PMID- 29301568 OWN - NLM STAT- MEDLINE DCOM- 20180918 LR - 20181113 IS - 2051-5960 (Electronic) IS - 2051-5960 (Linking) VI - 6 IP - 1 DP - 2018 Jan 4 TI - Surfen, a proteoglycan binding agent, reduces inflammation but inhibits remyelination in murine models of Multiple Sclerosis. PG - 4 LID - 10.1186/s40478-017-0506-9 [doi] LID - 4 AB - Proteoglycans are promising therapeutic targets in Multiple Sclerosis (MS), because they regulate many aspects of the immune response. This was studied using surfen, an agent that binds both heparan sulphate proteoglycans (HSPGs) and chondroitin sulphate proteoglycans (CSPGs). Initial cell culture work on bone marrow derived macrophages (BMDMs) found that surfen reduced concentrations of the chemokines CCL2, CCL4 and CCL5, with reduced messenger (m)RNA expression for Tumor Necrosis Factor, IL-6, IL-1beta and inducible nitric oxide synthase. These data were further explored using Experimental Autoimmune Encephalomyelitis (EAE) in mice. Surfen reduced clinical signs during EAE when administered from disease onset, and reduced infiltration by CD4 positive T cells and macrophages into the central nervous system. These mice also showed reduced mRNA expression for the chemokines CCL3 and CCL5, with reduced concentrations of CCL2, CCL3 and CCL5. During EAE, surfen treatment induced a persistent increase in Interleukin (IL)-4 concentrations which may enhance T helper 2 responses. During EAE, surfen treatment reduced mRNA expression for HSPGs (NDST1, agrin, syndecan-4, perlecan, serglycin, syndecan-1) and the CSPG versican. By contrast, surfen increased mRNA expression for the CSPG aggrecan, with no effect on neurocan. During EAE, significant positive correlations were found between mRNA expression and clinical score for syndecan-4, serglycin and syndecan-1 and a significant negative correlation for aggrecan. These correlations were absent in surfen treated mice. Repair in the later stages of MS involves remyelination, which was modeled by injecting lysolecithin (lysophosphatidylcholine, LPC) into mouse corpus callosum to create regions of demyelination. When surfen was injected 2 days after LPC, it delayed remyelination of the lesions, but had no effect when injected 7 days after LPC. The delayed remyelination was associated with local increases in CSPG expression. Therefore surfen suppresses inflammation but inhibits remyelination in these models. A mechanism in common may be increased CSPG expression. FAU - Warford, Jordan R AU - Warford JR AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Lamport, Anna-Claire AU - Lamport AC AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Clements, Derek R AU - Clements DR AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Malone, Alicia AU - Malone A AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Kennedy, Barry E AU - Kennedy BE AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Kim, Youra AU - Kim Y AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Gujar, Shashi A AU - Gujar SA AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Hoskin, David W AU - Hoskin DW AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. AD - Department of Microbiology and Immunology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. FAU - Easton, Alexander S AU - Easton AS AD - Department of Pathology, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, PO Box 15000, Halifax, NS, B3H 4R2, Canada. Alexander.Easton@dal.ca. LA - eng GR - 130574/CIHR/Canada GR - 2017-05339/Natural Sciences and Engineering Research Council of Canada/International GR - 34609/Dalhousie Medical Research Foundation/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180104 PL - England TA - Acta Neuropathol Commun JT - Acta neuropathologica communications JID - 101610673 RN - 0 (Chemokines) RN - 0 (Immunologic Factors) RN - 0 (Proteoglycans) RN - 0 (RNA, Messenger) RN - 08T7936572 (aminoquinuride) RN - 8W8T17847W (Urea) SB - IM MH - Animals MH - Bone Marrow/drug effects/pathology/physiology MH - CD4-Positive T-Lymphocytes/drug effects/pathology/physiology MH - Cells, Cultured MH - Chemokines/metabolism MH - Corpus Callosum/drug effects/pathology/physiopathology MH - Encephalomyelitis, Autoimmune, Experimental/*drug therapy/pathology/physiopathology MH - Female MH - Immunologic Factors/administration & dosage/*pharmacology MH - Inflammation/*drug therapy/pathology/physiopathology MH - Macrophages/drug effects/pathology/physiology MH - Mice, Inbred C57BL MH - Proteoglycans/metabolism MH - RNA, Messenger/metabolism MH - Remyelination/*drug effects/physiology MH - Spinal Cord/drug effects/pathology/physiopathology MH - Urea/adverse effects/*analogs & derivatives/pharmacology PMC - PMC5755315 OTO - NOTNLM OT - Experimental autoimmune encephalomyelitis OT - Lysolecithin OT - Multiple sclerosis OT - Proteoglycan OT - Surfen COIS- COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/01/06 06:00 MHDA- 2018/09/19 06:00 PMCR- 2018/01/04 CRDT- 2018/01/06 06:00 PHST- 2017/11/07 00:00 [received] PHST- 2017/12/17 00:00 [accepted] PHST- 2018/01/06 06:00 [entrez] PHST- 2018/01/06 06:00 [pubmed] PHST- 2018/09/19 06:00 [medline] PHST- 2018/01/04 00:00 [pmc-release] AID - 10.1186/s40478-017-0506-9 [pii] AID - 506 [pii] AID - 10.1186/s40478-017-0506-9 [doi] PST - epublish SO - Acta Neuropathol Commun. 2018 Jan 4;6(1):4. doi: 10.1186/s40478-017-0506-9.