dinoprost and Infarction--Middle-Cerebral-Artery

Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate NMDA receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli's salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. I.p. injection of AS (40 mumol/kg) in mice prior to middle cerebral artery occlusion exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose-deprivation of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity - that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo.

Topics: Animals; Blood Pressure; Brain Infarction; Cells, Cultured; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme-Linked Immunosorbent Assay; F2-Isoprostanes; Gas Chromatography-Mass Spectrometry; Glutamic Acid; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Mice; Mice, Inbred C57BL; Neuroglia; Neurons; Neuroprotective Agents; Nitrites; Nitrogen Oxides; Oxidative Stress; Statistics, Nonparametric; Tetrazolium Salts; Thiazoles; Time Factors

Formation of the lipid peroxidation product 8-epi-prostaglandin2alpha (8-epi-PGF2alpha) a bioactive marker of oxidative stress, was quantified in in vitro and in vivo models of neuronal death. In culture media of primary rat cortical neurones exposed to hypoxia followed by reoxygenation, a 3.7-fold increase of 8-epi-PGF2alpha concentration was observed in comparison to control cells. In rats submitted to 2h middle cerebral artery occlusion followed by a 22h reperfusion period, a 27-fold increase of 8-epi-PGF2alpha was observed in the ischaemic hemisphere compared with the corresponding hemisphere of sham-operated rats. Treatment with the neuroprotective agent BN 80933 significantly reduced both 8-epi-PGF2alpha elevations in vitro and in vivo. These data suggest that 8-epi-PGF2alpha elevations might reflect the damaging free radical overproduction and subsequent lipid peroxidation during neuronal injury induced by hypoxia and ischaemia. Inhibition of 8-epi-PGF2alpha elevations participates to the neuroprotective effects of BN 80933.

Topics: Animals; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Culture Media, Conditioned; Dinoprost; Enzyme Inhibitors; F2-Isoprostanes; Hypoxia, Brain; Infarction, Middle Cerebral Artery; L-Lactate Dehydrogenase; Neuroprotective Agents; Pyrazines; Rats; Rats, Wistar; Reperfusion Injury; Thiophenes