Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination

Lindsay, Susan L, McCanney, George A, Zhan, Jiangshan, Scheld, Miriam, Smith, Rebecca Sherrard, Goodyear, Carl S, Yates, Edwin A ORCID: 0000-0001-9365-5433, Kipp, Markus, Turnbull, Jeremy E and Barnett, Susan C (2023) Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination. GLIA, 71 (7). pp. 1683-1698.

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Official URL: http://dx.doi.org/10.1002/glia.24363

Abstract

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.

Item Type:	Article
Uncontrolled Keywords:	CNS repair, cuprizone, EAE, heparan sulfate, multiple sclerosis, myelination
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	17 Apr 2023 09:46
Last Modified:	12 May 2023 03:50
DOI:	10.1002/glia.24363
Open Access URL:	https://doi.org/10.1002/glia.24363
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169608