scholarly journals iNOS-Derived NO and Nox2-Derived Superoxide Confer Tolerance to Excitotoxic Brain Injury through Peroxynitrite

2007 ◽  
Vol 27 (8) ◽  
pp. 1453-1462 ◽  
Author(s):  
Takayuki Kawano ◽  
Alexander Kunz ◽  
Takato Abe ◽  
Hélène Girouard ◽  
Josef Anrather ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Cortical Neurons ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
No Donor ◽  
Inos Inhibitor ◽  
Common Carotid Artery Occlusion

Sublethal injurious stimuli induce tolerance to subsequent lethal insults, a phenomenon termed preconditioning. Inducible nitric oxide synthase (iNOS) is essential for the preconditioning induced by transient bilateral common carotid artery occlusion (BCCAO) or by systemic administration of the endotoxin lipopolysaccharide (LPS). We used a model of brain injury produced by neocortical injection of N-methyl-d-aspartate (NMDA) to investigate the mechanisms by which iNOS-derived nitric oxide (NO) contributes to tolerance induced by LPS or BCCAO. We found that the tolerance is blocked by the iNOS inhibitor aminoguanidine, is not observed in iNOS-null mice, and is rescued by the NO donor DTPA NONOate. Lipopolysaccharide failed to induce preconditioning in mice lacking the nox2 subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, suggesting that superoxide derived from NADPH oxidase is needed for the induction of the tolerance. Because superoxide reacts with NO to form peroxynitrite, we investigated the role of peroxynitrite. We found that LPS induces the peroxynitrite marker 3-nitrotyrosine in cortical neurons and that the peroxynitrite decomposition catalyst FeTPPS abolishes LPS-induced preconditioning. These results suggest that the protective effect of iNOS-derived NO is mediated by peroxynitrite formed by the reaction of NO with NADPH oxidase-derived superoxide. Thus, peroxynitrite, in addition to its well-established deleterious role in ischemic brain injury and neurodegeneration, can also be beneficial by inducing tolerance to excitotoxicity.

scholarly journals Inhibition of Vascular Nitric Oxide after Rat Chronic Brain Hypoperfusion: Spatial Memory and Immunocytochemical Changes

2005 ◽  
Vol 25 (6) ◽  
pp. 663-672 ◽  
Author(s):  
Jack C. de la Torre ◽  
Gjumrakch Aliev
Keyword(s):  
Nitric Oxide ◽  
Spatial Memory ◽  
Memory Function ◽  
Critical Role ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Significant Loss ◽  
Electron Microscopic ◽  
Vessel Occlusion ◽  
Common Carotid Artery Occlusion

An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance ( P=0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.

scholarly journals Nadph Oxidase Mediates Striatal Neuronal Injury after Transient Global Cerebral Ischemia

2010 ◽  
Vol 31 (3) ◽  
pp. 868-880 ◽  
Author(s):  
Hideyuki Yoshioka ◽  
Kuniyasu Niizuma ◽  
Masataka Katsu ◽  
Nobuya Okami ◽  
Hiroyuki Sakata ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nadph Oxidase ◽  
Late Phase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Striatal Neurons ◽  
Reactive Microglia ◽  
Transient Global Cerebral Ischemia

Medium spiny neurons (MSNs) constitute most of the striatal neurons and are known to be vulnerable to ischemia; however, the mechanisms of the vulnerability remain unclear. Activated forms of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (NOX), which require interaction between cytosolic and membrane-bound subunits, are among the major sources of superoxide in the central nervous system. Although increasing evidence suggests that NOX has important roles in neurodegenerative diseases, its roles in MSN injury after transient global cerebral ischemia (tGCI) have not been elucidated. To clarify this issue, C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion for 22 minutes. Western blot analysis revealed upregulation of NOX subunits and recruitment of cytosolic subunits to the cell membrane at early (3 to 6 hours) and late (72 hours) phases after tGCI. Taken together with immunofluorescent studies, this activation arose in MSNs and endothelial cells at the early phase, and in reactive microglia at the late phase. Pharmacological and genetic inhibition of NOX attenuated oxidative injury, microglial activation, and MSN death after tGCI. These findings suggest that NOX has pivotal roles in MSN injury after tGCI and could be a therapeutic target for brain ischemia.

scholarly journals Possible Pharmacodynamic Interaction of Azelnidipine with Citicoline Against Ischemic Brain Injury: Behavioral, Biochemical and Histological Alterations

2020 ◽  
Vol 27 (1) ◽  
pp. 9-17
Author(s):  
Varun Gupta ◽  
Zein Eddin Bader ◽  
Aakriti ◽  
Anil Kumar
Keyword(s):  
Brain Injury ◽  
Carotid Artery ◽  
Wistar Rats ◽  
Neuronal Damage ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Bilateral Common Carotid Artery ◽  
Common Carotid Artery Occlusion

