dinoprost and Brain-Infarction

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

Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 +/- 3.6% in vehicle pups (n = 28) to 11.9 +/- 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2alpha measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 +/- 7 pg/g in the shams (n = 6), 175 +/- 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 +/- 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

Topics: Animals; Animals, Newborn; Apoptosis; Atrophy; Body Temperature; Brain; Brain Infarction; Carotid Stenosis; Caspase 3; Caspases; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hypoxia-Ischemia, Brain; Male; Motor Activity; Niacinamide; Organ Size; Oxidative Stress; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vitamin B Complex

Oxidative stress and NO are thought to play important roles in arteriosclerosis pathogenesis, a major cause of white matter lesions in the brain. Therefore, we examined whether NO metabolites (NOx) and 8-iso-prostaglandin F(2alpha) (IsoP) levels in vivo correlated with the severity of periventricular hyperintensity (PVH) to evaluate potential roles of oxidative stress and NO in white matter lesions.. Participants (687 males and 528 females) of a health-screening examination were recruited into the study. The plasma NOx and urinary IsoP levels were measured using the Griess method and ELISA, respectively. PVH was diagnosed on the basis of MRIs. In nonparametric univariate trend analyses, plasma NOx as well as aging, presence of hypertension and of lacunes, mean blood pressure, and high-density lipoprotein cholesterol showed highly significant monotone correlation with PVH severity (P

Topics: Age Factors; Aged; Brain; Brain Diseases; Brain Infarction; Cholesterol, HDL; Dinoprost; Disease Progression; Female; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Risk Factors; Triglycerides