MDL-74180

The protective effect of MDL 74,180 (2,3-dihydro-2,2,4,6, 7-pentamethyl-3-(4-methylpiperazino)-methyl-1-benzofuran-5-ol dihydrochloride) and alpha-tocopherol analogue free radical scavenger, against cerebral ischaemia and reperfusion in conscious rats has been demonstrated. Tissue damage following middle cerebral artery occlusion (2 h) and reperfusion (8 days) was decreased by MDL 74,180 (0.1 and 1.0 mg/kg per h) infusion beginning 15 min before the onset of reperfusion and continuing for 2 h into the reperfusion period, in a dose-related manner. Nitroxide radical adducts, characterized and quantified by electron spin resonance spectroscopy, were formed on the addition of spin traps to homogenized rat brain tissue previously subjected to global ischaemia and reperfusion. The primary oxidative chain free radicals form diamagnetic intermediates whose slow homolytic decomposition subsequently yields the observed stable spin adducts. Infusion of MDL 74,180 (1-10 mg/kg per h) beginning 15 min before the induction of global cerebral ischaemia (20 min) until the end of reperfusion (5 min), led to a dose-dependent reduction in the final concentration of spin adducts.

Neuronal viability is affected by reactive oxygen species. Lipid peroxidation is often defined as a major reason for cellular breakdown. Additionally, certain indispensable proteins are possible targets for excessively formed reactive oxygen species. Evidence is given here that protease nexin-1 (PN-1), an endogenous thrombin inhibitor and neurite outgrowth promoter, is inactivated by xanthine oxidase-derived free radicals. Varying protection by superoxide dismutase and catalase was observed, depending on the reaction conditions. The water-soluble alpha-tocopherol analogues MDL 74,406 (R(+)-3,4-dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzopy ran-2- ethanaminium 4-methylbenzenesulfonate), MDL 74,180DA (2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methyl-piperazino)-1-benzo furan-5-ol dihydro-chloride) and trolox also protected PN-1. Neurodegeneration may be triggered by oxidative inactivation of protease inhibitors such as PN-1. Protection of PN-1 in Alzheimer's or Parkinson's diseases, could be a possible target for a therapeutic function of antioxidants in these diseases.