- Could A New, Better Drug For Bipolar Disorder Be On The Way?
- 4 Potential Uses of Ebselen + Side Effects & Dosage
- What Is Ebselen?
- Mechanism of Action
- Potential Uses of Ebselen
- 1) Stroke Recovery
- 2) Bipolar Disorder
- 3) Noise-Induced Hearing Loss
- 4) Impulsivity
- Animal and Cellular Research (Lacking Evidence)
- 5) Alzheimer’s Disease
- 6) Arthritis
- 7) Diabetes
- 8) Osteoporosis
- 9) Cancer
- Chemotherapy Side Effects
- 10) Inflammation
- 11) Liver Damage
- 12) Reproductive Health
- Limitations and Caveats
- Side Effects and Precautions
- Drug Interactions
- A safe lithium mimetic for bipolar disorder
- New drug for bipolar disorder may offer fewer side effects
- The Weirdness of Ebselen
Could A New, Better Drug For Bipolar Disorder Be On The Way?
LONDON, Jan 8 (Reuters) – A drug for bipolar disorder that works lithium – the most common and effective treatment – but without lithium's side-effects has been identified by British researchers in tests on mice.
Scientists say the drug, ebselen, may be a swift answer to long-sought after better medications for patients with the manic depressive disorder, since it is already known to be safe.
If the drug could be “repurposed” and licensed for the treatment of bipolar disorder, it could reduce the unpleasant side effects of weight gain, thirst and potential kidney damage that patients risk when taking lithium.
“Ebselen is an experimental drug that has been tested in people for other conditions, and does not have problematic side effects lithium does,” said Grant Churchill of the department of pharmacology at Britain's Oxford University.
Bipolar disorder effects around 1 percent of the population worldwide and sufferers can experience moods that swing from one extreme to another, and have periods of depression and mania lasting several weeks or longer. These high and low phases are often so extreme they interfere with everyday life and work.
In a telephone interview Churchill said that in tests, his team found that mice who were made manic with small doses of amphetamines were able to be calmed again with ebselen.
“In mice, ebselen works lithium,” Churchill said. “Now we urgently need to see if it works lithium in people.”
Some 60 years after it was first discovered, lithium – a mood stabiliser that can protect against both depression and mania, and reduce the risk of suicide – remains the most effective long-term treatment.
But it is very toxic – at only twice the right dose it could kill a patient, Churchill said – and its adverse side-effects mean many people stop taking the drug and relapse into episodes of mania and depression.
Churchill worked with Sridhar Vasudevan to filter through a library of existing drugs – the U.S. National Institutes of Health Clinical Collection – that are considered safe but do not currently have a proven use.
They screened the library for any drugs that blocked an enzyme that is key to lithium's success and found ebselen was a possible lithium mimic.
“This is one of the first handful of examples of drug repurposing, where a new use has been found for an existing drug,” Vasudevan said.
Ebselen is an antioxidant originally developed up to late stage, or phase III, clinical trials by the Japanese firm Daiichi Sankyo for the treatment of stroke, but which never reached market and is now patent.
Vasudevan said his study, reported in the journal Nature Communications, showed ebselen had the same or similar action as lithium in the brains of mice, blocking the same enzyme.
The researchers are a now starting a small study in healthy human volunteers to look for effects on brain function. If that shows ebselen has similar effects to lithium, they plan to move to second stage trial in bipolar patients. (Editing by Pravin Char)
4 Potential Uses of Ebselen + Side Effects & Dosage
Ebselen is a research substance that contains selenium and has anti-inflammatory and antioxidant properties. Scientists have examined it in clinical trials as a potential treatment for bipolar disorder and stroke, but the available evidence is inconclusive. Keep reading to find out more about the potential uses, side effects, and dosage of ebselen.
Disclaimer: This post is not a recommendation or endorsement for ebselen. It’s still not FDA-approved for any medical condition. We have written this post for informational purposes only, and our goal is to inform people about the science behind ebselen’s effects, mechanisms, and potential medical uses.
What Is Ebselen?
Ebselen is a research substance containing the element selenium .
It has multiple effects on the body, such as preventing inflammation and oxidative stress .
Ebselen was initially tested as a treatment for stroke and is now under investigation in a clinical trial as a potential treatment for bipolar disorder [3, 4, 5].
