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A brain-derived neurotrophic factor-based p75NTR peptide mimetic ameliorates experimental autoimmune neuritis induced axonal pathology and demyelination

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posted on 2023-05-21, 03:18 authored by Gonsalvez, DG, Tran, G, Jessica FletcherJessica Fletcher, Hughes, RA, Hodgkinson, S, Wood, RJ, Yoo, SW, De Silva, M, Agnes, WW, McLean, C, Kennedy, P, Kilpatrick, TJ, Murray, SS, Xiao, J
Axonal damage and demyelination are major determinants of disability in patients with peripheral demyelinating neuropathies. The neurotrophin family of growth factors are essential for the normal development and myelination of the peripheral nervous system (PNS), and as such are potential therapeutic candidates for ameliorating axonal and myelin damage. In particular, BDNF promotes peripheral nerve myelination via p75 neurotrophin receptor (p75NTR) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75NTR (cyclo-dPAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75NTR is abundantly expressed in affected peripheral nerves. We found that systemic administration of cyclo-dPAKKR ameliorates EAN disease severity and accelerates recovery. Animals treated with cyclo-dPAKKR displayed significantly better motor performance compared to control animals. Histological assessment revealed that cyclo-dPAKKR administration limits the extent of inflammatory demyelination and axonal damage, and protects against the disruption of nodal architecture in affected peripheral nerves. In contrast, a structural control peptide of cyclo-dPAKKR exerted no influence. Moreover, all the beneficial effects of cyclo-dPAKKR in EAN are abrogated in p75NTR heterozygous mice, strongly suggesting a p75NTR-dependent effect. Taken together, our data demonstrate that cyclo-dPAKKR ameliorates functional and pathological defects of EAN in a p75NTR-dependant manner, suggesting that p75NTR is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75NTR is a strategy worthy of further investigation.

History

Publication title

eNeuro

Volume

4

Pagination

1-17

ISSN

2373-2822

Department/School

Menzies Institute for Medical Research

Publisher

Society for Neuroscience

Place of publication

United States

Rights statement

Copyright 2017 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

Repository Status

  • Open

Socio-economic Objectives

Expanding knowledge in the biomedical and clinical sciences

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