Summary: Terazosin, a medication commonly used for enlarged prostate and high blood pressure, shows potential as a treatment for motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS).
Source: University of Edinburgh
A drug already prescribed for benign prostatic hyperplasia and hypertension has demonstrated protective effects on motor neurons in laboratory and animal studies, suggesting it could be repurposed as a therapy for motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS).
MND is a group of progressive neurological conditions that destroy motor neurons, the nerve cells responsible for transmitting signals from the brain and spinal cord to muscles. As motor neurons deteriorate, patients experience weakness, loss of motor control and eventual paralysis. In the UK, the condition affects approximately 5,000 adults, and average survival after symptom onset is around three years.
Researchers from the University of Edinburgh, in collaboration with the University of Oxford, investigated whether terazosin can protect motor neurons by boosting their energy production. Prior work has indicated that early in ALS, motor neurons exhibit reduced bioenergetic capacity, which undermines their ability to relay neural instructions to muscles. The team focused on enhancing cellular energy pathways as a therapeutic strategy.
Terazosin is known to increase activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1), a key player in cellular energy generation. The researchers tested the drug’s effects across multiple models: zebrafish genetically engineered to display ALS-like motor neuron defects, a mouse model exhibiting progressive paralysis, and motor neurons derived from embryonic stem cells carrying ALS-associated mutations.
In zebrafish, either genetic overexpression of PGK1 or treatment with terazosin improved motor neuron development and axon growth, and led to better motor behavior. In the mouse model, terazosin treatment extended survival, delayed paralysis, and increased the number of surviving motor neurons. In human cell-derived motor neurons, terazosin raised basal glycolysis, protected cells from oxidative stress–induced death, and helped restore normal stress granule dynamics—cellular structures that are often disrupted in ALS.
Taken together, these findings indicate that targeting PGK1 and cellular energy metabolism can reduce motor neuron vulnerability in multiple experimental settings. Because terazosin is already an approved drug with established safety data for other conditions, it represents a promising candidate for repurposing in ALS, potentially accelerating the route from laboratory research to clinical testing.
Following these promising preclinical results, the research team is launching a feasibility study in people with MND. Fifty participants will be recruited from the Oxford MND Care and Research Centre to assess the safety, tolerability and initial effects of terazosin on clinical and biochemical markers of disease progression. If the feasibility study produces encouraging results, the investigators plan to progress to a larger clinical trial to test therapeutic benefit more rigorously.
This work was conducted at the Euan MacDonald Centre for Motor Neurone Disease at the University of Edinburgh, a centre established to drive research and improve outcomes for people living with MND. The study was funded by MND Scotland and the My Name’5 Doddie Foundation, with additional support from other funders noted in the original publication.
Dr Helena Chaytow, senior postdoctoral researcher at the Euan MacDonald Centre and first author of the study, said the data show terazosin protects motor neurons across several models of MND and highlighted the advantage that the drug is already used in clinical practice for other conditions. Professor Tom Gillingwater, co-lead of the study, emphasized the importance of collaboration between basic scientists and clinicians to identify targets that can move into human studies. Professor Kevin Talbot, co-lead from the University of Oxford, stressed the need to accelerate translation from laboratory models into patient trials using approaches that increase confidence drugs will be effective in people with MND.
Representatives from funding charities also welcomed the findings and the move toward clinical testing. The collaborative effort aims to shorten the time between discovery and patient benefit by repurposing a well-characterized drug with a known safety profile.
About this neuropharmacology and ALS research news
Author: Shane Canning
Source: University of Edinburgh
Contact: Shane Canning – University of Edinburgh
Image: The image is in the public domain
Original Research: Open access. “Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis” by Helena Chaytow et al. Published in EBioMedicine.
Abstract
Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis
Background
ALS is a fatal, heterogeneous neurodegenerative disease with complex genetic and environmental contributors. Because diverse causes converge on shared pathways—such as impaired energy metabolism—therapies that restore cellular bioenergetics may have broad efficacy across different forms of ALS.
Methods
The study increased activity of the glycolytic enzyme PGK1 either genetically or pharmacologically with terazosin in zebrafish, a mouse model and embryonic stem cell–derived motor neurons carrying ALS-linked mutations. Investigators evaluated axon growth, motor behavior, survival, resistance to oxidative stress and other disease-relevant phenotypes to determine therapeutic potential.
Findings
Enhancing PGK1 activity improved motor neuron integrity and function in vivo. In zebrafish, PGK1 overexpression or terazosin treatment rescued axon defects and improved motor behavior. In mice, terazosin extended survival, reduced progression of paralysis and increased motor neuron counts. In stem cell–derived motor neurons, terazosin increased basal glycolysis, protected against oxidative stress–induced death and restored stress granule dynamics.
Interpretation
These results show terazosin protects motor neurons through multiple mechanisms, including upregulation of glycolysis and normalization of stress granule formation. Repurposing terazosin may therefore offer a feasible strategy to expand therapeutic options for ALS across different causes of disease.
Funding
The work was supported by MND Scotland, the My Name’5 Doddie Foundation, a Medical Research Council Doctoral Student Training Fellowship and an Academy of Medical Sciences grant.