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SCIENCE CHINA Life Sciences, Volume 63 , Issue 6 : 905-914(2020) https://doi.org/10.1007/s11427-019-9821-2

Phloroglucinol derivative compound 21 attenuates cuprizone-induced multiple sclerosis mice through promoting remyelination and inhibiting neuroinflammation

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  • ReceivedJul 30, 2019
  • AcceptedSep 3, 2019
  • PublishedOct 17, 2019

Abstract

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease in the central nervous system. The myelin loss is mainly caused by dysfunction of oligodendrocytes and inflammatory responses of microglia and astrocytes further aggravate the demyelination. Current therapies for MS focus on suppressing the overactivated immune response but cannot halt the disease progress, so effective drugs are urgently needed. Compound 21 is a phloroglucinol derivative that has been proved to have an outstanding anti-inflammatory effect. The purpose of the present study is to investigate whether this novel compound is effective in MS. The cuprizone-induced model was used in this study to mimic the pathological progress of MS. The results showed that Compound 21 significantly improved the neurological dysfunction and motor coordination impairment. Luxol Fast Blue staining and myelin basic protein immunostaining demonstrated that Compound 21 remarkably promoted remyelination. In addition, Compound 21 significantly promoted oligodendrocytes differentiation. Furthermore, we found that Compound 21 decreased microglia and astrocytes activities and the subsequent neuroinflammatory response, indicating that the anti-inflammatory effect of Compound 21 was also involved in its neuro-protection. All the data prove that Compound 21 exerts protective effect on MS through promoting remyelination and suppressing neuroinflammation, indicating that Compound 21 might be a potential drug candidate for MS treatment.


Funded by

the National Natural Sciences Foundation of China(81630097,81773718)

the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2016-I2M-3-011)

the CAMS Fundamental Research Funds for the Central Universities(2018RC350002)

and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Thirteenth Five-year Plan Period(2018ZX09711001-003-005,2018ZX09711001-008-005,2018ZX09711001-003-020)


Acknowledgment

This work was supported by the National Natural Sciences Foundation of China (81630097 and 81773718), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-3-011), the Chinese Academy of Medical Sciences Fundamental Research Funds for the Central Universities (2018RC350002), and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Thirteenth Five-year Plan Period (2018ZX09711001-003-005, 2018ZX09711001-008-005 and 2018ZX09711001-003-020).


Interest statement

The author(s) declare that they have no conflict of interest.


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  • Figure 1

    The chemical structure of Compound 21.

  • Figure 2

    (Color online) Compound 21 improved body weight of CPZ-challenged mice. A, The flowchart of mouse treatments. B, Body weight of mice before subgrouping (n=16 for Control group, n=112 for Model group). C, Body weight of mice in different subgroups of Control, Compound 21(1, 5, 10, 20 or 50 mg kg−1 d−1) or CyA (70 mg kg−1) from week 5 to week 8 of CPZ intoxication (n=16 for each group). Results were shown as mean±SEM.

  • Figure 3

    (Color online) Compound 21 improved motor coordination and neurological function of CPZ-challenged mice. A, Rota-Rod test in week 5. B. Rota-Rod test in week 6. C, Rota-Rod test in week 7. D, Rota-Rod test in week 8. E, Clinical disease scores in week 5. F, Clinical disease scores in week 6. G, Clinical disease scores in week 7. H, Clinical disease scores in week 8. I, Rota-Rod test of Control and CPZ-challenged mice from week 5 to week 8. J, Clinical disease scores of Control and CPZ-challenged mice from week 5 to week 8. Results were shown as mean±SEM (n=16 for each subgroup). ###, P<0.001 versus Control mice. *, P<0.05; **, P<0.01; ***, P<0.001 versus CPZ- challenged mice.

  • Figure 4

    (Color online) Compound 21 promoted remyelination and oligodendrocytes differentiation. A, Representative LFB staining images of the corpus callosum. B, The IOD analysis result of LFB staining images, n=4 for each group (3 sections per mouse). C, Representative IHC images of MBP in the corpus callosum. D, The IOD analysis result of IHC images of MBP, n=4 for each group (3 sections per mouse). E, Representative Western blot brands of MBP and Olig2. F, The density analysis result of MBP Western blot (n=3 for each group). G. The density analysis result of Olig2 Western blot (n=3 for each group). Results were shown as mean±SEM. #, P<0.05; ##, P<0.01; ###, P<0.001 versus Control mice. *, P<0.05; **, P<0.01; ***, P<0.001 versus CPZ-challenged mice.

  • Figure 5

    (Color online) Expression of Iba-1 in the corpus callosum. A, Representative IHC images of the corpus callosum staining with Iba-1. B, The IOD analysis result of IHC images, n=4 for each group (3 sections per mouse). C, Representative Western blot brand of Iba-1 and the corresponding density analysis result (n=3 for each group). Results were shown as mean±SEM. ##, P<0.01, ###, P<0.001 versus Control mice. *, P<0.05, **, P<0.01, ***, P<0.001 versus CPZ-challenged mice.

  • Figure 6

    (Color online) Expression of GFAP in the corpus callosum. A, Representative IHC images of the corpus callosum staining with GFAP. B, The IOD analysis result of IHC images, n=4 for each group (3 sections per mouse). C, Representative Western blot brand of GFAP and the corresponding density analysis result (n=3 for each group). Results were shown as mean±SEM. ##, P<0.01, ###, P<0.001 versus Control mice. *, P<0.05, **, P<0.01, ***, P<0.001 versus CPZ-challenged mice.

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