Combination Treatment of C16 Peptide and Angiopoietin-1 Alleviates Neuromyelitis Optica in an Experimental Model

Abstract

Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease that mainly affects the spinal cord and optic nerve, causing blindness and paralysis in some individuals. Moreover, NMO may cause secondary complement-dependent cytotoxicity (CDC), leading to oligodendrocyte and neuronal damage. In this study, a rodent NMO model, showing typical NMO pathogenesis, was induced with NMO-IgG from patient serum and human complement. We then tested whether the combination of C16, an αvβ3 integrin-binding peptide, and angiopoietin-1 (Ang1), a member of the endothelial growth factor family, could alleviate NMO in the model. Our results demonstrated that this combination therapy significantly decreased disease severity, inflammatory cell infiltration, secondary demyelination, and axonal loss, thus reducing neural death. In conclusion, our study suggests a possible treatment that can relieve progressive blindness and paralysis in an animal model of NMO through improvement of the inflammatory milieu.

C16 Peptide Promotes Vascular Growth and Reduces Inflammation in a Neuromyelitis Optica Model

“…We demonstrated that these pathological changes can be ameliorated by treatment with C16 peptide which delayed disease progression and severity. These findings are consistent with the results of our previous study using the EAE model (Zhang et al, 2018). The Tie2 KI and PI3K/Akt inhibitor LY294002 compromised the effects of C16, indicating the importance of the Tie2 and PI3K/Akt pathways in C16-mediated NMO therapy.…”

“…The presence of NMO-IgG distinguishes the NMO model from MS. NMO-IgG selectively binds to AQP4. Pathological characteristics of NMO include loss of AQP4 and GFAP, granulocyte and macrophage infiltration, as well as demyelination and axonal injury primarily in the spinal cord and optic nerves (Zhang et al, 2018). The pathogenicity of NMO-IgG (anti-AQP4 autoantibodies) and human complement has been found to contribute to the initial NMO model (Zhang et al, 2018).…”

“…Pathological characteristics of NMO include loss of AQP4 and GFAP, granulocyte and macrophage infiltration, as well as demyelination and axonal injury primarily in the spinal cord and optic nerves (Zhang et al, 2018). The pathogenicity of NMO-IgG (anti-AQP4 autoantibodies) and human complement has been found to contribute to the initial NMO model (Zhang et al, 2018). The procedure for establishing the NMO model involves daily intraventricular and intrathecal delivery of (1 µl/h) AQP4-Ab and human complement for 3 days, unlike that for establishing the MS model.…”

“…Pathological data from previous studies reported the importance of CD8 + T-cells and B-lymphocytes in propagating inflammation and tissue damage in established MS model (Lassmann and Bradl, 2017). It is thus crucial to distinguish between NMO and MS because certain MS treatments could exacerbate NMO (Zhang et al, 2018). Given the similarities between NMO and MS, we speculated that C16 would exert comparable effects in the NMO model.…”

“…The synthetic peptide C16 (KAFDITYVRLKF) has a functional laminin domain that can selectively bind αvβ3 and α5β1 integrins. Previous studies showed that αvβ3 integrin could competitively inhibit monocyte transendothelial migration as well as regulate their migration from the vasculature to endothelia (Han et al, 2013; Zhang et al, 2018). Thus, C16 could competitively reduce the binding of inflammatory cells to the endothelium, thereby inhibiting leukocyte transmigration and relieving inflammatory immune responses in NMO patients.…”