Terazosin shows promise as a treatment for ALS

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A drug typically used to treat enlarged prostates and high blood pressure has shown promise as a potential new therapy for motor neuron disease (MND) – also known as amyotrophic lateral sclerosis (ALS) – according to a new study.

MND is a group of rare diseases that destroy nerve cells known as motor neurons, causing patients to slowly lose function of their muscles.

In studies using zebrafish, mice and stem cell models, experts have demonstrated that the drug terazosin protects against the death of motor neurons by increasing their energy production.

Researchers say the drug could help to slow the progression of a disease that affects around 5,000 adults in the UK. The average life expectancy is three years from the onset of symptoms.

The team are starting a feasibility study into the drug’s effect in MND patients. If this proves successful, they will look to launch a full clinical trial.

It is still unclear why motor neurons die, but experts know that a decrease in their energy production takes place at an early stage of the disease.

Motor neurons need to produce energy to carry the brain’s instructions to the muscles. If there is not enough energy, the messages cannot be transferred effectively and movement is affected.

Researchers from the University of Edinburgh, working with partners at the University of Oxford, targeted the energy production of motor neurons as a potential therapeutic strategy for treating MND.

Using terazosin, which has previously been shown to be effective at increasing energy production in models of stroke and Parkinson’s disease, the team wanted to determine if this drug could also protect motor neurons from MND.

They focused on an enzyme – an active molecule in the cells – involved in energy production called PGK1.

Zebrafish models of MND showed that either genetically increasing the amount of PGK1 in the zebrafish or treating them with terazosin to increase PGK1’s activity improved the growth of motor neurons.

Terazosin also protected motor neurons in a mouse model of MND, improving survival and delaying the progression of paralysis.

The team also grew motor neurons in a dish and demonstrated that terazosin protects these cells by increasing energy levels.

To investigate this further the teams at the Universities of Edinburgh and Oxford are inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study, which will examine the impact of terazosin on key indicators of disease progression.

The study is published in eBioMedicine. It was funded by MND Scotland and the My Name’5 Doddie Foundation.

Research at the University of Edinburgh was carried by a team at the Euan MacDonald Centre for Motor Neurone Disease, which was established by Euan MacDonald and his father Donald to improve the lives of people with MND.

Dr Helena Chaytow, senior postdoctoral researcher at University of Edinburgh’s Euan MacDonald Centre and first author of the study, said: “Our work shows that terazosin is protective of motor neuron cell death in multiple models of MND, making it an exciting new potential therapy. The benefit of working with terazosin is that it is already prescribed for a different health condition, so we know that it is safe for humans and could quickly move to the clinic.”

Professor Tom Gillingwater, Professor of Anatomy at University of Edinburgh’s Euan MacDonald Centre and study co-lead, said: “We are excited about the potential for terazosin to impact on the breakdown of motor neurons in MND. The current work illustrates the importance of bringing together scientists and clinicians in order to identify new targets for therapy suitable for taking forward into studies in human MND patients”

Professor Kevin Talbot, Professor of Motor Neuron Biology at the University of Oxford and study co-lead, said: “We urgently need to accelerate the way drugs are developed from laboratory models into trials in patients. Our work uses a combination of approaches to increase the confidence that drugs will actually work in people with MND and significantly slow disease progression. It represents an important new step in the search for therapies.”

Dr Jane Haley MBE, Director of Research for MND Scotland, said: “As key funders of this research study, we are delighted to see a potential new therapy for MND on the horizon. After testing in a range of models, the results of this study show us that terazosin, a drug currently used to treat enlarged prostates and high blood pressure, may be able to protect motor neurons.

We are delighted that, as a result, the drug will move to a feasibility study in Oxford, involving people living with MND. This is a wonderful example of researchers, clinicians and MND charities working together to try and speed up the search for new treatments for MND – because it’s about time we found a cure.”

Jill Douglas, CEO of My Name’5 Doddie Foundation, said: “The Foundation is encouraged that the collaborative nature of this work will aid translation from the lab to the clinic – it means that basic scientific research will be more meaningful in clinical practice. We are proud to have supported this collaboration and are continuing to support the first clinical trial of terazosin in people living with MND.”


Neuroprotection

Neuroprotective strategies are explored to protect the retina from degeneration in eye pathologies such as glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa.[20] In a coincidence seen as a result of these investigations, the retina appeared to prevent or delay neuroprotection and neuronal cell death.

After the initial movement of the retina, it appears to maintain its neural function and thus has a defense mechanism designed to block vision loss. There is also the effect of neuroprotection to acute brain damage. Neuroprotective strategies that limit secondary tissue loss or improve functional outcomes are identified in multiple animal models of cerebral lesions with no ischemic, hemorrhagic, and traumatic effects.

This potential intervention has been attempted to be used in randomized controlled trials in humans, but these studies have unfortunately yielded negative results.[21,22] Neuroprotection has been the center of attention because it stands out in the fight against diseases. Based on this popularity, some research has focused on determining whether several natural compounds, called nutraceuticals, can perform neuroprotective actions in the developing, adult, and aging nervous system.[13]

A polyphenol called quercetin, commonly found in nature, has attracted the most attention in this regard. A study conducted in a laboratory environment have revealed evidence in animals and humans that quercetin is supportive of neuroprotective effects against neurotoxic chemicals or in various patterns of neuronal damage and neurodegenerative diseases.

