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Moringin activates Wnt canonical pathway by inhibiting GSK3β in a mouse model of experimental autoimmune encephalomyelitis

Authors Giacoppo S, Soundara Rajan T, De Nicola GR, Iori R, Bramanti P, Mazzon E

Received 13 April 2016

Accepted for publication 14 July 2016

Published 4 October 2016 Volume 2016:10 Pages 3291—3304

DOI https://doi.org/10.2147/DDDT.S110514

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Chiung-Kuei Huang

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Frank M. Boeckler


Sabrina Giacoppo,1 Thangavelu Soundara Rajan,1 Gina Rosalinda De Nicola,2 Renato Iori,2 Placido Bramanti,1 Emanuela Mazzon1

1IRCCS Centre Neurolesi “Bonino-Pulejo”, Messina, Italy; 2Council for Agricultural Research and Economics, Research Centre for Industrial Crops (CREA-CIN), Bologna, Italy

Abstract: Aberrant canonical Wnt–β-catenin signaling has been reported in multiple sclerosis (MS), although the results are controversial. The present study aimed to examine the role of the Wnt–β-catenin pathway in experimental MS and also to test moringin (4-[α-L-rhamnopyranosyloxy]-benzyl isothiocyanate), resulting from exogenous myrosinase hydrolysis of the natural phytochemical glucomoringin 4(α-L-rhamnosyloxy)-benzyl glucosinolate as a modulator of neuroinflammation via the β-catenin–PPARγ axis. Experimental autoimmune encephalomyelitis (EAE), the most common model of MS, was induced in C57BL/6 mice by immunization with MOG35–55. Released moringin (10 mg/kg glucomoringin +5 µL myrosinase/mouse) was administered daily for 1 week before EAE induction and continued until mice were killed on day 28 after EAE induction. Our results clearly showed that the Wnt–β-catenin pathway was downregulated in the EAE model, whereas moringin pretreatment was able to avert this. Moringin pretreatment normalizes the aberrant Wnt–β-catenin pathway, resulting in GSK3β inhibition and β-catenin upregulation, which regulates T-cell activation (CD4 and FoxP3), suppresses the main inflammatory mediators (IL-1β, IL-6, and COX2), through activation of PPARγ. In addition, moringin attenuates apoptosis by reducing the expression of the Fas ligand and cleaved caspase 9, and in parallel increases antioxidant Nrf2 expression in EAE mice. Taken together, our results provide an interesting discovery in identifying moringin as a modulator of the Wnt–β-catenin signaling cascade and as a new potential therapeutic target for MS treatment.

Keywords: Wnt–β-catenin pathway, GSK3β, multiple sclerosis, moringin, PPARγ, apoptosis
 

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