Mechanism of Action
Oxidants (hydroxyl radicals and hydrogen peroxide) can damage proteins, fats, and DNA. This speeds up aging and leads to age-related diseases, including stroke heart disease, Parkinson’s and Alzheimer’s disease .
Ebselen blocks the activity of oxidants and reduces cell damage via multiple mechanisms:
- Mimics activity of an antioxidant enzyme (glutathione peroxidase): Ebselen converts harmful products made by oxidants back to harmless products (such as converting selenic acid to selenol). It also converts oxidants, such as hydrogen peroxide to water .
- Prevents cell death (apoptosis) caused by injury or toxic exposure by blocking proteins involved in apoptosis (thiol groups) .
- Crosses the blood-brain barrier and blocks an enzyme in the brain involved in the breakdown of acetylcholine (acetylcholinesterase), which may improve memory [2, 6].
- Irreversibly blocks an enzyme involved in cell communication and growth (Inositol Monophosphatase) in a similar way to lithium (approved treatment for bipolar disorder) .
- Prevents the spread of brain cancer cells (glioblastoma cells) by [7, 8].
- Decreases the production of pro-inflammatory compounds (cytokines IL-6, IL-8)
- Prevents iron overload in the heart, a major cause of heart failure .
- Decreases the production of proteins involved in Alzheimer’s disease (amyloid precursor protein and β-secretase) and reduces toxic protein accumulation (amyloid plaques) in the brain .
- Increases serotonin production .
Potential Uses of Ebselen
Ebselen has been studied for different health conditions. However, keep in mind that the evidence supporting these potential applications is still preliminary, and a lot more additional research is needed before they are approved. Therefore, take all of the information below with a grain of salt.
1) Stroke Recovery
In a study, 300 stroke patients were given either ebselen or placebo for 2-weeks. Ebselen greatly improved stroke symptoms compared to placebo after 1 month, if patients received it within 24 hours of the stroke .
In two other studies, ebselen reduced brain damage from a stroke (ischemic and hemorrhagic stroke). The effect was greater if the patients received ebselen within 6 hours of the stroke [12, 13].
In a study, 286 stroke patients received either ebselen or placebo for 2 weeks. Ebselen prevented brain damage from stroke 2 weeks, 1 month, and 3 months after treatment .
Intravenous ebselen decreased damage to gray and white matter in mice with stroke by reducing the damage caused by oxidants (free radical species) in the brain [14, 12].
In rabbits, ebselen protected the brain from damage when it was given shortly after stroke .
2) Bipolar Disorder
Lithium is an effective treatment for bipolar disorder but has unwanted side effects and can be toxic even with normal doses .
In the first study of 16 healthy participants, ebselen mimicked the effects of lithium in the brain (by reducing levels of an enzyme, inositol monophosphatase). It also increased the recognition of emotions disgust and happiness, reduced impulsivity, and improved decision-making, all important for bipolar disorder .
In another study of 20 healthy participants, ebselen reduced the glutamate and the enzyme Inositol Monophosphatase in the brain in a similar way to lithium .
Ebselen increased the recognition of positive emotions and decreased impulsive behavior in a study on 20 healthy participants, highlighting its potential to be used for bipolar disorder .
3) Noise-Induced Hearing Loss
In a study, 83 healthy adults received ebselen at 200 mg, 400 mg, and 600 mg or placebo twice daily for 4 days before listening to music for 4 hours. Ebselen prevented noise-induced hearing loss better than placebo, with the most effective dosage being 400 mg .
In rats, treatment with ebselen before and immediately after exposure to noise decreased the loss of sound-sensing cells of the ear and prevented hearing loss [19, 20].
Ebselen decreased impulsive actions during a gambling task in a study on 20 healthy participants. The treated participants recognized positive emotions more than negative emotions, suggesting that ebselen may be used in impulsive and mood disorders .
Animal and Cellular Research (Lacking Evidence)
No clinical evidence supports the use of ebselen for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based studies; they should guide further investigational efforts, but should not be interpreted as supportive of any health benefit.
5) Alzheimer’s Disease
Ebselen shows potential both for the prevention and treatment of memory impairment diseases. In mice with symptoms of Alzheimer’s disease, ebselen improved learning and memory [22, 10].
