How do statins work?

H

When I see Sir jeremy I ask the question of how do statins work in MS?

Statins are cholesterol lowering drugs, that block an enzyme called HMG-Co Reductase. In doing so it stopped cholesterol formation and any intermediates in the pathway

cholesterol pathway

Years ago we found that certain molecules had to be prenylated (lipidated) in the blood vessels to allow lymphocytes to migrate through them by rearranging its skeleton. As you can see above, prenylated proteins (Green) can be controlled by proteins derived from the cholesterol pathway and therefore should be susceptible to modification by statins.

Indeed we showed that statins had the potential to inhibit white blood cell trafficing into the brain at the same time another group said it changed the mediators relased to be anti-inflammatory. The referees of the papers said we had to prove the mechanism, but blocking the key molecule called Rho, in the idea would mean a dead mouse as it (Rho) was used as part of one of lifes mediators. They accepted the other groups work, but I must admit, we thought this latter explanation unlikely because when we gave beasties statins there was no disease but when we stopped it there was disease in all beasties two days later. How could there be a switch so quickly given the dogma at the time that once the T cells were committed to producing the mediators there was no turning back. The drug had a half-life such that therapeutic levels would be lost within a couple of days. This important data was originally put in supplementary online stuff

Beasties developed disease about 14-22 days after induction and relapsed from 30 days onways (blue), Beasties were given statins (Lovastatin=red) and disease never retuned until drug was stopped.

Trials were done in relapsing MS and the data was not compelling, but was the dose right….However the UK was slow to the show and decided to target secondary progressive MS not relapsing MS and surprisingly there seemed to be some benefit in slowing brain loss in the MS-STAT trial. It had no major effect on neurofilaments (a marker of inflammation-induced nerve loss) or inflammatory lesions, suggesting it was not working on the relapsing element but the elements that drive progressive MS. So the question is how do the statins work? If you look at the cholesterol pathway, which is target by statins, it is the most disrupted pathways in chronic EAE, MS and Alzheimers. There is a suggestion that statins may help save nerves. Will it show benefit in progressive MS? The MS-STAT-2 is ongoing and should finish in 2023. In the trial people should not have relapses, or have used a DMT (NCT03387670) for making predictions so I will keep quiet.

However the question of how do statins work becomes even more relevant,

  • Block white blood cells entry into the CNS or
  • Inducing inhibitory White blood cell cytokines (TH1 to TH2 switch)

Do not cut the mustard. So what else can statins do?

  • Statins could affect myelination and cholesterol is used in making myelin. It has been suggested a short burst improves remylination but on longer term there is a negative influence to block remyelination
  • Inhibition of microglial activation
  • Neuroprotection

But what is neuroprotective an effect on oxysterols via potassium channels or something else.

Here we have another mechanism which is via an action of the nuclear receptor 4A2 (NR4A2) (nuclear receptor subfamily 4 group A member 2) also known as nuclear receptor related 1 protein (NURR1) is a member of the nuclear receptor family of intracellular transcription factors, whic make proteins from DNA.

If MS-STAT2 works it wont matter how it works in most peoples eyes, although if you know how it works you can do better. If it doesn’t let’s not go there.

Willems S, Marschner JA, Kilu W, Faudone G, Busch R, Duensing-Kropp S, Heering J, Merk D. Nurr1 Modulation Mediates Neuroprotective Effects of Statins. Adv Sci. 2022 Apr 30:e2104640

The ligand-sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects are demonstrated, is reported. Several statins directly affect Nurr1 activity in cellular and cell-free settings with low micromolar to sub-micromolar potencies. Simvastatin as example exhibits anti-inflammatory effects in astrocytes, which are abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1-silenced cells reveals strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induces several neuroprotective mechanisms via Nurr1 involving changes in inflammatory, metabolic and cell cycle gene expression. Further in vitro evaluation confirms reduced inflammatory response, improved glucose metabolism, and cell cycle inhibition of simvastatin-treated neuronal cells. These findings suggest Nurr1 involvement in the well-documented but mechanistically elusive neuroprotection by statins.

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  • How do statins work?

