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
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