a-simple-approach-to-induce-experimental-autoimmune-neuritis-c57bl6

A Simple Approach to Induce Experimental Autoimmune Neuritis in C57BL/6 Mice for Functional and Neuropathological Assessments

Experimental autoimmune neuritis (EAN) is a well-appreciated experimental model of autoimmune peripheral demyelinating diseases. EAN disease is induced by ...

The University of Melbourne

We assessed novel disability-based parameters and neuropathological features of the P0180-190 peptide-induced model of experimental autoimmune neuritis (EAN) in C57BL/6 mice. We show that functional assessments such as running capacity provide a more sensitive method for detecting alterations in disease severity than a classical clinical scoring paradigm. We performed detailed ultrastructural analysis and show for the first time that tomaculous neuropathy is a neuropathological feature of this disease model. In addition, we demonstrate that ultrastructural assessments of myelin pathology are sufficiently sensitive to detect significant differences in both mean G-ratio and mean axon diameter between mice with EAN induced with different doses of pertussis toxin. In summary, we have established a comprehensive assessment paradigm for discriminating variations in disease severity and the extent of myelin pathology in this model. Our findings indicate that this model is a powerful tool to study the pathogenesis of human peripheral demyelinating neuropathies and that this assessment paradigm could be used to determine the efficacy of potential therapies that aim to promote myelin repair and protect against nerve damage in autoimmune neuritides.

A Functional and Neuropathological Testing Paradigm Reveals New Disability-Based Parameters and Histological Features for P0180-190-Induced Experimental Autoimmune Neuritis in C57BL/6 Mice.

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(NTR)) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75(NTR) (cyclo-dPAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75(NTR) 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(NTR) heterozygous mice, strongly suggesting a p75(NTR)-dependent effect. Taken together, our data demonstrate that cyclo-dPAKKR ameliorates functional and pathological defects of EAN in a p75(NTR)-dependant manner, suggesting that p75(NTR) is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75(NTR) is a strategy worthy of further investigation.

A Brain-Derived Neurotrophic Factor-Based p75(NTR) Peptide Mimetic Ameliorates Experimental Autoimmune Neuritis Induced Axonal Pathology and Demyelination.

Rhiannon J. Wood

Department of Anatomy and Neuroscience,
School of Biomedical Sciences,
Faculty of Medicine,
Dentistry and Health Sciences,
Department of Anatomy and Neuroscience, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences

The University of Melbourne

A Simple Approach to Induce Experimental Autoimmune Neuritis in C57BL/6 Mice for Functional and Neuropathological Assessments