Numerous metabolic reactions (i.e., energy depletion, disturbed calcium homeostasis, acidosis, phospho-lipid degradation, rapid release of excitatory neurotransmitters, and accumulation of reduced substrates) triggered by brain ischemia, have been thought to play a role in the pathomechanism of brain injury. Although many of these reactions are initiated during ischemia alone, substantial brain damage develops during the reperfusion in models of transient ischemia. In this study, we evaluated the effects of the following drugs: nimodipine (1 mg~kg b.w., i.p.), 2-amino-5-phosphonovaleric acid (4 mg~kg b.w., i.p.) and propentofylline (25 mg~kg b.w., i.p.), administered (alone or in combination) at the end of 15 min bilateral ischemia in gerbils on mitochondrial superoxide dismutase (SOD), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), monoamine oxidase (MAO) activities, and thiobarbituric acid reactive material (TBARM), and brain water content at 1 hr of reperfusion. The combined treatment virtually abolished early postischemic brain edema (4.1% vs. 0.6%) and efficiently counteracted ischemia~induced changes [decreased SOD (79% vs. 98%), GR (52% vs. 105%), and MAO (25% vs. 79%), and increased TBARM (198% vs. 108%)]. The same combination of drugs administered 15 min before ischemia had a similar effect (e.g., reduced brain swelling and lipid peroxidation) as when given at the end of ischemia, whereas a limited or absent impact was seen when the drugs were given 15 min or 1 hr after ischemia, respectively. The data suggest that free radical-mediated mitochondrial dysfunction and (post)ischemia brain swelling can be reduced by drugs which synchronously prevent processes induced in the early stages of reperfusion. These findings may provide a foundation for a novel approach to the treatment of free radical-mediated brain damage.