In a coducted study, when investigating the neuroprotective effect of oxygen, basically results related to stroke and TBH, and the oxygen paradigm revealed difference between experiments. Consequently, this study reviewed current comparative clinical trials of oxygen treatment among injuries in the nervous system.[23]

The study aims to compare the efficacy and safety of normobaric oxygen and hyperbaric oxygen in the case of stroke and TBI. It could clarify the function of oxygen treatment in different nervous system injuries and give an overall view of oxygen in neuroprotection, which is thought to be a good indicator in clinical applications. To summarize, neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide, and their incidence increases dramatically with increased life expectancy.

These diseases often cause deficiencies in certain brain functions, and these are a heterogeneous group of chronic progressive disorders characterized by gradual neuron loss in the central nervous system. Alzheimer’s disease (AD), PD, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington’s disease are the most common neurodegenerative diseases. The etiology of most neurodegenerative diseases is mainly unknown, but it is widely accepted that they share the common molecules and cellular properties that contribute to the advances of these disorders.[24]

AlphA Blocker

Alpha blockers prevent plain muscle contraction and inhibit smooth muscle by binding to alpha-1 adrenergic receptors. Benign prostatic hyperplasia and hypertension are among the major uses of alpha blockers. Terazosin is an example of an alpha-1 adrenergic receptor blocker. Venous capacitance increases in use for the treatment of hypertension, which then results in a drop in blood pressure. However, alpha blockers are not recommended for hypertension today, so they are not used as monotherapy.

In the treatment of benign prostatic hyperplasia, alpha blockers are used to cause smooth muscle relaxation in the bladder, prostate, neck, and arterioles and are therefore used to treat urinary blockage symptoms. However, based on the detriment of alpha blockers, there has been an increase in heart failure, stroke, and cardiovascular disease.[25] A study attempted to evaluate the effects of alpha blockers, rather than the standard treatment, in adult people showing symptoms of urethral stone disease to examine the efficacy of medical expulsive therapy, which is commonly used to improve the stone passage of 1 cm or smaller ureter stones.[26] It was observed that alpha blockers increase stone clearance but slightly increase the risk of severe side effects, and it was concluded that they are less effective in 5 mm stones or stones smaller or larger than 5 mm stones.

Terazosin and Parkubson’s disease


Parkinson’s disease, with close to six million people affected worldwide, is the second most common neurodegenerative disease. There has been a significant increase in PD cases over the past 30 years, and the rate of illness has increased as age progresses. Patients with PD also have difficulty with motor symptoms, such as slow movements, tremors, along with neuropsychiatric abnormalities.[35,36] Terazosin studies in China have shown that it is activated by binding to the enzyme phosphoglycerate kinase 1 (PGK1), which is involved in the making of adenosine triphosphate (ATP), and the activation of PGK1 increases the ATP levels.

The TZ’s 2,4-diamino-6,7 methoxyisoquinazoline structure binds to PGK1 during adenosine diphosphate (ADP)-ATP binding. In this case, TZ increases PGK1, the ATP level rises, and apoptosis is inhibited. The increase in PGK1 by TZ in PD brought to mind whether there could be a condition slowing or preventing apoptotic neurodegeneration. Studies have been conducted in mice, rats, flies, and induced human stem cells to find the answer to this question.[37] It was observed that TZ reduces neurodegeneration caused by 1-methyl-4-phenyl- 1,2,5,6-tetrahydropyridine (MPTP) in mice. Adenosine triphosphate levels are reduced in human, monkey, and mouse models by MPTP, enabling PD formation with dopaminergic neuron loss.

Terazosin’s prevention of ATP decline allowed PD formation to slow as well.[37,38] Oxidopamine or 6-hydroxydopamine (6-OHDA), known for attention deficit and hyperactivity disorder, consumes immune activity in the middle brain in mice and rats, causing neurological diseases such as PD. Studies aimed to measure the effect of TZ after the induction of PD symptoms by injecting 6-OHDA into rats, and it was found that PGK1 activity along with TZ slowed neurodegeneration in rats.[37,39] Rotenone is a natural compound that consists of the roots of some tropical plants, and it causes symptoms of PD in rats and flies. Phosphoglycerate kinase 1 increase was observed by alleviating rotenone- induced neurodegeneration when the flies were given rotenone and then treated with TZ.[37,40] All of these studies support the idea that TZ can slow down PD.[37] Most neurodegenerative diseases occur as a result of the overwhelming activation of cell death. Since it is known to prolong apoptosis in studies on TZ, similar experiments have been carried out in sepsis- modeled organisms, and it has been observed that organ damage is minimized because it inhibits apoptosis. It is understood that TZ confers stress resistance by activating PGK1 and heat shock protein 90(HSP90). Terazosininteracts with PGK1 and causes an increase in ATP. As observed in studies, PGK1 regulates ATP increase by interacting with HSP90 ATPase.[10]

In conclusion, TZ, which is an alpha-1 antagonist, is used for the treatment of hypertension and BPH. Especially for BPH, it is the first choice in drug treatment. There was a considerable reduction in the number of patients undergoing surgery after TZ was administered as a medication in BPH patients. As a result of recent studies, the effectiveness of TZ on neurodegenerative diseases has also been proven. Especially in experiments on PD, it has been proven to reduce PD symptoms by inhibiting apoptosis. It is thought that TZ may also be effective on AD, a disease of the same scope as PD in terms of tissue damage size and formation. Terazosin interacts with the causative mechanism of many diseases, providing hope and welfare to patients.

doi: 10.5606/dsufnjt.2021.022


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. EBioMedicine

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