Comparison of tirilazad mesylate (U-74006F) and methylprednisolone sodium succinate treatments in experimental allergic encephalomyelitis in the guinea pig.
The effects of the non-glucocorticoid 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 i.p. on day 0-12 after immunization. Additionally, the 3 mg/kg/day i.p. 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 T1-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.
Karlik
S J
SJ
Department of Diagnostic Radiology and Nuclear Medicine, University of Western Ontario, London, Canada.
Stavraky
R T
RT
Hall
E D
ED
D000208:Acute Disease; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D006168:Guinea Pigs; D008776:Methylprednisolone Hemisuccinate / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011281:Pregnatrienes / Q000627:therapeutic use*; D012016:Reference Values; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D011281:Pregnatrienes; D008776:Methylprednisolone Hemisuccinate; C053355:tirilazad