scholarly journals Modulation by Nitric Oxide of Cerebral Neutrophil Accumulation after Transient Focal Ischemia in Rats

2000 ◽  
Vol 20 (5) ◽  
pp. 812-819 ◽  
Author(s):  
Sophie Batteur-Parmentier ◽  
Isabelle Margaill ◽  
Michel Plotkine
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Focal Ischemia ◽  
Left Middle Cerebral Artery ◽  
No Production ◽  
Myeloperoxidase Activity ◽  
Transient Focal Ischemia

A beneficial role of nitric oxide (NO) after cerebral ischemia has been previously attributed to its vascular effects. Recent data indicate a regulatory role for NO in initial leukocyte-endothelial interactions in the cerebral microcirculation under basal and ischemic conditions. In this study, the authors tested the hypothesis that endogenous NO production during and/or after transient focal cerebral ischemia can also be neuroprotective by limiting the process of neutrophil infiltration and its deleterious consequences. Male Sprague-Dawley rats were subjected to 2 hours occlusion of the left middle cerebral artery and the left common carotid artery. The effect of NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, intraperitoneally), an NO synthase inhibitor, was examined at 48 hours after ischemia on both infarct size and myeloperoxidase activity, an index of neutrophil infiltration. L-NAME given 5 minutes after the onset of ischemia increased the cortical infarct volume by 34% and increased cortical myeloperoxidase activity by 60%, whereas administration of L-NAME at 1, 7, and 22 hours of reperfusion had no effect. Such exacerbations of infarction and myeloperoxidase activity produced when L-NAME was given 5 minutes after the onset of ischemia were not observed in rats rendered neutropenic by vinblastine. These results suggest that after transient focal ischemia, early NO production exerts a neuroprotective effect by modulating neutrophil infiltration.

scholarly journals Short Therapeutic Window for MK-801 in Transient Focal Cerebral Ischemia in Normotensive Rats

1996 ◽  
Vol 16 (1) ◽  
pp. 107-113 ◽  
Author(s):  
I. Margaill ◽  
S. Parmentier ◽  
J. Callebert ◽  
M. Allix ◽  
R. G. Boulu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptors ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Activity ◽  
Therapeutic Window ◽  
Left Middle Cerebral Artery ◽  
Mk 801 ◽  
Transient Focal Cerebral Ischemia

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg−1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

scholarly journals Mito-Tempo prevents nicotine-induced exacerbation of ischemic brain damage

2018 ◽  
Vol 125 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Chun Li ◽  
Hong Sun ◽  
Guodong Xu ◽  
Kimberly D. McCarter ◽  
Jiyu Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Ischemic Brain Damage ◽  
Mitochondrial Oxidative Stress ◽  
Ischemic Brain

Nicotine may contribute to the pathogenesis of cerebrovascular disease via the generation of reactive oxygen species (ROS). Overproduction of ROS leads to brain damage by intensifying postischemic inflammation. Our goal was to determine the effect of Mito-Tempo, a mitochondria-targeted antioxidant, on ischemic brain damage and postischemic inflammation during chronic exposure to nicotine. Male Sprague-Dawley rats were divided into four groups: control, nicotine, Mito-Tempo-treated control, and Mito-Tempo-treated nicotine. Nicotine (2 mg·kg−1·day−1) was administered via an osmotic minipump for 4 wk. Mito-Tempo (0.7 mg·kg−1·day−1ip) was given for 7 days before cerebral ischemia. Transient focal cerebral ischemia was induced by occlusion of the middle cerebral artery for 2 h. Brain damage and inflammation were evaluated after 24 h of reperfusion by measuring infarct volume, expression of adhesion molecules, activity of matrix metalloproteinase, brain edema, microglial activation, and neutrophil infiltration. Nicotine exacerbated infarct volume and worsened neurological deficits. Nicotine did not alter baseline ICAM-1 expression, matrix metallopeptidase-2 activity, microglia activation, or neutrophil infiltration but increased these parameters after cerebral ischemia. Mito-Tempo did not have an effect in control rats but prevented the chronic nicotine-induced augmentation of ischemic brain damage and postischemic inflammation. We suggest that nicotine increases brain damage following cerebral ischemia via an increase in mitochondrial oxidative stress, which, in turn, contributes to postischemic inflammation.NEW & NOTEWORTHY Our findings have important implications for the understanding of mechanisms contributing to increased susceptibility of the brain to damage in smokers and users of nicotine-containing tobacco products.

scholarly journals Neuroprotective Effect of DAHP via Antiapoptosis in Cerebral Ischemia

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yanhua Qin ◽  
Weiming Hu ◽  
Yang Yang ◽  
Zhiying Hu ◽  
Weiyun Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Tunel Staining ◽  
Cox 2

