Inhibition of Ras attenuates the course of experimental autoimmune neuritis Michal Kafri a , Yoel Kloog d , Amos D. Korczyn a,c , Ramona Ferdman-Aronovich a , Vivian Drory b , Aviva Katzav a , Itzhak Wirguin e , Joab Chapman a,b, * a Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Israel b Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Israel c Sieratzky chairof Neurology, Sackler Faculty of Medicine, Tel Aviv University, Israel d Department of Neurobiochemistry, Wise Faculty of Life Sciences, Tel Aviv University, Israel e Department of Neurology, Soroka Medical Center, Ben Gurion University, Beer Sheba, Israel Received 5 January 2004; received in revised form 5 July 2005; accepted 6 July 2005 Abstract EAN induced in Lewis rats by immunization with peripheral bovine myelin was treated by the Ras inhibitor farnesylthiosalicylate (FTS). Treatment from day 0 with FTS (5 mg/kg intraperitoneally twice daily) attenuated peak clinical scores (mean T S.E., 2.5 T 0.5 compared to 4.1 T 0.5 in saline treated controls, p = 0.018, t -test) but not recovery. Treatment from day 10 with FTS attenuated peak disability (2.5 T 0.6, p = 0.032 compared to saline treated controls) and improved recovery (0.84 T 0.42, untreated controls 2.4 T 0.6, p = 0.028 by repeated measures ANOVA). Effects were confirmed by rotarod and nerve conduction studies. An inactive analogue, geranylthiosalicylate, had no clinical effect. Inhibition of Ras is of potential use in the treatment of inflammatory neuropathies. D 2005 Elsevier B.V. All rights reserved. Keywords: Ras; Experimental autoimmune neuritis; Farnesylthiosalicylate; Guillain – Barre ´ syndrome; Nerve conduction; Rat 1. Introduction Experimental autoimmune neuritis (EAN) is a T cell mediated acute demyelinating inflammatory disease of the peripheral nervous system (PNS) that can be induced in susceptible animals by active immunization with PNS tissue, purified PNS myelin proteins or synthetic P2 peptide (Kadlubowski and Hughes, 1979; Shin et al., 1989; Waksman and Adams, 1955). EAN is an estab- lished animal model of human acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (Hahn, 1996; Notterpek and Tolwani, 1999), a major cause of acute neuromuscular paralysis (Parry, 1993). Guillain – Barre ´ syndrome (GBS) is the most common form of AIDP with a yearly incidence of 2 : 100,000 (Soffer et al., 1978). The severe form of GBS requires prolonged mechanical ventilation and intensive care in patients who, however, may eventually make a complete recovery. EAN is a useful tool for studies of pathogenic mecha- nisms and novel therapeutic strategies for the treatment of AIDP. Animals, like humans, develop a monophasic disease with ascending paresis and electrophysiological evidence for demyelinating neuropathy (Cragg and Tho- mas, 1964; Wietholter et al., 1988). The pathogenesis of EAN comprises breakdown of the blood–nerve barrier, infiltration of peripheral nerves with macrophages and activated T lymphocytes and focal demyelination of the peripheral nerves (Hahn, 1996; Rostami et al., 1984). In addition to immunological findings, which indicate enhanced lymphocyte activation (Hartung and Toyka, 1990), the established induction of EAN by passive transfer of myelin reactive T lymphocytes (Linington et al., 1984) and the efficiency of various T cell directed 0165-5728/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2005.07.008 * Corresponding author. Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel. Tel.: +972 58546170; fax: +972 36409113. E-mail address: jchapman@post.tau.ac.il (J. Chapman). Journal of Neuroimmunology 168 (2005) 46 – 55 www.elsevier.com/locate/jneuroim