Agents and Actions,vol. 34, 1/2 (1991)

0065-4299/91/020172-03$1.50+ 0.20/0 9 1991 BirkhguserVerlag, Basel

Effect of the leukotriene B 4 receptor antagonist, SC-41930, on experimental allergic encephalomyelitis (EAE) in the guinea pig D.J. Fretland, D.L. Widomski, R. L, Shone, S. Levin * and T.S. Gaginella GastrointestinalDiseases Researchand Departmentof Pathology*, SearleResearchand Development,4901 SearleParkway, Skokie, II 60077,USA

Abstract

The accepted model for the human demyelinating disease, multiple sclerosis (MS), is experimental allergic encephalomyelitis (EAE). We assessed the ability of SC-41930(7-[3(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxyl acid), to modulate the symptoms of acute EAE generated in guinea pigs. Animals were pretreated with SC-41930 (20 mg/kg, i.p.) for two days followed by thrice-weekly maintenance. At day 52, a significant number of the SC-41930-treated animals were alive as compared to EAE alone. Control animals had an increase in body weight while EAE animals lost over 20% (p < 0.5) of their body weight by day 18. SC-41930-treatment significantly reduced, but did not completely inhibit the cachectic response. The results indirectly implicate LTB4 in the pathogenesis of EAE. Agents that modify this model be useful in the treatment of human MS.

Introduction

Multiple sclerosis (MS) is a chronic, relapsing, demyelinating inflammatory disease of the central nervous system of unknown etiology. Experimental allergic encephalomyelitis (EAE) is an animal model of MS induced by a single intradermal exposure to multiple or purified CNS antigens in an adjuvant-driven paradigm [1]. The clinical signs of EAE include cachexia, tail-droop, incontenence and partial or complete hind limb paralysis. Numerous inflammatory mediators have been implicated in MS and EAE including platelet activating factor, interleukin-1, turnout necrosis factor, bradykinin, complement components and products of arachidonic acid metabolism. SC-41930 (7-[3(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-l-benzopyran-2-carboxylic acid) is a leukotriene B4(LTB4) receptor antagonist and anti-inflammatory agent

with known oral activity [2]. We tested SC-41930 against acute EAE generated in guinea pigs. Materials and methods

Animals EAE was induced in male Hartley guinea pigs (Charles River, Crl:(HA)BR), 500-600 g body weight. Animals were weighed daily and allowed food and water ad libitum.

Inflammation induction Whole spinal cords were isolated from male Hartley guinea pigs killed by COz anoxia. Cord material was finely minced on ice, homogenized in saline, mixed with Freunds complete adjuvant (1:2:3, w/v/ v) and 0.1 cc injected intradermally at 3 different sites on the shaven guinea pig backs, along with adjuvant alone on control animals.

Agents and Actions, vol. 34, 1/2 (1991)

173 Cl&ical scoring and h&tological evaluation

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Results

Figure 1

Effect of SC-41930 treatment on the cachexia associated with experimental allergic encephalomyelitis (EAE) in guinea pigs. EAE was induced at day 0. SC-41930(20 mg/kg, i.p.) was given 2 days ahead of EAE induction with maintenance 3 times weekly. n = 6-8/group. Weight gain or loss versus day 0: *p < 0.05.

Table 1

Effect of SC-41930 treatment on clinical signs in experimental allergic encephalomyelitis(EAE). A. Effect on survival rate Group Animal alive at day 1 8/8 8/8 10/10

2o 8/8 3/8 9/10

52 8/8 2/8 8/10a

B. Effect on hindlimb paralysis Group Cumulativeindexb of hindlimb paralysis at day Control EAE EAE + SC-41930

1 0/8 0/8 0/10

Statistics. Weight changes between groups were assessed by t-test after analysis o f variance. A n a l y sis o f variance between treatment groups in assessing suvival and paralysis was by Mantel-Haenszel test with significance ascribed when p < .05.

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Control EAE EAE + SC-41930

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Effect of the leukotriene B4 receptor antagonist, SC-41930, on experimental allergic encephalomyelitis (EAE) in the guinea pig.

The accepted model for the human demyelinating disease, multiple sclerosis (MS), is experimental allergic encephalomyelitis (EAE). We assessed the abi...
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