LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats
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ORIGINAL ARTICLE
LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats Alaa Eldin H. Youssef 1 & Abeer E. Dief 1 & Nesrine M. El Azhary 1 & Doaa A. Abdelmonsif 2,3 & Ola S. El-fetiany 1 Received: 1 December 2017 / Accepted: 13 December 2018 # University of Navarra 2019
Abstract Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have emerged as having potential neuroprotective and neuroregenerative properties. We investigated the effect of intranasal administration of LINGO-1–directed siRNA-loaded chitosan nanoparticles on demyelination and remyelination processes in a rat model of demyelination. Adult male Wistar rats were randomly assigned to one of 6 groups (n = 10 each) and subjected to intrapontine stereotaxic injection of ethidium bromide (EB) to induce demyelination. EB-treated rats were either left untreated or received intranasal LINGO-1–directed siRNA–chitosan nanoparticles from day 1 to day 7 (demyelination group) or from day 7 to day 21 (remyelination group) after EB injection. Chitosan nanoparticle (50 μl) was given alone after EB stereotaxic injection for both demyelination and remyelination groups. Two additional groups received 10 μl of saline by stereotaxic injection, followed by intranasal saline as controls for demyelination and remyelination groups (n = 10/ group). Behavioural testing was conducted for all rats, as well as terminal biochemical assays and pathological examination of pontine tissues were done. After EB injection, rats had compromised motor performance and coordination. Pathological evidence of demyelination was observed in pontine tissue and higher levels of caspase-3 activity were detected compared to control rats. With LINGO-1–directed siRNA–chitosan nanoparticle treatment, animals performed better than controls. Remyelination-treated group showed better motor performance than demyelination group. LINGO-1 downregulation was associated with signs of repair in histopathological sections, higher expression of pontine myelin basic protein (MBP) mRNA and protein and lower levels of caspase-3 activity indicating neuroprotection and remyelination enhancement. Keywords Demyelination . Remyelination . LINGO-1 . siRNA–chitosan nanoparticles . Myelin basic protein
Abbreviations EB Ethidium bromide MBP Myelin basic protein OPCs Oligodendrocyte precursor cells
SiRNA
Small interfering RNA
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13105-018-00660-6) contains supplementary material, which is available to authorized users. * Abeer E. Dief [email protected] 1
Department of Medical Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2
Department of Medical Biochemistry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
3
Molecular Biology and Nanomedicine Labs, Centre of Excellence for Regenerative Medicine Research & Applica
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