. Epub 2014 Nov 10 PubMed.
2. Patel A, Malinovska L, Saha S, Wang J, Alberti S, Krishnan Y, Hyman AA. ATP as a biological hydrotrope. Science. 2017 May 19;356(6339):753-756. PubMed.
3. Hayes MH, Peuchen EH, Dovichi NJ, Weeks DL. Dual roles for ATP in the regulation of phase separated protein aggregates in Xenopus oocyte nucleoli. Elife. 2018 Jul 17;7 PubMed.

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