Astrocytic disease control. Have we found the magic treatment for progressive MS

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We have been spending all our time looking at T and B cells but there has been insufficient attention paid to the glial response, which is important given the the glial cells are probably very important in progressive MS.

This study looks at astrocytes

This paper looks at how astrocytes may be involved and the signalling molecules involved. I am sorry but I don’t have the time or the will, to try and explain this. The take home message is they have found drugs to treat the issues.

All sexy science, except the EAE. Again the work uses a model cited as being progressive, but without any real validation, and is possibily untrue, but without access to the raw data we will never know. But here the disease is chronic and static and so does not replicate the group’s own work. The positive controls linger around a limp tail and a bit of limb problem and it is clear that death of nerves, which is usually the cause of persistent disability in mice, can be resurrected at seeming long-term disability can be reversed, suggesting something is wrong.

The claim is that Miglustat saves the day and a patent has been filed so it may be coming your way soon.

Looking at the data, to me it is not so much neuroprotective but probably immunomodulatory. This is perhaps not surprising as they us 600mg/kg. I know the drug has been used at grammes/kg in mice, but based on rats some form of toxicity develops above 60mg/kg a day on repeated feeding and as the human dose is about 5-20mg/kg. This suggests that the animal data is not going to inform much about human studies. Importantly the animal work is let down as there is dose-response. Let’s hope that it wasn’t a case of keep going until it does something…as too much tooth paste could be immunomodulatory…so doing a lot for mechanistic science but not much for translational science and possibly suggests all the hard work will end being on the maggot pile, but lets see where it goes. So perhaps don’t hold your breathe with this

Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS.Chao CC, Gutiérrez-Vázquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, Zandee SEJ, Blain M, de Lima KA, Takenaka MC, Avila-Pacheco J, Hewson P, Liu L, Sanmarco LM, Borucki DM, Lipof GZ, Trauger SA, Clish CB, Antel JP, Prat A, Quintana FJ. Cell. 2019 Dec 12;179(7):1483-1498.e22. doi: 10.1016/j.cell.2019.11.016. Epub 2019.

Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of phospholipase A2 with mitochondrial antiviral signaling protein (MAVS), boosting transcriptional programs that promote CNS inflammation. PLA2 recruitment to MAVS also disrupts the production of lactate involved in the metabolic support of neurons. Miglustat, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities and identifies candidate targets for therapeutic intervention.

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MouseDoctor

4 comments

  • Looking at miglustat, what about the other forms of iminosugars- miglitol is what I found which is used for diabetes. How about a short post on metabolic mechanisms of cell death and alpha glucosidase inhibitors?

  • How is this for good science-

    “Identification of Potent and Selective Glucosylceramide Synthase Inhibitors from a Library of N-Alkylated Iminosugars” PMC4017989

    Tested several forms of inhibitors looking for improvement in selectivity against glucosylceramide using clear biochemical screens and identified an improved selectivity against GBA2 vs GBA1 for some compounds. Would be interesting to try those compounds.

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