An imbalance between antioxidants and oxidants is another early marker of Alzheimer’s disease. Ebselen decreased oxidative stress in mice. It also decreased the production of toxic proteins in the brain (by reducing the compounds needed to make Aβ proteins) .
Ebselen decreased the movement of white blood cells (polymorphonuclear leukocytes, T-lymphocytes) to joints and reduce inflammation in rats. These effects may be beneficial in treating arthritis, where joint inflammation can cause serious damage [23, 24, 25].
Diabetes can lead to various complications, including hardening of arteries (atherosclerosis) and kidney damage .
In mice with diabetes, ebselen protected against artery hardening and kidney damage by reducing oxidative stress [27, 28].
Osteoporosis is a disease where bones become fragile and more susceptible to damage.
In mice, ebselen reduced the breakdown of bone tissue by decreasing the production of cells that degrade bones .
Ebselen reduced tumor growth by a remarkable 58% in mice with human pancreatic tumors .
In breast cancer cells, the use of ebselen and radiation therapy increased cancer cell death and stopped cancer progression .
It also decreased tumor growth and invasion in kidney and pancreatic cancer cells [32, 30].
Chemotherapy Side Effects
In rats, ebselen reduced toxicity in the kidneys caused by cisplatin, a type of chemotherapy. Cisplatin reduces the kidneys’ antioxidant defense, which ebselen helps to restore [33, 34].
Still, these results do not support the actual anticancer effects in humans. At this point, ebselen can’t be recommended for cancer prevention or treatment.
Ebselen prevented fluid buildup in the lungs and reduce inflammation of the lungs and airways (bronchi) in rats and mice [35, 36, 37, 38].
It reduced inflammation in muscles and restored the function of small blood vessels in rats .
11) Liver Damage
Ebselen prevented liver injury caused by a bacterial toxin (staphylococcal enterotoxin B) by reducing inflammation and cell death in mice .
In multiple rat studies, ebselen prevented:
- Alcohol-induced liver damage by reducing oxidative stress and inflammation .
- Liver injury caused by activated liver immune cells (Kupffer cells) by decreasing the production of pro-inflammatory cytokines and oxidants [42, 43].
- Bile acid-induced liver injury .
12) Reproductive Health
Excess manganese increases sperm abnormalities and decreases sperm motility and count. It also reduces the levels of testosterone and luteinizing hormone. In rats, ebselen reversed the toxic effects of manganese on male fertility, thus protecting male reproductive organs .
It reduced cadmium-induced damage to testes in mice by decreasing oxidative stress .
In roundworms, ebselen was effective in treating a drug-resistant bacterial infection (MRSA) better than current antibiotics (vancomycin and linezolid). It also increased the effects of antibiotics, helping to combat the infection [47, 48].
In test tubes, ebselen was effective in rapidly killing fungi within 2 hours of treatment, including :
- Cryptococcus, which can be especially dangerous in people with a very weak immune response
It was more effective than common antifungal drugs (fluconazole, flucytosine, and amphotericin) in killing fungi in roundworms .
In cells, ebselen blocked the activity of the following viruses [50, 51]:
- Herpes simplex type 1, which causes cold sores and genital herpes
- Hepatitis C
- Vesicular stomatitis virus, which humans often contract from animals
Limitations and Caveats
Most studies on ebselen were done on animals.
There have been few clinical trials performed to test this drug. They were small-scale and most have not moved past phase 1 or 2 of the drug development process [4, 18, 3, 5].
Although ebselen is a clinically safe drug, there is no real proof of use yet.
Side Effects and Precautions
Keep in mind that the safety profile of ebselen is relatively unknown, given the lack of well-designed clinical studies. The list of side effects below is not a definite one, and you should consult your doctor about other potential side effects, your health condition and possible drug or supplement interactions.
Ebselen is listed as a safe drug but without a proven use by the National Institute of Health Clinical Collection .
Few patients in clinical trials reported drowsiness .
Most clinical studies did not report any side effects [52, 53, 14, 19].
Ebselen can break down skin pigments and reduce melanin in the body, which might increase the risk of cancer .
In yeast, ebselen may damage DNA and turn off genes that help reduce the damage .
High doses of ebselen can kill specific cells (HepG2 cells, hybridoma cells) .
