A synthetic heparin-mimicking polyanionic compound inhibits central nervous system inflammation

Irony-Tur-Sinai, Michal; Vlodavsky, Israel; Ben-Sasson, Shmuel A; Pinto, Florence; Sicsic, Camille; Brenner, Talma

« Previous Next »Journal of the Neurological Sciences
Volume 206, Issue 1 , Pages 49-57, 15 January 2003

A synthetic heparin-mimicking polyanionic compound inhibits central nervous system inflammation

Michal Irony-Tur-Sinai
- Laboratory of Neuroimmunology, Department of Neurology, Hadassah University Hospital and Hebrew University Medical School, P.O. Box 12000, Jerusalem 91120, Israel
Israel Vlodavsky
- Department of Oncology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem 91120, Israel
Shmuel A Ben-Sasson
- Department of Experimental Medicine and Cancer Research, Hadassah University Hospital and Hebrew University Medical School, Jerusalem 91120, Israel
Florence Pinto
- Laboratory of Neuroimmunology, Department of Neurology, Hadassah University Hospital and Hebrew University Medical School, P.O. Box 12000, Jerusalem 91120, Israel
Camille Sicsic
- Laboratory of Neuroimmunology, Department of Neurology, Hadassah University Hospital and Hebrew University Medical School, P.O. Box 12000, Jerusalem 91120, Israel
Talma Brenner
- Corresponding author. Tel.: +972-2-6776957; fax: +972-2-6437782.
- Laboratory of Neuroimmunology, Department of Neurology, Hadassah University Hospital and Hebrew University Medical School, P.O. Box 12000, Jerusalem 91120, Israel

Received 14 May 2002; received in revised form 14 August 2002; accepted 15 August 2002.

Abstract

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 sPLA₂ and inhibited CNS PGE₂ production both in vivo and in vitro.

Keywords: Heparin-mimicking polyanionic compound (HMPAC), CNS inflammation, EAE, Multiple sclerosis, Immunomodulation, Heparanase