Saturday, 1 April 2017

Fingolimod doesnt extinguish the hot microglia

Sucksdorff M, Rissanen E, Tuisku J, Nuutinen S, Paavilainen T, Rokka J, Rinne J, Airas L.Evaluation of the effect of fingolimod treatment on microglial activation using serial PET imaging in multiple sclerosis. J Nucl Med. 2017 Mar 23. pii: jnumed.116.183020.
Traditionally, multiple sclerosis (MS) has been considered a white matter (WM) disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, i.e. in areas of normal appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using an 18 kDa translocator protein (TSPO) binding radioligands and positron emission tomography (PET). It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS (RRMS) patients were studied using the TSPO radioligand 11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 weeks of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio (DVR) of 11C-(R)-PK11195. Results: The patients had had MS for an average of 7.9 years (± 4.3, mean ± standard deviation (SD)), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod due to safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 months. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients compared with healthy controls (P = 0.021). 11C-(R)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after six months of fingolimod treatment (P = 0.040), but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.
Fingo blocks relapses and blocks new lesion formation and so blocked microglial activity as detected with TSPO (which one has to say binds to more than just microglia). However, it did not inhibit the widespread microglial activation that we are assuming in associated with progressive MS. Is this a reason why fingolimod failed in primary progressive MS, so what would happen with siponimod which has a similar mechanism to fingolimod?

5 comments:

  1. Ok the fact: not reduces, after 24 wks, but fingo might reduces the growing of it's activation or might stabilize it after more longer period! Last yr fingo long term trial shows this drug delayed SPMS, fourfold the wheelchair use, and we also know it has remarkable effect the Ms related brain loss! Am I wrong?

    ReplyDelete
  2. I thought these "hot microglia" might just be clearing up bits of dead oligodendrocytes - "killed" by the mechanism of progressive MS which is so poorly understood. And which is possibly where MS begins.

    ReplyDelete
  3. I think is more complex than that
    Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis
    https://wellcomeopenresearch.org/articles/1-10/v1

    ReplyDelete
  4. Ok. We are good at identifying compounds that do not dampen activated microglia, now the million dollar question is...what does?:-)

    ReplyDelete
    Replies
    1. Oxcarbazepine currently being trialled maybe laquinimod, lets see the trial data...

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.