Ebselen causes calcium release from the mitochondria, disrupting mitochondrial function. This may result in loss of energy and quicker aging [2, 57, 58].
Drug interactions can be dangerous and, in rare cases, even life-threatening. Always consult your doctor before supplementing and let them know about all drugs and supplements you are using or considering.
In rabbits, ebselen enhanced the activity of tissue plasminogen activator (tPA), the current treatment for stroke .
Ebselen contains selenium, which can interact with different medications in various ways, listed below :
- Selenium stimulates the immune system, so drugs such as corticosteroids that suppress the immune system should be avoided.
- Selenium reduces blood clotting, so taking it with other anticoagulants aspirin can increase bruising and bleeding.
- Selenium taken with beta-carotene, Vitamin C, and Vitamin E may decrease the effectiveness of medications that lower cholesterol levels (statins and niacin).
- Selenium may slow down how fast the body breaks down sedatives, increasing their effects and side effects.
The below doses may not apply to you personally. If your doctor suggests using ebselen, work with them to find the optimal dosage according to your health condition and other factors.
The dose in patients with stroke was 150 mg of ebselen granules in water twice daily [12, 3].
For the prevention of hearing loss, patients were given 200 mg, 400 mg, or 600 mg twice daily .
Ebselen was administered as capsules at a total dose of 3600 mg in the span of 24 hours in clinical trials in healthy volunteers. This should not be taken as the therapeutic dose, as higher doses are used in healthy volunteers to investigate how safe the drug is and how it is metabolized in the body [16, 21].
A safe lithium mimetic for bipolar disorder
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New drug for bipolar disorder may offer fewer side effects
A drug that mimics the effect of lithium but without its side-effects would be a great improvement for patients, and has long been sought after.
While the study has been conducted in mice, the newly identified drug is an existing compound called ebselen. It is known to be safe in humans and so its use for bipolar disorder can begin to be tested in clinical trials straight away.
'Lithium has been used for over 60 years and remains the most effective treatment for bipolar disorder, but suffers from toxicity and has many side effects,' says co-principal investigator Dr Grant Churchill of the Department of Pharmacology at Oxford University. 'In mice, ebselen works lithium. Most importantly, ebselen is an experimental drug that has been tested in people for other conditions, and does not have problematic side effects lithium does.'
He adds: 'We urgently need to test if ebselen works lithium in people.'
The researchers report their findings in the journal Nature Communications. The work was funded by the UK Biotechnology and Biological Sciences Research Council.
Bipolar disorder is relatively common and can occur at any age. It is estimated to affect around one person in 100.
People with bipolar disorder can experience moods that swing from one extreme to another, having periods of depression and mania lasting for several weeks or longer. These phases of feeling high and low are often so extreme that they interfere with everyday life.
60 years after its discovery, lithium remains the most effective long-term therapy for bipolar disorder – it is a mood stabiliser that has been shown to protect against both depression and mania, and reduce the risk of suicide. But it is toxic at only twice the right dose and it has unpleasant side-effects, such as weight gain and thirst, and long-term use can lead to kidney damage.
A drug that worked lithium without the toxicity or side-effects would be a great improvement for patients, but efforts so far to develop such a drug have proved unsuccessful.
A lithium mimic would also lessen the burden on healthcare systems.
Lithium's toxicity means that getting the dose right is important, and several visits to the clinic may be required to get this right when the drug is initially prescribed.
Regular check-ups are required to monitor the treatment. The side-effects also mean many people stop taking the drug and can see a return of the episodes of mania and depression.
The Oxford researchers used a library of existing drugs that are considered safe but don't currently have a proven use. The US National Institutes of Health Clinical Collection includes compounds that may have been originally developed for various different diseases or conditions. These compounds have been tested in clinical trials, so their safety in humans is known.
They screened this library for any drugs that blocked an enzyme that is a prominent candidate for how lithium works in stabilising mood in bipolar disorder. In this way, they identified ebselen as a possible lithium mimic.
Ebselen is an antioxidant originally developed up to phase III clinical trials by a Japanese drug company for use in the treatment of stroke, but which never reached market and is now patent.
The researchers showed that ebselen has the same or similar action as lithium in the brains of mice, blocking the same enzyme.
They have also shown ebselen has the same effects as lithium in mouse models of bipolar disorder, dampening down this behaviour in the same way.