Aberrant production of nitric oxide following inducible nitric oxide synthase (iNOS) expression has been implicated in cell death and contributes to ischemic brain injury. Tetrahydrobiopterin (BH4) is an essential cofactor of NOS activity. Herein, we evaluated antiapoptotic and anti-inflammatory effects of diamino-6-hydroxypyrimidine (DAHP), a guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) inhibitor on focal cerebral ischemia-reperfusion injury by middle cerebral artery occlusion and reperfusion (MCAO) and investigated the underlying mechanism. Sprague-Dawley rats were divided into five groups. Experimental groups were subjected to 1.5 h transient MCAO. T2-weighted imaging was performed to evaluate brain edema lesions in the stroke rats. Infarct volume was estimated by 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24 h reperfusion. Western blotting and immunohistochemistry were performed to detect iNOS, caspase-3, Bcl-2, COX-2, and TNF-α protein expressions. Apoptosis was determined by TUNEL staining. T2 hyperintensity changes were observed in primary ischemic region. DAHP pretreatment significantly suppressed iNOS overexpression, caspase-3, and TNF-α. There was also attenuation of neuronal apoptosis with decrement in proteins Bcl-2 and COX-2 expressions. On the basis of our results, we hypothesize DAHP to have a neuroprotective function against focal cerebral ischemia and might attenuate brain injury by decreasing reactive oxygen species (ROS) production, subsequently inhibiting apoptosis.

Effect of intermittent reperfusion and nitric oxide synthase inhibition on infarct volume during reversible focal cerebral ischemia

1995 ◽  
Vol 83 (3) ◽  
pp. 491-495 ◽  
Author(s):  
Brian A. Iuliano ◽  
Robert E. Anderson ◽  
Fredric B. Meyer
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Nitric Oxide Synthase ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Vascular Occlusion ◽  
Artery Occlusion ◽  
Content Type ◽  
Infarction Size ◽  
Oxide Synthase

✓ The authors examined the effects of both intermittent reperfusion and nitric oxide synthase (NOS) inhibition, caused by NG-nitro-l-arginine methyl ester (l-NAME) during episodes of focal cerebral ischemia induced to simulate the neurosurgical setting. Seventy-eight Wistar rats underwent single (60 minutes of ischemia) or repetitive (four 15-minute periods of ischemia separated by 5 minutes of reperfusion) episodes of middle cerebral artery occlusion while under anesthesia (1.0% halothane). Twenty-four hours after the procedure, the animals were given neurological examinations and then sacrificed for histological preparation and examination. The intermittent reperfusion groups tended to have smaller mean cortical infarctions. There was also a trend showing a decrease in infarction size in groups given l-NAME. The combination of intermittent reperfusion and preischemic administration ofl-NAME (10 mg/kg) resulted in a 65% reduction in infarction size (p < 0.05) when compared to that caused by 60 minutes of single occlusion without l-NAME. The use of NOS inhibition combined with intermittent reperfusion may be a technique to provide intraoperative cerebral protection during neurovascular procedures that require temporary vascular occlusion.

scholarly journals Effects of Tissue Type Plasminogen Activator in Embolic versus Mechanical Models of Focal Cerebral Ischemia in Rats

1999 ◽  
Vol 19 (12) ◽  
pp. 1316-1321 ◽  
Author(s):  
Wei Meng ◽  
Xiaoying Wang ◽  
Minoru Asahi ◽  
Tsuneo Kano ◽  
Kazuko Asahi ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cerebral Perfusion ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Tissue Type ◽  
Negative Effects ◽  
Tissue Type Plasminogen Activator ◽  
Rat Models ◽  
Type Plasminogen Activator ◽  
Transient Focal Ischemia

Tissue type plasminogen activator (tPA) can be effective therapy for embolic stroke by restoring cerebral perfusion. However, a recent experimental study showed that tPA increased infarct size in a mouse model of transient focal ischemia, suggesting a possible adverse effect of tPA on ischemic tissue per se. In this report, the effects of tPA in two rat models of cerebral ischemia were compared. In experiment 1, rats were subjected to focal ischemia via injection of autologous clots into the middle cerebral artery territory. Two hours after clot injection, rats were treated with 10 mg/kg tPA or normal saline. Perfusion-sensitive computed tomography scanning showed that tPA restored cerebral perfusion in this thromboembolic model. Treatment with tPA significantly reduced ischemic lesion volumes measured at 24 hours by >60%. In experiment 2, three groups of rats were subjected to focal ischemia via a mechanical approach in which a silicon-coated filament was used intraluminally to occlude the origin of the middle cerebral artery. In two groups, the filament was withdrawn after 2 hours to allow for reperfusion, and then rats were randomly treated with 10 mg/kg tPA or normal saline. In the third group, rats were not treated and the filament was not withdrawn so that permanent focal ischemia was present. In this experiment, tPA did not significantly alter lesion volumes after 2 hours of transient focal ischemia. In contrast, permanent ischemia significantly increased lesion volumes by 55% compared with transient ischemia. These results indicate that in these rat models of focal cerebral ischemia, tPA did not have detectable negative effects. Other potentially negative effects of tPA may be dependent on choice of animal species and model systems.

