How do statins work?

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We all know that statins are used as cholesterol lowering drugs. They are on trial for progressive MS. However the questions arises….If they work, how do statins work in progressive MS?

If the answer is “I don’t know”….it is becuase the listener thinks that it is a trick question?

They should say it is an HMG-CoA inhibitor and it blocks the conversion of HMG-Co-A into mevalonic acid in the cholesterol synthesis pathway and therefore stops the the production of cholesterol……..you daft bugger.

However they sometimes don’t and squirm

HMG-CoA - Wikipedia

Believe it on not we did the pioneering work on Statins with Prof Greenwood. This was long before Sir Jeremy and Prof Greenword got together to do the MS-STAT trial that show a slowing of brain volume loss.

We started with the view was that prenylated proteins, the PPs in the above pathway, where important entities and the cholesterol was not important. Indeed if we blocked the production of squalene, which is above cholesterol in the pathway and so blocks cholesterol but leaves the rest of the pathway intact, there was no inhibition in the assays we were using. This says the important molecule wasn’t cholesterol. We showed the PP proteins were used to allow the blood vessel walls to re-arrange their cell skeletons (called actin) to allow white blood cells to get into the brain…. Block this and the cells can’t get into the brain and disease was held in check.

However the T cell immunologists said it was because they changed the cytokine balance of T cells….Yawn. But when it is a “big swinger” (Big swinging another word for Richard) who says this, the World thinks that is true. However, it was obvious to us that this was not the problem. Because you stopped the dug and disease came back as quick as it left the body which it would not have done if it was working by a cytokine balance

However, a trial in relapsing MS was done and it did not succeed again. You now have to ask why does it potentially work in progressive MS?

I asked this question of the MS-STAT2 scientists and won’t tell you the answers that they gave, but they did not come up with this one.

The cholesterol pathway way is the most dysregulated pathways in progressive EAE and MS and in Alzheimers. But before I knew this and anything about the oxysterols

I saw a study by Prof Lizard a lipid biologist and contacted him about doing a study with a potassium channel modulating drug that would block oligodendrocyte and potential neurotoxicity caused by the oxysterol pathway. These come from the sterols (see pathway above). At this point I realised the oxysterols would be inhibited by statins.

Oxysterols are a product of the cholesterol pathway. We tried a few times to get support for this by putting grants into French grant funding agencies. Prof Lizard had no track record in multiple sclerosis and found no support in France, we tried to help get support for the person who did the original work in the Lizard lab and had no joy. We also tried the UK to put cash into the labs in France and again no interest. So that’s where it stopped..You can only try so many times before you more on. They would have looked at my favoured potassium channel as well as their favoured potassium channel as a way to stop oligodendrocyte damage. I am still trying to get this approached funded.

I have just seen this paper

Vejux A, Ghzaiel I, Nury T, Schneider V, Charrière K, Sghaier R, Zarrouk A, Leoni V, Moreau T, Lizard G. Oxysterols and Multiple Sclerosis: physiopathology, evolutive biomarkers and therapeutic strategy. J Steroid Biochem Mol Biol. 2021 Mar 5:105870. doi: 10.1016/j.jsbmb.2021.105870 Multiple sclerosis is an autoimmune disease that affects the central nervous system. Dysfunction of the immune system leads to lesions that cause motor, sensory, cognitive, visual and/or sphincter disturbances. In the long term, these disorders can progress towards an irreversible handicap. The diagnosis takes time because there are no specific criteria to diagnose multiple sclerosis. To realize the diagnosis, a combination of clinical, biological, and radiological arguments is therefore required. Hence, there is a need to identify multiple sclerosis biomarkers. Some biomarkers target immunity through the detection of oligoclonal bands, the measurement of the IgG index and cytokines. During the physiopathological process, the blood-brain barrier can be broken, and this event can be identified by measuring metalloproteinase activity and diffusion of gadolinium in the brain by magnetic resonance imaging. Markers of demyelination and of astrocyte and microglial activity may also be of interest as well as markers of neuronal damage and mitochondrial status. The measurement of different lipids in the plasma and cerebrospinal fluid can also provide suitable information. These different lipids include fatty acids, fatty acid peroxidation products, phospholipids as well as oxidized derivatives of cholesterol (oxysterols). Oxysterols could constitute new biomarkers providing information on the form of multiple sclerosis, the outcome of the disease and the answer to treatment.

