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