Inhibition of iron-dependent and ischemia-induced brain damage by the alpha-tocopherol analogue MDL 74,722

Free radical-induced lipid peroxidation is an important factor in the patho genesis of ischemic brain damage. We studied the effects of the alpha-tocop herol analogue MDL 74,722 on iron-dependent lipid peroxidation and infarct volume after transient focal cerebral ischemia. The effects of MDL 74,722 o n iron-induced lipid peroxidation were tested in cerebellar granule cell cu ltures by means of a thiobarbituric acid reactive substances (TBARS) assay. The absorbance resulting from mitochondrial reduction of 3-(4,5-dimethylth iazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was taken as a measure o f cell viability Besides, in male Wistar rats the left middle cerebral arte ry (MCA) was occluded for 3 h by means of an intraluminal filament. Rats we re treated with vehicle (n = 19) or MDL 74,722 (n = 17), administered intra venously for 3 h in a dose of 2 mg/(kg.h), starting 105 min after MCA occlu sion. Infarct volume was measured in coronal brain sections stained with he matoxylin and eosin. In cerebellar granule cell cultures, MDL 74,722 result ed in a dose-dependent inhibition of TEARS formation and prevention of cell toxicity The compound reduced infarct volume after transient occlusion of the MCA in rats by 49%. It is concluded that MDL 74,722 is a potent inhibit or of lipid peroxidation and reduces infarct volume by about one half, even when treatment is delayed. This contributes to its potential clinical usef ulness. (C) 1999 Academic Press.