    Good question

    When you go to a meting (i.e Ectrims ) and you ask the speaker some question and he or she says good question , it means

    1º Its real hard question to answer

    2ºNobody knows

    And this is a really dificult question to answer

    It seems that statins work and work alot in manny diferent diseases much like mettformin

    So its fair to say that statins have also manny mechanisms at play to influence a broad specrum of human biology

    Cancer

    Simvastatin is a potential candidate drug in ovarian clear cell carcinomas

    https://www.oncotarget.com/article/27747/text/

    Common cholesterol drugs could slow spread of breast cancer to brain

    https://medicalxpress.com/news/2020-06-common-cholesterol-drugs-breast-cancer.html

    Statins starve cancer cells to death

    https://medicalxpress.com/news/2020-03-statins-starve-cancer-cells-death.html

    Infections diseases

    https://medicalxpress.com/news/2019-09-statins-older-patients-severe-pneumonia.html

    Ms

    Applying causal models to explore the mechanism of
    action of simvastatin in progressive multiple sclerosis

    http://www.pnas.org/cgi/doi/10.1073/pnas.1818978116

    Alzheimer

    Simvastatin Modulates the Alzheimer’s
    Disease-Related Gene seladin-1

    https://pubmed.ncbi.nlm.nih.gov/21987590/

    Psoriasis

    Efficacy of Adding Oral Simvastatin to Topical Therapy for Treatment of Psoriasis: The Vietnamese Experience

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364708/

    Microglia

    The Antineuroinflammatory Effect of Simvastatin on Lipopolysaccharide Activated Microglial Cells

    https://pubmed.ncbi.nlm.nih.gov/30524484/

    Parkinson

    Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

    https://pubmed.ncbi.nlm.nih.gov/30513525/

    Systemic Sclerosis

    Statins Inhibit Cytokines in a Dose-Dependent Response in Patients with Systemic Sclerosis

    https://pubmed.ncbi.nlm.nih.gov/30288636/

    Lupus

    Simvastatin reduces antiphospholipid antibodies formation in patients with systemic lupus erythematosus: a preliminary study

    https://pubmed.ncbi.nlm.nih.gov/29699441/

    Spinal cord ischemic injury

    https://pubmed.ncbi.nlm.nih.gov/29587636/

    Fragile X

    Early statin treatment may help children with Fragile X

    https://medicalxpress.com/news/2019-05-early-statin-treatment-children-fragile.html

    Has someone said some time ago statins should be add to the drinking water of a city population

    🙂

    So no easy task here

    Nice post thanks

    • My you have been busy and stations would be part of the polypill. Asking a question at a meeting when you know there is no answer suggests you are about of a d*CK. How ever the wrong answer is ” I don t know” unless there is clarification

      • So why design the trial to exclude people on DMTs? Your reply likely is to show the exclusive effect of statin upon relapse and disease. But in reality no patient is going to stop taking their DMT when they take a statin, right? Is the fear that the endpoints for a trial comparing anti CD20 vs anti CD20 + statin too slight to succeed? If so, then are there more creative trial designs that would answer the question of the benefit of statins for people on DMTs? Like upping the dose of statin? Increasing the number of trial participants to boost the n? Or better/more quantifiable measures of actual disability? Just worried that the clemastine/metformin trial and this statin trial are both more classical in design, and any hint of a negative result in the absence of DMT activity will doom any future use. I don’t understand why drug design is still limited to single agent thinking when it is going to end up in combination anyway.

      • Loll

        The good speakers often use the “i dont know ” response

        I really like that response ,it makes for a good scientist

        • Good speakers will clarify it…unless it is an impossible question.
          P.S. I was directing this to people doing trials

          • Please need opinions if you dont think why you are doing what you do…it isn;t good

    • Wow. Inhibiting cholesterol synthesis via statins really is a modern “snake oil” do everything class of drugs. “Step right up people”😊

  • Statins are talked about as a great drug. The facts are only around 50% of people recommended to take them actually do.

    Why’s this? Side effects and possible side effects

    There are a lot of questions over statins. If they don’t reduce nerve loss based on the neurofiliment levels. Are the neuroprotective effects being based on MRI brain atrophy levels? If so if may not actually be doing anything beneficial for people with MS, it just looks good on a brain scan.

    Let’s hope they are beneficial

  • Could Statins help prevent MS? There must be very many people on Statins, though probably predominantly of an older age. So a comparison could be made between those on Statins, and those not, and the occurrence of MS. Not having MS prior to going on Statins, would I assume have to be a prerequisite.

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