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LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats

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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.

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Abbreviations

EB:

Ethidium bromide

MBP:

Myelin basic protein

OPCs:

Oligodendrocyte precursor cells

SiRNA:

Small interfering RNA

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Acknowledgements

The authors are grateful to Dr. Teshreen M. Zeitoun, Ass. Prof in the Department of Medical Histology and Cell Biology-Alexandria Faculty of Medicine for her great support in Luxol fast blue staining and interpretation; and to Dr. Bassma El-Saba, Professor of Pathology-Alexandria Faculty of Medicine for her assistance in the histopathology analysis.

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Authors and Affiliations

  1. Department of Medical Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

    Alaa Eldin H. Youssef, Abeer E. Dief, Nesrine M. El Azhary & Ola S. El-fetiany

  2. Department of Medical Biochemistry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt

    Doaa A. Abdelmonsif

  3. Molecular Biology and Nanomedicine Labs, Centre of Excellence for Regenerative Medicine Research & Applications, University of Alexandria, Alexandria, Egypt

    Doaa A. Abdelmonsif

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  1. Alaa Eldin H. Youssef
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Correspondence to Abeer E. Dief.

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Youssef, A.E.H., Dief, A.E., El Azhary, N.M. et al. LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats. J Physiol Biochem 75, 89–99 (2019). https://doi.org/10.1007/s13105-018-00660-6

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