The researchers say the next step is to test whether ebselen has the same effects as lithium in people through appropriate clinical trials.
They are beginning a small study in healthy volunteers to look for effects on brain function. If that shows that ebselen continues to have similar effects to lithium in humans, the plan would be to move to a small phase II trial in people with bipolar disorder.
Should these prove successful, ebselen will be one of only a few examples of 'drug repurposing', where new uses are found for drug compounds originally developed for another condition but that may have failed for one reason or another.
Rather than these fully-developed compounds remaining unused on the shelf of a pharmaceutical company or academic laboratory, there have been recent moves to make such drug compounds more available for study by others to see if they might find other uses. So far, there have been only a few successes, but this work might add another.
'This is one of the first handful of examples of drug repurposing, where a new use has been found for an existing drug,' says the other lead author, Dr Sridhar Vasudevan of the Department of Pharmacology at Oxford University.
The Oxford researchers have obtained a patent for the use of ebselen in bipolar disorder through Isis Innovation, the technology transfer company of Oxford University.
The Weirdness of Ebselen
I think that most medicinal chemists look at the structure of ebselen and say “That’s not a drug”. Selenium atoms don’t belong in drugs, we figure, and Se-N bonds most certainly don’t.
But it stands as a rebuke to our intuitions, because it’s been kicking around in the clinic for some time (and has certainly looked more interesting there than a lot of stuff that I’ve worked on over the years).
One recent application has been treatment of Clostridium infection. In 2015 it was reported that ebselen could be an antivirulence agent, and a mechanism was proposed where it affected the cysteine protease activity in the autoprocessing of the Toxin B virulence factor.
That’s quite plausible, because (as you might well expect) ebselen is known for hitting Cys residues and inactivating them, which accounts for the weird variety of conditions and targets it’s been studied against over the years.
The screen was for autoprocessing inhibitors, and ebselen bubbled to the top quickly.
Now comes word that further study has made things a bit more complicated. This new work took advantage of a Toxin B construct that had all of its Cys residues mutated, and you would expect ebselen to be pretty much useless in that situation.
But it was equipotent versus wild-type and “de-Cys-ified” protein, which takes care of that theory. Moving to another domain of Toxin B, though, it appears that ebselen may be doing its work on the toxin’s glucosyltransferase activity.
The human target of that activity is a GTPase protein called Rac1, and ebselen covalently modifies its three cysteines, which makes it no longer a substrate.
So far, so good: but the 2015 paper had specifically reported that ebselen didn’t have an effect on the glucosyltransferase function. The authors dug down into the details:
To reconcile these conflicting findings, we evaluated all aspects of the two studies to find any differences between our methodologies that might account for the discrepancies in our results.
The answer turned out to be that the reducing agent dithiothreitol (DTT), which removes ebselen from Cys side chains, was included by Bender et al. in their assay of GTD activity, but not in their assay of APD activity (1).
To demonstrate this, we tested inhibition of APD by ebselen in the absence and presence of DTT and saw that inclusion of DTT completely abrogated inhibition by ebselen (Fig. 1G). Similarly, addition of DTT to ebselen-labeled Rac1 relieved the inhibition of GTD activity (fig. S1).
Thus, in the absence of DTT, ebselen can covalently inhibit both the APD and the GTD; however, as outlined above, on the basis of its ability to protect cells from intoxication by wild-type and Cys-less TcdB equally, it is not the APD inhibition that is responsible for the protective effects of ebselen.
There you go – if your mechanism of action depends on messing with Cys residues, the temptation is to make sure that you’ve added DTT to ensure that they’re all reduced and ready, but in this case, that same reagent is also wiping out the effects of the compound under study. This would seem to nail down ebselen’s activity against C. dificile toxin, but given the way that it hits proteins from every direction, it’s going to be hard to say when this story is over.
As everyone who’s worked on the compound knows, that also complicates its potential clinical development.
Ebselen has been in clinical trials for stroke, and it’s being looked at now for bipolar disorder, suggested for use against osteoporosis, as an antifungal, and many more applications.
Normally, one would get a bad feeling about a compound that seems to hit so many things (witness the curcumin story from the other day), but ebselen appears to be more real, although still a very hard candidate to develop. We’ll see if it ever finds a home!