Can Terazosin be Repurposed to Treat ALS?

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There were 35 clinical trial of Terazosin, most recents are related to various neurodegenerative diseases. enter image description here

Terazosin, is normally used to treat symptoms of a (non cancerous) enlarged prostate and high blood pressure. It was recently discovered to increase energy levels (in the form of ATP molecules) in the brain by enhancing glycolysis.

Hypertension is prevalent in obese and diabetic patients. As soon as 1991, scientists hypothesized that people with hypertension are also likely to suffer from insulin resistance, glucose intolerance, and hyperinsulinemia.

They noted that commonly used antihypertensive agents, such as thiazide, thiazide-like diuretics, and beta-blockers, are associated with glucose intolerance and increased insulin resistance. In contrast, angiotensin-converting enzyme inhibitors, calcium antagonists, and peripheral alpha-blockers (such as prazosin and terazosin) do not adversely affect glucose tolerance or insulin sensitivity.

Yet Terazosin is not without side effects: Orthostatic hypotension, asthenia, dizziness, faintness and syncope.

Insulin stimulates glycolysis. glycolysis is an anaerobic pathway to make ATP (as opposed to the usual Krebs-cycle way, the citric acid cycle and oxidative phosphorylation).

Fixing the underlying insulin resistance would be nice, but we don't actually understand the biochemical mechanisms behind it enough to do that directly yet. Metformin is probably the closest thing, and it has several other beneficial effects as well, but we don't really understand its mechanism(s) of action either.

In 2019 Terazosin suddenly leapt into a growing pool of drugs that might have a repurposed role in Parkinson’s disease, such as exenatide, salbutamol, ursodeoxycholic acid, nilotinib, deferiprone, and ambroxol.

An article with contributors from many laboratories tell that as Terazosin stimulates glycolysis and increases cellular ATP levels, it may change the course of Parkinson’s disease. In toxin-induced and genetic Parkinson's disease models in mice, rats, flies, and induced pluripotent stem cells, Terazosin increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function.

The scientists also interrogated 2 distinct human databases and found slower disease progression, decreased Parkinson's disease-related complications, and a reduced frequency of Parkinson's disease diagnoses in individuals taking Terazosin and related drugs.

So other teams of scientists tried to replicate this success with other neurodegenerative diseases, including ALS.

In this later case, they increased activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) using Terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.

The scientists found that targeting PGK1, indeed modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour.

Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, Terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.

The team is now inviting 50 patients from the Oxford MND Care and Research Centre to participate in a feasibility study to examine the impact of terazosin on key indicators of disease progression. If this proves successful and if they find financial sponsors, they will look to move forward into a full clinical trial.

As usual, ALS mice models are not realistic, they live only 25 days when an healthy mouse lives 2 years (30 times more). As ALS in humans strikes mostly after 50 years old, a realistic mice model should live 14 months before being ill. Indeed this would create insanely long experiments, slow publication rates, and it would be costly. As in the old joke, scientists prefer to look where it's easy even if they know that current neurodegenerative diseases mice models are useless.

Let's cross our fingers, who knows, this time it may work.

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