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Inhibition of iron-dependent and ischemia-induced brain damage by the alpha-tocopherol analogue MDL 74,722
H B van der Worp1, C E Thomas, L J Kappelle
1Department of Neurology, University Hospital Utrecht, Utrecht, G 03. 228, the Netherlands.
Abstract:
Free radical-induced lipid peroxidation is an important factor in the pathogenesis of ischemic brain damage. We studied the effects of the alpha-tocopherol analogue MDL 74,722 on iron-dependent lipid peroxidation and infarct volume after transient focal cerebral ischemia. The effects of MDL 74,722 on iron-induced lipid peroxidation were tested in cerebellar granule cell cultures by means of a thiobarbituric acid reactive substances (TBARS) assay. The absorbance resulting from mitochondrial reduction of 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was taken as a measure of cell viability. Besides, in male Wistar rats the left middle cerebral artery (MCA) was occluded for 3 h by means of an intraluminal filament. Rats were treated with vehicle (n = 19) or MDL 74,722 (n = 17), administered intravenously for 3 h in a dose of 2 mg/(kg.h), starting 105 min after MCA occlusion. Infarct volume was measured in coronal brain sections stained with hematoxylin and eosin. In cerebellar granule cell cultures, MDL 74,722 resulted in a dose-dependent inhibition of TBARS 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 inhibitor of lipid peroxidation and reduces infarct volume by about one half, even when treatment is delayed. This contributes to its potential clinical usefulness.
Insights
The alpha-tocopherol analogue MDL 74,722 effectively inhibits lipid peroxidation and significantly reduces brain infarct volume by 49% after ischemic stroke, even with delayed treatment, showing clinical potential.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Free radical-induced lipid peroxidation contributes to ischemic brain damage.
- Understanding lipid peroxidation's role is crucial for developing neuroprotective strategies.
Purpose of the Study:
- To investigate the effects of MDL 74,722, an alpha-tocopherol analogue, on iron-dependent lipid peroxidation.
- To evaluate MDL 74,722's efficacy in reducing infarct volume following transient focal cerebral ischemia.
Main Methods:
- Lipid peroxidation was assessed using thiobarbituric acid reactive substances (TBARS) assay in cerebellar granule cell cultures.
- Cell viability was measured by MTT assay.
- In vivo studies involved transient middle cerebral artery occlusion in rats, followed by intravenous administration of MDL 74,722 or vehicle, with infarct volume measured post-treatment.
Main Results:
- MDL 74,722 demonstrated dose-dependent inhibition of TBARS formation and prevented cell toxicity in vitro.
- Intravenous administration of MDL 74,722 reduced infarct volume in rats by 49% compared to vehicle control.
- The compound was effective even when treatment was initiated 105 minutes after the onset of ischemia.
Conclusions:
- MDL 74,722 is a potent inhibitor of lipid peroxidation.
- MDL 74,722 significantly reduces infarct volume in a model of ischemic stroke.
- The delayed efficacy of MDL 74,722 suggests its potential clinical utility in treating ischemic brain damage.