I was delighted to see the paper above by Prof Lizard, putting his ideas in the context of MS. Here he is looking at oxysterols as a marker of disease activity in MS and maybe he will get some funding. Sadly it is not viewing them as a useful target to inhibit. Maybe we were just before our time. In a search for new targets for progressive MS it is amazing that the potassium channels were totally ignored.

Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis.Cunniffe N, Vuong KA, Ainslie D, Baker D, Beveridge J, Bickley S, Camilleri P, Craner M, Fitzgerald D, de la Fuente AG, Giovannoni G, Gray E, Hazlehurst L, Kapoor R, Kaur R, Kozlowski D, Lumicisi B, Mahad D, Neumann B, Palmer A, Peruzzotti-Jametti L, Pluchino S, Robertson J, Rothaul A, Shellard L, Smith KJ, Wilkins A, Williams A, Coles A.J Neurol Neurosurg Psychiatry. 2021;92(3):295-302

P.S. I kept it secret as there are no licenced drugs for my target

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MouseDoctor

27 comments

  • Hi MouseDoctor,

    This is a great article but some bits are garbled. You need to re-read and check what you’ve written before posting it.

    “We all know that statins are used as cholesterol lowing drugs.” – lowing is what cows do.

    “it is becuase the listener think, it is a trick question?” – becuase? the listener think? either ‘the listeners think’ or the ‘listener thinks’, but not ‘the listener think’, that doesn’t make sense.

    “Believe it on not we did the pioneering work on Statins with Prof Greenwood which was long before Sire Jermeny and ProfGreenword got together” – Prof. Greenwood’s name seems to be unstable.

    “Indeed if we blocked squalene which is above cholesterol in the pathway and there was no inhibition in the assyas were were looking at.” – this sentence is too garbled to make sense, there is no follow-on from the ‘if’, and ‘were were’ doesn’t make sense.

    Please do proof-read your excellent articles before posting them. They will be much more impressive if they make sense, and will – if they make sense – not bring the admirable Barts MS research venture into disrepute.

    • Please remember that MD is dyslexic.
      Also that many of us rely on his posts as some of the most informative. Also he hardly ever fails to post on breaking news, latest studies etc. It might take a little effort to decipher some bits, but is worth it.
      He’s a cracking sense of humour too!

    • “…not bring the admirable Barts MS research venture into disrepute”.

      It’s a bit late for that 😉

  • I believe STAT2 still recruiting if any readers in the UK are interested.
    Guess there are also a few people taking simvastatin 80mg off-label since STAT1 published. Kinda thinking about doing this myself (unfortunately I don’t qualify for trial), not worried about side effects as such, it’s more the long-term effects of not producing cholesterol I wonder about?

    Re
    P.S. I kept it secret as there are no licenced drugs for my target

    Yep, difficult to repurpose a drug that doesn’t exist!

    • PCSK9 inhibitors were discovered through identifying a couple of people who had almost 0 cholesterol which led to identification of a genetic mutation. They had no long term effects from very low cholesterol levels.

    • The problem I have with STAT2 is on what basis is the 80mg dose selected? It is a high dose and comes with side effects, they have not looked at the usual 20mg dose with reduce side effects. If this was a pharma trial they would not get away with this.

      If we were desinging a poly pill I guss statins would have beenpresent. The best rial would be to compare simvastatin with pravastatin, the latter does not cross the blood brain barrier

      • If you’re treating heart disease risk, atorvastatin 20mg is the starting dose, or Simvastatin 40mg. If you then consider the dose/response curve, Simvastatin 80mg is only one dose up from standard baseline. Fortunately, there aren’t many doctors who think they can justify doses of 60mg.

        • The thing with statin dose response curves in terms of cholesterol reduction is the that are really flat, meaning you get about 80% of the cholesterol lowering effects with 50% of maximal dose. So if you don’t achieve a reasonable response with the starting dose, not a lot more is achieved by increasing the statin dose. However, that doesn’t necessarily mean that it would be the same for the other effects that statins have been shown to have.

  • What spelling mistakes? 😉

    We can always do back to the posts and edit, I usually go back to posts once they appear and re read but have been busy.

    Check before posting….at 1.00-3.00 when they are being written, bed is more appealing than proof reading

  • It’s very special MD Speak. We all enjoy decoding it and his quality posts; something to do during lockdown after finishing the Xword. Respect MD.

