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A Brain-Derived Neurotrophic Factor-Based p75 NTR Peptide Mimetic Ameliorates Experimental Autoimmune Neuritis Induced Axonal Pathology and Demyelination.
- Source :
-
ENeuro [eNeuro] 2017 Jul 04; Vol. 4 (3). Date of Electronic Publication: 2017 Jul 04 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- 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 (p75 <superscript>NTR</superscript> ) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75 <superscript>NTR</superscript> (cyclo-dPAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75 <superscript>NTR</superscript> 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 p75 <superscript>NTR</superscript> heterozygous mice, strongly suggesting a p75 <superscript>NTR</superscript> -dependent effect. Taken together, our data demonstrate that cyclo-dPAKKR ameliorates functional and pathological defects of EAN in a p75 <superscript>NTR</superscript> -dependant manner, suggesting that p75 <superscript>NTR</superscript> is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75 <superscript>NTR</superscript> is a strategy worthy of further investigation.
- Subjects :
- Amyloid beta-Protein Precursor metabolism
Animals
Axons pathology
Axons ultrastructure
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Gene Expression Regulation drug effects
Gene Expression Regulation genetics
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Microscopy, Electron, Transmission
Myelin Basic Protein metabolism
RNA, Messenger metabolism
Rats
Rats, Inbred Lew
Receptors, Nerve Growth Factor chemistry
Receptors, Nerve Growth Factor genetics
Receptors, Nerve Growth Factor therapeutic use
Statistics, Nonparametric
Axons drug effects
Demyelinating Diseases drug therapy
Demyelinating Diseases etiology
Neuritis, Autoimmune, Experimental complications
Neuritis, Autoimmune, Experimental genetics
Neuritis, Autoimmune, Experimental pathology
Oligopeptides therapeutic use
Receptors, Nerve Growth Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2373-2822
- Volume :
- 4
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- ENeuro
- Publication Type :
- Academic Journal
- Accession number :
- 28680965
- Full Text :
- https://doi.org/10.1523/ENEURO.0142-17.2017