Neurodegenerative disorders are among the most feared medical diagnoses owing to both the devastating nature of these conditions and to the lack of truly effective treatments for them. These disorders may ultimately lead patients to be prisoners in their own mind, as in Alzheimer’s disease, or in their physical body, as in amyotrophic lateral sclerosis. In the case of Parkinson’s disease (PD), drugs that are effective at first—such as levodopa—lose this efficacy over time, leaving patients with limited options for symptom management. Moreover, some pharmaceutical drugs for PD come with undesirable and even dangerous side-effects stemming from their influence on the dopamine system, such as increased risk for impulsive or compulsive behavior including gambling, hypersexuality and compulsive shopping. This is a terrible tradeoff to have to make, so effective alternatives would be most welcome. Intriguing new evidence suggests that a drug commonly used for hypertension and enlarged prostate might have promise to be repurposed for PD.
This finding was published last month in the Journal of Clinical Investigation as a paper titled “Enhancing glycolysis attenuates Parkinson’s disease progression in models and clinical databases.” The research was a collaboration between researchers at the University of Iowa and Capital Medical University in Beijing, China and it suggests that the drug terazosin may have beneficial effects for individuals with PD. Terazosin is an alpha-blocker that lowers blood pressure by facilitating vasodilation and ameliorates symptoms of benign prostatic hyperplasia (BPH) by relaxing the muscles of the bladder and prostate. An additional mechanism for this drug is activation of the enzyme phosphoglycerate kinase 1 (PGK1), and it’s this effect that may hold promise for PD.
PGK1 is involved in glycolysis—the conversion of glucose to pyruvate and the generation of ATP. Reduced neuronal glucose metabolism is a feature of PD, so it stands to reason that a drug that may facilitate ATP synthesis might have a positive impact. Researchers found that in animal models (mice, rats, flies) and induced pluripotent stem cells, terazosin increased ATP levels in the brain and slowed or prevented neuron loss while also increasing dopamine levels and partially restoring motor function.
This is encouraging, but does it translate to humans? Researchers realized that older men are the most likely population to be living with PD and many of them may also have BPH, so they would be able to find a subset of PD patients who are taking terazosin (TZ). They queried the Parkinson’s Progression Markers Initiative database (sponsored by The Michael J. Fox Foundation for Parkinson’s Research) along with a larger database and found “slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs.”
The effect of terazosin on PGK1 was identified as the likely mechanism at work after this drug was compared to tamsulosin, an alpha-blocking drug also used for BPH but one that does not affect PGK1. Among PD patients taking tamsulosin or one of three drugs that affect PGK1 (terazosin, doxazosin or alfuzosin), those taking PGK1 activating drugs had statistically significantly less motor decline than those taking tamsulosin.
The connection to enhancing glycolysis deserves a closer look. As is the case with Alzheimer’s disease—often called “type 3 diabetes”—a growing body of evidence suggests that chronic hyperinsulinemia and impaired glucose and/or insulin signaling may be a major risk factor for PD. (In fact, drugs used for type 2 diabetes are being investigated for repurposing for use in PD patients and the noted decline in sense of smell as an early warning sign of PD may result from hyperinsulinemia.) Terazosin is prescribed for hypertension and BPH, both of which can be tied back to chronically elevated insulin. If a shared pathological state—chronic hyperinsulinemia (a.k.a. insulin resistance)—is a driving factor in all three of these conditions, it makes sense that a drug that may affect this via improving glucose metabolism might have a beneficial impact on them all. The present study offers hope for patients with PD should clinical trials be undertaken to assess the efficacy of terazosin for treatment of PD symptoms or possibly even disease prevention, and it also provides new insights into the etiology of the condition.
Another interesting point worth mentioning is that incidence of PD among men is almost double that in women, and the reason for this discordance is not known for certain. The researchers point out that the gene for PGK1 is located on the X chromosome, so a reduction in enzyme activity stemming from alterations to this gene may manifest more often in men than in women.
Regarding hope for the future and finding novel therapies for PD that are effective without the negative side-effects of existing drugs, study co-author Nandakumar Narayanan, MD, PhD, said, “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.”