nitrophenols and Brain-Ischemia

Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ΔN-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited ΔN-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for ΔN-Bcl-x(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x(L) could be a potentially important therapeutic target in ischemic brain injury.

Topics: Animals; bcl-X Protein; Biphenyl Compounds; Brain Ischemia; Cell Death; Cells, Cultured; Female; Gene Knock-In Techniques; Male; Mice; Mice, Knockout; Neurons; Nitrophenols; Organ Culture Techniques; Piperazines; Rats; Rats, Sprague-Dawley; Sulfonamides

Aggregation cultures of rat brain were exposed to a combination of anoxia and hypoglycaemia for 30 minutes. Thereafter, the release of lactate dehydrogenase into the cell culture medium was monitored up to 4 days as a measure of cell damage after the ischemic insult. Some cultures were treated with different concentrations of deprenyl or tolcapone, selective inhibitors of monoamine oxidase B and catechol-O-methyltransferase, respectively. After 1 day in culture, the release of lactate dehydrogenase was significantly reduced in cultures treated with deprenyl (at 1 nM. 100 nM, and 10 microM), as well as in cultures treated with 1 nM or 100 nM tolcapone; 10 microM of tolcapone, on the other hand, resulted in a toxic effect on the cell aggregates. No differences in the release of lactate dehydrogenase into the medium was observed in the aggregates treated with drugs as compared with the control cultures after 2 or 4 days post-ischemia.

Topics: Animals; Benzophenones; Brain Ischemia; Catechol O-Methyltransferase Inhibitors; Cell Survival; Cells, Cultured; Embryo, Mammalian; Enzyme Inhibitors; L-Lactate Dehydrogenase; Models, Neurological; Monoamine Oxidase Inhibitors; Neurons; Neuroprotective Agents; Nitrophenols; Prosencephalon; Rats; Rats, Sprague-Dawley; Selegiline; Time Factors; Tolcapone

Foetal rat brain aggregation cultures were exposed to a single episode of anoxia and hypoglycaemia for 30 min. Lactate dehydrogenase specific activity was estimated in the culture medium after ischaemia as a marker of lost cell integrity. Release of lactate dehydrogenase was most prominent during the first 24 hr period after the ischaemic damage, then it gradually declined. Immediately after ischaemic exposure, the cultures were treated with different concentrations of L-deprenyl or tolcapone. Significantly lower amounts of lactate dehydrogenase leaked into the culture medium during the first 24 hr after the ischaemic episode in cultures treated with deprenyl or tolcapone (1-100 nM). These results suggest that deprenyl and tolcapone may reduce cell damage after ischaemia, at doses causing enzyme inhibition.

Topics: Animals; Benzophenones; Brain Ischemia; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cell Hypoxia; Cells, Cultured; Cytoprotection; Drug Combinations; Female; Hypoglycemia; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Nitrophenols; Pregnancy; Prosencephalon; Rats; Rats, Sprague-Dawley; Selegiline; Tolcapone

The anti-ischemic and anti-anoxic effects of efonidipine, a dihydropyridine calcium antagonist, were studied in several models for cerebral ischemia and anoxia in mice and rats, and the effects were compared with those of nicardipine and flunarizine. Both efonidipine and flunarizine showed protective effects in the models of KCN-induced anoxia and complete ischemia induced by decapitation in mice 6 hr after the treatment, while nicardipine did not show such a long-lasting effect. Efonidipine (1 mg/kg, i.p.), but not nicardipine and flunarizine, prolonged the tolerance times in the asphyxic anoxia model. In mice, efonidipine (4 mg/kg, i.p.) significantly reduced the cumulative mortality rate after bilateral carotid artery ligation. The survival rates at 20 hr after bilateral carotid artery ligation were 33% in the group treated with efonidipine, significantly higher than that in the control group, 0%. On the other hand, the treatment with nicardipine or flunarizine did not increase the rates at 20 hr after the ligation. Moreover, efonidipine attenuated the disturbance of cerebral energy metabolism induced by decapitation in rats. These effects of efonidipine observed in this study were on the whole superior to those of the reference drugs, strongly suggesting the improving effect of efonidipine on cerebral ischemia and anoxia.

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Flunarizine; Hypoxia; Male; Mice; Mice, Inbred ICR; Nicardipine; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Wistar