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Background: The risk factors among the types of ischemic stroke (atherothrombotic cerebral infarction: ATI, cardio-embolic infarction: CEI, lacunar infarction: LI) in aged stroke patients have rarely been compared to each other., Methods: We compared the clinical parameters of 300 elderly patients with ischemic stroke, age 65-98years, to 100 age-matched control patients., Results: Comparison by parametric test and logistic regression analysis between all 300 and 100 control patients showed higher systolic and diastolic blood pressures (p<0.001, p=0.03), lower estimated glomerular filtration rate (eGFR) (p=0.01), larger cardiothoracic ratio (CTR) (p<0.001), smoking (p<0.01) and possibly poor adherence to anti-hypertensive agents in the ischemic stroke patients (p<0.001). Comparisons among three types (n=100 for each) showed the highest atheromatous risk factors for ATI to be hemoglobin A1c (p=0.01) and low-density lipoprotein (p<0.001) and for CEI to be largest cardiac load, indicated by largest left atrial dimension (p<0.001), and CTR (p<0.001). Triglyceride level was found to be a borderline risk factor for LI (p=0.054). Comparison between those aged <74 versus ≥75years (n=150 for each) showed a lower eGFR (p=0.02) and larger right atrial dimension (p<0.001) in patients ≥75., Conclusion: The risk factors were quite different among the subtypes and aging., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Epidemiological studies suggest that the intake of flavonoids is inversely associated with risk of cardiovascular diseases and stroke, but there is no evidence showing the effect of flavonoids on vascular dementia. Because quercetin, a natural flavonoid, is known to scavenge free radicals, we investigated whether quercetin attenuates white matter damage in rats with chronic cerebral hypoperfusion, as a model of vascular dementia. Chronic hypoperfusion was induced by ligation of the bilateral carotid arteries in male Wistar rats, which received vehicle alone, 100 mg/kg quercetin, or 200 mg/kg quercetin intraperitoneally at 4-day intervals for 8 weeks after operation. Sham-operated rats were also studied. The area of vacuoles in the optic tract observed after hematoxylin and eosin staining was significantly reduced in the 200 mg/kg quercetin-treated hypoperfusion group versus the vehicle-treated hypoperfusion group (1.7+/-0.2% versus 3.9+/-0.3%; P<0.05). The present results are consistent with the idea that chronic treatment with quercetin could be protective against at least a part of ischemic white matter damage.

The aim of this study is to determine experimentally whether N-methyl-D-aspartate (NMDA) receptor is involved in nitrotyrosine formation in rat brain subjected to focal ischemia-reperfusion, by using the NMDA receptor antagonist MK-801. Halothane-anesthetized and artificially ventilated rats were given MK-801 (5 mg/kg, i.p.) or vehicle prior to 2 h of focal cerebral ischemia followed by 0.5 h of reperfusion. The brain was then removed and divided into four sections, cortical ischemic core, peri-ischemic cortex, lateral caudate-putamen and non-ischemic cortex. Tissue nitrotyrosine was measured by means of hydrolysis/HPLC. MK-801 significantly attenuated nitrotyrosine formation in the lateral caudate-putamen. We conclude that nitrotyrosine formation required activation of NMDA receptors, at least in part.

Peroxynitrite, generated by the reaction of nitric oxide and superoxide, has toxic effects including oxidation of sulfhydryls, lipid peroxidation and nitration of amino acid residues. So far peroxynitrite has not yet been detected in the ischemic brain because of its short half-life. Recently, we have succeeded in detecting 3-nitro-L-tyrosine, which is considered to be a footprint of peroxynitrite, in ischemic brain. Production of nitrotyrosine started during the ischemic period, increased after reperfusion, peaked at 48 hours, then declined up to 72 hours. Nitrotyrosine level was highest in the peri-infarct region, second highest in the core-of-infarct region, and lowest in the caudoputamen and the non-infarct region. Studies using pharmacological agents including MK-801, 7-nitroindazole and aminoguanidine suggest that peroxynitrite production originates from nNOS in the early phase of reperfusion, and from iNOS in the later phase of reperfusion. Further, the immunohistochemical study indicates that iNOS, located mainly in vascular cells, is predominantly responsible for nitrotyrosine production. Thus, peroxynitrite production depends on the stage of evolution of the ischemic process and on the cell type producing NO. These findings have important implications for the therapeutic time window and choice of NOS inhibitors in patients with cerebral infarction.

The purpose of this study was to evaluate the role of neuronal nitric oxide synthase (nNOS) in nitrotyrosine (NO2-Tyr) formation in the early phase of ischemia-reperfusion in mouse brain. Using a hydrolysis/high pressure liquid chromatography (HPLC) procedure (0.6 microM detection limit), we measured %NO2-Tyr (ratio of NO2-Tyr to total tyrosine) in 23 male C57Black/6J mice subjected to 2-h middle cerebral artery occlusion followed by 0.5-h reperfusion, in the presence (25 or 50 mg/kg) and absence of 7-nitroindazole (7-NI), a relatively specific nNOS inhibitor. At 25 mg/kg, 7-NI reduced NO2-Tyr formation to about a half of that in the vehicle-treated group (0.10 +/- 0.07 vs. 0.18 +/- 0.05%), while 50 mg/kg suppressed NO2-Tyr formation to below the limit of detection, indicating that nNOS is responsible for most of the NO2-Tyr formation in the early phase after reperfusion.

The purpose of this study was to establish the dynamics of nitrotyrosine (NO2-Tyr) formation and decay during the rise of NO2-Tyr in rat brain subjected to 2-hour focal ischemia-reperfusion, and to evaluate the role of inducible nitric oxide synthase in the rise. The authors first determined the half life of NO2-Tyr in rat brain at 24 hours after the start of reperfusion by blocking NO2-Tyr formation with N(G)-monomethyl-L-arginine and after the decay of NO2-Tyr by means of a hydrolysis/HPLC procedure. The values obtained were approximately 2 hours in both peri-infarct and core-of-infarct regions. Using the same hydrolysis/HPLC procedure, the ratio of nitrotyrosine to tyrosine from the 2-hour occlusion to as much as 72 hours after the start of reperfusion was measured in the presence and absence of aminoguanidine (100 mg/kg intraperitoneally twice a day). In the absence of aminoguanidine, the ratio of NO2-Tyr in the peri-infarct and core-of-infarct regions reached 0.95% +/- 0.34% and 0.52% +/- 0.34%, respectively, at 1 hour after the start of reperfusion. The elevated levels persisted until 48 hours, then declined. The peri-infarct region showed the highest percent NO2-Tyr level, followed by the core of infarct, then the caudoputamen. Aminoguanidine significantly reduced NO2-Tyr formation (up to 90% inhibition) during 24 to 48 hours. The authors conclude that inducible nitric oxide synthase is predominantly responsible for NO2-Tyr formation, at least in the late phase of reperfusion. These results have important implications for the therapeutic time window and choice of nitric oxide synthase inhibitors in patients with cerebral infarction.