Parkinson’s disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.
Rong Cai, Yu Zhang, Jacob E. Simmering, Jordan L. Schultz, Yuhong Li, Irene Fernandez-Carasa, Antonella Consiglio, Angel Raya, Philip M. Polgreen, Nandakumar S. Narayanan, Yanpeng Yuan, Zhiguo Chen, Wenting Su, Yanping Han, Chunyue Zhao, Lifang Gao, Xunming Ji, Michael J. Welsh, Lei Liu
Submitter: Michael Welsh | email@example.com
Authors: Michael Welsh and Liu Lei
University of Iowa
Published October 25, 2019
We appreciate the comments of Drs. Messerli, Rexhaj, Grodzicki, and Kreutz.
As they note, using data from the Truven database, we compared people with Parkinson's disease (PD) who were taking terazosin (TZ), doxazosin (DZ), or alfuzosin (AZ) (TZ/DZ/AZ) to people with PD who were taking tamsulosin (1). All the agents are alpha-1 adrenergic receptor antagonists. We also noted that “Although all the drugs were prescribed for benign prostatic hyperplasia, we cannot exclude the possibility that some other factor might have influenced prescribing behavior. For example, orthostatic hypotension is a complication of both the autonomic dysfunction in PD and of the drugs, and there are reports suggesting that tamsulosin may elicit less orthostatic hypotension than TZ (2)”. However, in contrast to TZ/DZ/AZ, tamsulosin does not have a quinazoline motif that binds to and enhances PGK1 activity and glycolysis.
We found that compared to people with PD using tamsulosin, those using TZ/DZ/AZ had a reduced relative risk of receiving diagnoses of orthostatic hypotension, falls, syncope and collapse (1). Thus, despite the potential combined risk of orthostatic hypotension due to PD plus the risk of orthostatic hypotension from using TZ/DZ/AZ, the Truven database indicated that the relative risk of receiving a diagnosis of orthostatic hypotension or falls, syncope and collapse were decreased. This is an interesting and surprising finding. There are at least two possible interpretations.
#1. We said that, “In PD, neurons that have not yet degenerated almost certainly have compromised cellular function, and we speculate that TZ/DZ/AZ improved their functional integrity.” Thus, we speculate that improved function of neurons responsible for blood pressure control outweighed the risk.
#2. Drs. Messerli, Rexhaj, Grodzicki, and Kreutz suggest the interpretation that “if a PD patient tolerates and survives 15 months of exposure to TZ/DZ/AZ, he must have a rather benign, minimally progredient form of PD with an intact autonomic nervous system. In other words, exposure to TZ/DZ/AZ simply serves as a litmus test identifying PD patients who are not susceptible to hypotension and syncope, despite continuously being provoked to do so.”
We favor interpretation #1 for two main reasons. First, our data in many models of PD suggest that TZ improves the function of the neurons that have not degenerated. Second, at the time of enrollment into a separate independent database, the PPMI, disease severity assayed by the MDS UPDRS part 3 was the same for people taking TZ/DZ/AZ, tamsulosin, or none of these drugs. However, progression for patients on TZ/DZ/AZ was less than for those in the other two groups.
If interpretation #2 is correct, we would predict that PD patients who receive a new prescription for TZ/DZ/AZ would use it for a shorter period of time than patients who receive a new prescription for tamsulosin. To test this prediction, we probed an expanded Truven database to determine the duration of use after people with PD began taking the drugs. The data are in the following table.
Number of patients beginning drug 4,070 22,292
Number of days patients were followed 5,516,674 28,743,678
Number of days patients were on drug 2,126,753 11,992,055
Number of days a patient was on drug 522.5 538.0
Mean (95% confidence intervals) (499.6, 545.4) (528.2, 547.8)
These results suggest that after PD patients are prescribed TZ/DZ/AZ or tamsulosin, there is not a substantial difference between the duration that they take the medications (p=0.225).
Nevertheless, we cannot exclude interpretation #2, as we indicated when we said, “we cannot exclude the possibility that some other factor might have influenced prescribing behavior”. Thus, prospective trials in people with PD will be important and must consider the potential adverse effect of orthostatic hypotension. We hope that those clinical trials will soon be underway.
1. Cai R, Zhang Y, Simmering JE, et al. Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases. The Journal of clinical investigation 2019;129(10) doi: 10.1172/JCI129987
2. Dong Z, Wang Z, Yang K, Liu Y, Gao W, Chen W. Tamsulosin versus terazosin for benign prostatic hyperplasia: a systematic review. Syst Biol Reprod Med. 2009;55(4):129–136.
Submitter: Franz H. Messerli | firstname.lastname@example.org
Authors: Franz H. Messerli, Emrush Rexhaj, Tomasz Grodzicki, Reinhold Kreutz,
Swiss Cardiovascular Center, University of Bern, Switzerland
Published October 4, 2019
In their provocative paper reporting that enhancing glycolysis attenuated Parkinson’s disease (PD), Cai et al. state that “the risk of orthostatic hypotension and falls was reduced, not increased, for patients with PD taking Terazosin (TZ), Doxazosin (DZ), or Alfuzosin (AZ) versus those on tamsulosin” (1). Based on thorough experimental data the authors convincingly demonstrate that in not yet degenerated neurons, these drugs improve functional integrity.
However, we take issue with the interpretation of their clinical data. The most common incapacitating cardiovascular adverse event in PD is hypotension and syncope. Senard et al. reported a fall in systolic blood pressure (BP)of at least 20 mm Hg in 58.2% and orthostatic hypotension in 38.5% of unselected PD patients (2). Similarly, the most common incapacitating cardiovascular adverse events of alpha-blockers are hypotension and syncope. In a large recent study of women at least 66 years old, add-on therapy of alpha blockers including TZ and DZ conferred a 71 % higher risk for hypotension and 44% higher risk for syncope than did other antihypertensives (3). In the present study the reported decrease in risk of hypotension with non-selective alpha-blockers TZ and DZ compared to tamsulosin in this group of elderly men (mean age about 77 years) is puzzling. Of note, low BP or an excessive orthostatic BP decrease has been documented to be a risk factor for cognitive decline in older patients (4, 5).
It follows that if a PD patient tolerates and survives 15 months of exposure to TZ/DZ/AZ, he must have a rather benign, minimally progredient form of PD with an intact autonomic nervous system. In other words, exposure to TZ/DZ/AZ simply serves as a litmus test identifying PD patients who are not susceptible to hypotension and syncope, despite continuously being provoked to do so. According to the principle of “surviving of the fittest”, these are the very patients who will have the mildest, least progressive form of PD, regardless of whether or not TZ/DZ/AZ enhance glycolysis and possibly attenuate neurodegeneration.