20 Sep 2019

A drug commonly prescribed to keep enlarged prostates in check may hold promise for Parkinsons disease. According to a study published September 16 in the Journal of Clinical Investigation, terazosin (TZ), an 1-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 TZs energy-boosting prowess serendipitously, Welsh explained. In Beijing, TZ popped up as a top hit in Lius screen for cell death inhibitors in fruit flies. Flies lack 1-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.

Shrinking Both Prostate and Synuclein? In iPSC-derived neurons from Parkinsons patients, -synuclein (green) accumulates in dopaminergic neurons (red). TZ treatment reduced accumulation to control neuron levels. [Courtesy of Cai et al., JCI, 2019]

In genetic models of Parkinsons, 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 -synucleinthe primary component of the Lewy body inclusions that define the diseasetreatment 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-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 60an age group at risk for PDWelsh reasoned that database sleuthing could begin to answer this question. The researchers first turned to the Parkinsons 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 drugsdoxazosin (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 1-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.

Drugs Help Pee and PD? Men with PD who took TZ, DZ, or AZ had a lower relative risk of 69 of 79 PD-related diagnoses in their charts compared to men who took tamsulosin. Yellow dots represent a statistically significant difference. Diagnoses are grouped into categories. [Courtesy of Cai et al., JCI, 2019]

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 Parkinsons, 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 TZs 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 Parkinsons, and so careful evaluation of its safety is needed."

Clemens Scherzer of Brigham and Womens 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 1 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 -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 mgas prescribed for prostate enlargementbut 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

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In Mice and Men, Prostate Drug Reportedly Treats Parkinson's Disease? - Alzforum