Medroxyprogesterone acetate attenuates demyelination, modulating microglia activation in a cuprizone neurotoxic demyelinating mouse model

Mohammadi, Maryam and Abdi, Mahdad and Alidadi, Mehdi and Mohamed, Wael Mohamed Yousef and Zibara, Kazem and Kashani, Iraj Ragerdi (2021) Medroxyprogesterone acetate attenuates demyelination, modulating microglia activation in a cuprizone neurotoxic demyelinating mouse model. American Journal of Neurodegenerative Disease, 10 (5). pp. 57-68. ISSN 2165-591X

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Abstract

: Clinical data reported a reduction of Multiple sclerosis (MS) symptoms during pregnancy when progesterone levels are high. Medroxyprogesterone acetate (MPA) is a synthetic progestin contraceptive with unknown neuroprotective effects. This study investigated the effect of a contraceptive dose of MPA on microglia polarization and neuroinflammation in the neurotoxic cuprizone (CPZ)-induced demyelinating mouse model of MS. Mice received 1 mg of MPA weekly, achieving similar serum concentrations in human contraceptive users. Results revealed that MPA therapy significantly reduced the demyelination in the corpus callosum. In addition, MPA treatment induced a significant reduction in microglia M1-markers (iNOS, IL-1β and TNF-α) while M2-markers (Arg-1, IL-10 and TGF-β) were significantly increased. Moreover, MPA resulted in a significant decrease in the number of iNOS positive cells (M1), whereas TREM-2 positive cells (M2) significantly increased. Furthermore, MPA decreased the protein expression levels of NF-κB and NLRP3 inflammasome as well as mRNA expression levels of the downstream product IL-18. In summary, MPA reduces the level of demyelination and has an anti-inflammatory role in CNS demyelination by inducing M2 microglia polarization and suppressing the M1 phenotype through the inhibition of NF-κB and NLRP3 inflammasome. Our results suggest that MPA should be a suitable contraceptive pharmacological agent in demyelinating diseases.

Item Type:	Article (Journal)
Subjects:	R Medicine > R Medicine (General)
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Medicine Kulliyyah of Medicine > Department of Basic Medical
Depositing User:	Dr Wael Mohamed
Date Deposited:	17 Nov 2021 08:54
Last Modified:	17 Nov 2021 08:54
URI:	http://irep.iium.edu.my/id/eprint/93804

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