    • Cunncliffe report where they were selecting drugs for progressive MS looks at metformin….However Cambridge have given you an easy to digest explanation in that metformin is a rejuvenating agent. In the paper they talk about making the oligo precurosrs young but in the sam paper the old macrophages become young. So if this is the case then there is a human experiment. COVID-19 severity is related to age (FACT old people suffer), Old people do not repair as quick as young people [FACT] they will have old macrophages. [FACT] Macrophages are important for COVID-19 virus elimate [MD hypothesis]. Obsetity is risk factor for covid-19 [Fact] Some type II diabetic people take metformin [Fact]. Therefore people on metformin should do better than people who do not. Literature search people on metoformin particulalrly females do better with COVID

      • Metformin longevity benefits are reversed with age

        The research team led by Dr. Ermolaeva found that the very same metformin treatment that prolonged life when C. elegans worms were treated at young age, was highly toxic when animals of old age were treated. Up to 80% of the population treated at old age were killed by metformin within the first 24 hours of treatment. Consistently, human primary cells demonstrated a progressive decrease in metformin tolerance as they approached replicative senescence. The researchers were able to link this detrimental phenotype to the reduced ability of old cells and old nematodes to adapt to metabolic stressors like metformin. Under these circumstances, the exact same dose of the drug that increased longevity of young-treated organisms by triggering adaptive stress responses was harmful in animals treated at old age, which were unable to activate such protective signals.

        Rapamycin alleviates metformin toxicity

        Using proteome and lipid metabolism analysis, the team showed that metformin treatment initiated at an advanced age induces a cascade of metabolic failures culminating in lethal mitochondrial decline, exhaustion of ATP and ultimately in cell death. Interestingly, the toxic effect of metformin in old animals was reduced by simultaneous administration of rapamycin, an immunosuppressive drug found by the authors to stabilize the ATP levels in metformin-treated cells—a possibility to alleviate metformin toxicity in older organisms and advance the idea of metformin as an anti-aging drug.

        “Our study, performed in C. elegans and human primary fibroblasts shows that there is an age-related decrease in metformin tolerance, which in later life leads to toxicity of all metformin doses tested. This shows possible safety risks of late life administration of metformin to individuals without diabetes,” explains Ermolaeva. “Our data raises serious questions about the suitability of metformin as an anti-aging drug for older individuals without diabetes,” says Dr. Ermolaeva about the results.

        This work links the reversal of metformin benefits in late life to a decline of key metabolic activities (mitochondria, glycolysis, lipid turnover) in old animals, describing the unique molecular and genetic mechanism of the age-specific adverse effects of metformin. It underlines the emerging importance of personalized approaches to longevity treatments and warrants further detailed studies in mammals to probe the suitability of metformin as an intervention to promote healthy aging in non-diabetic humans.

        https://medicalxpress.com/news/2020-11-age-decisive-positive-negative-effects.htmlF

          • This ties toghether the metabolic pathway which rapamycin is a key modulator, and also a anti ageing drug

            We identify cellular senescence occurring in neural progenitor
            cells (NPCs) from primary progressive multiple sclerosis (PPMS).
            In this study, senescent progenitor cells were identified within
            demyelinated white matter lesions in progressive MS (PMS)
            autopsy tissue, and induced pluripotent stem-derived NPCs
            from patients with PPMS were found to express cellular senescence
            markers compared with age-matched control NPCs.
            Reversal of this cellular senescence phenotype, by treatment
            with rapamycin, restored PPMS NPC-mediated support for oligodendrocyte
            (OL) maturation. Proteomic and histological
            analyses identify senescent progenitor cells in PMS as a source
            of high-mobility group box-1, which limits maturation and
            promotes transcriptomic changes in OLs. These findings provide
            evidence that cellular senescence is an active process in
            PMS that may contribute to limited remyelination in disease

            Cellular senescence in progenitor cells contributes to
            diminished remyelination potential in progressive
            multiple sclerosis

            https://www.pnas.org/content/116/18/9030

            Now Rapamycin its fasting on steroids

            Can fastinng alone induce these phenotypes?

  • Is an anti-oxydant in that case more effective in treating the secondary progressive phase of the disease ?

        • Good point I remember having this argument for months me saying DMF doesnt get in the brain…but I think they showed that monomethyl fumarate the active metabolite of DMF got into the brain.

  • Statins aren’t used to treat cholesterol per se, they are typically used to treat cardiovascular event risk. Given that studies showing reduction of cholesterol from non-statins generally haven’t shown the same reduction in cardiovascular end points, I don’t think it is logical to believe that statins work by suppressing cholesterol. There have long been weak arguments about plaque stabilisation, but it’s been clear for 20 years that something else is going on. I’ve always personally favoured an anti-inflammatory effect, which on a simplistic level explains why STAT MS worked.

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