scholarly journals Deficiency of Intercellular Adhesion Molecule 1 Attenuates Microcirculatory Disturbance and Infarction Size in Focal Cerebral Ischemia

1998 ◽  
Vol 18 (12) ◽  
pp. 1336-1345 ◽  
Author(s):  
Kazuo Kitagawa ◽  
Masayasu Matsumoto ◽  
Takuma Mabuchi ◽  
Yoshiki Yagita ◽  
Toshiho Ohtsuki ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Knockout Mice ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Intercellular Adhesion Molecule ◽  
Wild Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Transient Focal Ischemia

Recent evidence has shown crucial roles for cell-adhesion molecules in inflammation-induced rolling, adhesion, and accumulation of neutrophils in tissue. Intercellular adhesion molecule-1 (ICAM-1) is one of these adhesion molecules. Previous studies have shown marked reduction in the size of infarction after focal cerebral ischemia by depletion of granulocytes and administration of the antibody against ICAM-1. In the present study we investigated the role of ICAM-1 in the size of ischemic lesions, accumulation of granulocytes, and microcirculatory compromise in focal cerebral ischemia by using ICAM-1–knockout mice. Ischemic lesions were significantly mitigated in knockout mice after permanent and transient focal ischemia, even though the number of granulocytes in the infarcted tissue was almost the same between knockout and wild-type mice. Depletion of granulocytes further decreased the size of ischemic lesions after transient focal ischemia in ICAM-1–knockout mice. Microcirculation was reduced after focal ischemia, but it was better preserved in the cerebral cortex of knockout mice than that of wild-type mice. The present study demonstrated that ICAM-1 played a role in microcirculatory failure and subsequent development and expansion of infarction after focal cerebral ischemia. However, it is highly unlikely that ICAM-1 played a key role in accumulation of granulocytes after focal cerebral ischemia.

scholarly journals Neuroprotective Effects of the CRF1 Antagonist R121920 after Permanent Focal Ischemia in the Rat

2001 ◽  
Vol 21 (10) ◽  
pp. 1208-1214 ◽  
Author(s):  
Kenneth B. Mackay ◽  
Haig Bozigian ◽  
Dimitri E. Grigoriadis ◽  
Sarah A. Loddick ◽  
Gail Verge ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Experimental Models ◽  
Suture Technique ◽  
Bolus Administration ◽  
Neuroprotective Effects ◽  
Crf1 Antagonist ◽  
Hemispheric Infarct

The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood–brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 ± 0.40 μg/mL), which were approximately 2-fold greater than those in plasma (0.98 ± 0.24 μg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly ( P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction ( P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF1 antagonists in two experimental models of permanent focal cerebral ischemia.

scholarly journals THE COMBINED USE OF PROPARGYLGLYCINE AND L-CYSTEINE PREVENTS OXIDATIVE AND NITROSATIVE STRESS IN CARDIAC TISSUES IN FOCAL CEREBRAL ISCHEMIA-REPERFUSION

2021 ◽  
Vol 67 (3) ◽  
pp. 3-9
Author(s):  
N.O. Dorofeeva ◽  
◽  
Yu.P. Korkach ◽  
P.R. Sharipov ◽  
V.F. Sagach ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Nitrosative Stress ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Focal Ischemia ◽  
Oxidative And Nitrosative Stress ◽  
Cardiac Tissues ◽  
Combined Use

Cerebral ischemia is a neurogenerative disoder that leads to partial or general paralysis and subsequent disability. The development of oxidative-nitrosative stress on the background of insufficient production of nitric oxide (NO) and hydrogen sulfide (H2S) are the main reasons behind the pathogenesis of focal ischemia-reperfusion and cerebrocardial syndrome. We studied the combined use of propargylglycine and L-cysteine as drugs that prevent oxidative and nitrosative stress and are activators of gasotransmitters - NO and H2S in the heart tissues of rats with focal ischemia. It was shown that focal ischemiareperfusion was accompanied by a significant increase in the heart of rats calcium-independent inducible synthesis of NO (iNOS) and an increase in markers of oxidative stress (superoxide anion radical, hydroxyl radical, diene conjugates) NO-synthase (cNOS). This caused disruption of nitric oxide synthesis due to the uncoupling state of cNOS in the rat heart. The use of a combination of DL-proparlgylglycine (11.31 mg/ kg) and L-cysteine (112.1 mg / kg) 40 min before the modeling of focal ischemia significantly reduced the activity of iNOS and the content of markers of oxidative metabolism in the heart of adult rats and increased the constitutive synthesis of NO, which led to restoration of the cNOS incoupling. We observed activation of endogenous synthesis of H2S, which interacts closely with the nitric oxide system and is a powerful antioxidant. It should also be noted an increase in animal survival after 24 h by 25%. Thus, the combined use of propargylglycine and Lcysteine in rats prevented disruption of NO and H2S synthesis in cardiac tissues in ishemia-reperfusion due to a slowing of the development of oxidative stress, which helped to restore cNOS coupling.

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