Background: Currently, no drug has been approved for the management of postischemic neuronal damage. Existing studies show that calcium channel blockers have neuroprotective properties, while citicoline is involved in maintaining neuronal integrity. Purpose: This study was envisaged to investigate the effect of azelnidipine (novel calcium channel blocker) alone and in combination with citicoline (phosphatidyl-choline analogue) against ischemic brain damage in Wistar rats. Methods: Previously standardized bilateral common carotid artery occlusion model was used to induce cerebral ischemic injury in Wistar rats. Pretreatment with azelnidipine (1.5 mg/Kg and 3 mg/Kg; p.o.) or citicoline (250 mg/Kg; i.p.) was done every 24 h starting 7 days before the bilateral common carotid artery occlusion surgery. Pharmacological assessments (behavioral, biochemical, mitochondrial, molecular, and histological) were done after 48 h of the reperfusion period. Results: Azelnidipine and citicoline were found to protect the brain from progressive neuronal damage as seen by improved sensorimotor behavior (locomotion, rota rod, and beam balance performance) and reduced oxidative stress (decreased malondialdehyde (MDA), nitrite, increased glutathione (GSH), superoxide dismutase (SOD)). Impairment of mitochondrial enzyme system and increase in the infarct area were found to be arrested by individual treatments with azelnidipine and citicoline. These effects were further potentiated synergistically as the combination of citicoline and azelnidipine was found to decrease glutamate levels, caspase-3 activity and histological alterations as compared to their individual effects. Conclusion: Azelnidipine and citicoline synergistically decrease excitotoxic and oxidative damage against ischemic brain injury in Wistar rats and, therefore, propose a clinically relevant combination for the prevention of postischemic neuronal damage.

scholarly journals Strain-Related Differences in Mouse Neonatal Hypoxia-Ischemia

2018 ◽  
Vol 40 (5-6) ◽  
pp. 490-496 ◽  
Author(s):  
R. Ann Sheldon ◽  
Christine Windsor ◽  
Donna M. Ferriero
Keyword(s):  
Brain Injury ◽  
Mouse Model ◽  
Strain Differences ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Cresyl Violet ◽  
Posterior Cortex ◽  
Carotid Ligation ◽  
Hypoxia Ischemia ◽  
Cd1 Mice

Neonatal hypoxic-ischemic brain injury is commonly studied by means of the Vannucci procedure in mice or rats (unilateral common carotid artery occlusion followed by hypoxia). Previously, we modified the postnatal day 7 (P7) rat procedure for use in mice, and later demonstrated that genetic strain strongly influences the degree of brain injury in the P7 mouse model of hypoxia-ischemia (HI). Recently, the P9 or P10 mouse brain was recognized as the developmental equivalent of a term neonatal human brain, rather than P7. Consequently, the Vannucci procedure has again been modified, and a commonly used protocol employs 10% oxygen for 50 min in C57Bl/6 mice. Strain differences have yet to be described for the P9/P10 mouse model. In order to determine if the strain differences we previously reported in the P7 mouse model are present in the P9 model, we compared 2 commonly used strains, CD1 and C57Bl/6J, in both the P7 (carotid ligation [in this case, right] followed by exposure to 8% oxygen for 30 min) and P9 (carotid ligation [in this case left] followed by exposure to 10% oxygen) models of HI. Experiments using the P7 model were performed in 2001–2012 and those using the P9 model were performed in 2012–2016. Five to seven days after the HI procedure, mice were perfused with 4% paraformaldehyde, their brains were sectioned on a Vibratome (50 µm) and alternate sections were stained with Perl’s iron stain or cresyl violet. Brain sections were examined microscopically and scored for the degree of injury. Since brains in the P7 group had been scored previously with a slightly different system, they were reanalyzed using our current scoring system which scores injury in 11 regions: the anterior, middle, and posterior cortex; the anterior, middle, and posterior striatum; CA1, CA2, CA3, and the dentate gyrus of the hippocampus and thalamus, on a scale from 0 (none) to 3 (cystic infarct) for a total score of 0–33. Brains in the P9 group were scored with the same system. Given the same insult, the P7 CD1 mice had greater injury than the C57Bl/6J mice, which agrees with our previous findings. The P9 CD1 mice also had greater injury than the C57Bl/6J mice. This study confirms that CD1 mice are more susceptible to injury than C57Bl/6J mice and that strain selection is important when using mouse models of HI.

scholarly journals Common Carotid Artery Occlusion Treatment: Revealing a Gap in the Current Guidelines

2013 ◽  
Vol 58 (3) ◽  
pp. 846 ◽  
Author(s):  
C. Klonaris ◽  
G.N. Kouvelos ◽  
M. Kafeza ◽  
A. Koutsoumpelis ◽  
A. Katsargyris ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Common Carotid Artery ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Common Carotid Artery Occlusion ◽  
Current Guidelines

scholarly journals Endovascular Revascularization of a Symptomatic Common Carotid Artery Occlusion

2016 ◽  
Vol 44 (1) ◽  
pp. 120-123 ◽  
Author(s):  
Julie Kromm ◽  
Tim E. Darsaut ◽  
Khurshid Khan ◽  
Robert Ashforth ◽  
Esseddeeg Ghrooda
Keyword(s):  
Carotid Artery ◽  
Common Carotid Artery ◽  
Clinical Presentation ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Common Site ◽  
Extracranial Carotid Artery ◽  
The Common ◽  
Common Carotid Artery Occlusion ◽  
Diagnostic Investigations

AbstractAlthough the common carotid artery is the second most common site for extracranial carotid artery stenosis, complete symptomatic occlusion in the absence of devastating stroke is rare. We present a case of complete common carotid artery occlusion failing medical management and requiring endovascular intervention. The clinical presentation, diagnostic investigations, and management of complete carotid artery occlusions are discussed.

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