Comparison of Tirilazad Mesylate (U-74006F) and Methyl Prednisolone Sodium Succinate Treatments in Experimental Allergic Encephalomyelitis in the Guinea Pig

Author:

Karlik SJ123,Stavraky RT2,Hall ED4

Affiliation:

1. Department of Diagnostic Radiology and Nuclear Medicine, University of Western Ontario, London, Ontario, Canada

2. Department of Physiology and University of Western Ontario, London, Ontario, Canada

3. Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada

4. Department of Central Nervous System Diseases Research, The Upjohn Company, Kalamazoo, Michigan, USA

Abstract

The effects of the non-glucocortioid 21-aminosteroid, tirilazad mesylate (U-74006F), on MRI and clinical findings in guinea pigs with experimental allergic encephalomyelitis were compared to treatment with methylprednisolone sodium succinate (MPSS). A dose response experiment for U-74006F was performed 1, 3 and 10 mg/kg/day IP on day 0–12 after immunization. Additionally, the 3 mg/kg/day IP dose was extended to 24 and 35 days. MPSS was given in three different protocols at doses ranging from 0.8 to 3.2 mg/kg/day. Abnormalities in T2-weighted images were assessed as measures of edema and inflammation and gadolinium-DTPA enhanced TI-weighted images were used to determine blood-brain barrier integrity. U-74006F improved the clinical status at doses of 3 and 10 mg/kg. For example, maximum clinical score was halved at 10 mg/kg/day (P < 0.01). The presence of gadolinium-DTPA in the parenchyma was also decreased at 3 and 10 mg/kg/day U-74006F although maximum MRI scores were decreased only in the 10 mg/kg U-74006F group. Clinical disease suppression seen with 3 mg/kg treatment on days 0–12 reverted to control at > 24 days of dosing. MPSS treatment considerably worsened the clinical outcome of EAE Mean clinical scores for vehicle and the highest MPSS dose were 0.94 ± 0.66 versus 2.64 ± 1.49 (P < 0.05). The combination of decreased T2-weighted abnormalities, clinical signs and gadolinium-DTPA permeation in the U-74006F treated animals suggested protection of the blood–brain barrier without the severe glucocorticoid effects associated with steroid therapy.

Publisher

SAGE Publications

Subject

Neurology (clinical),Neurology

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