A synthetic heparin-mimicking polyanionic compound inhibits central nervous system inflammation.
The immunomodulating capacity of heparin led us to test the effect of the synthetic heparin-mimicking and low anticoagulant compound RG-13577 on the course of experimental autoimmune encephalomyelitis (EAE) and central nervous system (CNS) inflammation. EAE was induced in SJL mice by inoculation with whole mouse spinal cord homogenate. RG-13577, delivered intraperitoneally, inhibited the clinical signs of acute EAE and markedly ameliorated inflammation in the spinal cord, primarily by inhibiting heparanase activity in lymphocytes and astrocytes and thus impairing lymphocyte traffic. RG-13577 treatment was effective when started on day of disease induction or day 7 after induction. The low molecular weight heparin, enoxaparin, tested under the same conditions, exerted only a minor insignificant inhibitory effect. RG-13577 also inhibited the tyrosine phosphorylation of several proteins, particularly Erk1 and Erk2 of the MAP kinase signaling pathways associated with inflammation and cell proliferation. RG-13577 blocked the activity of sPLA(2) and inhibited CNS PGE(2) production both in vivo and in vitro.
Irony-Tur-Sinai
Michal
M
Laboratory of Neuroimmunology, Department of Neurology, Hadassah University Hospital and Hebrew University Medical School, P.O. Box 12000, 91120 Jerusalem, Israel.
Vlodavsky
Israel
I
Ben-Sasson
Shmuel A
SA
Pinto
Florence
F
Sicsic
Camille
C
Brenner
Talma
T
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000503:physiopathology*; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology*; D005260:Female; D005966:Glucuronidase / Q000235:genetics; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D010642:Phenoxyacetates / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011108:Polymers / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D000099175:Heparanase
D000925:Anticoagulants; D017931:DNA Primers; D015232:Dinoprostone; D005966:Glucuronidase; D006493:Heparin; D010642:Phenoxyacetates; D019000:Phosphotyrosine; D011108:Polymers; D000099175:Heparanase; C090697:2-(4-hydroxyphenoxy)acetic acid-formaldehyde polymer