scholarly journals Glibenclamide Administration Attenuates Infarct Volume, Hemispheric Swelling, and Functional Impairments following Permanent Focal Cerebral Ischemia in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Bushra Wali ◽  
Tauheed Ishrat ◽  
Fahim Atif ◽  
Fang Hua ◽  
Donald G. Stein ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Grip Strength ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Constant Infusion ◽  
Lesion Volume ◽  
Functional Impairments ◽  
Sprague Dawley ◽  
Neuroprotective Effects

Studies from a single laboratory have shown that in rodent models of permanent stroke, administration of the sulfonylurea glibenclamide (Glib) is highly effective in reducing edema, mortality, and lesion volume. The Stroke Therapy Academic Industry Roundtable (STAIR) recommends that new acute treatments for ischemic stroke to be replicated across different laboratories. Accordingly, we examined the effect of low-dose Glib in a permanent suture occlusion model of stroke. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO) followed by an initial intraperitoneal injection of Glib (10 μg/kg) and the start of a constant infusion (200 ng/h) via miniosmotic pump at the onset of ischemia. Functional deficits were assessed by Neurological Severity Score (NSS) and grip-strength meter at 24 and 48 h after pMCAO. Glib-treated rats showed a significant reduction in infarct volume, lower NSS, and less hemispheric swelling compared to vehicle. Grip strength was decreased significantly in pMCAO rats compared to shams and significantly improved by treatment with Glib. Taken together, these data indicate that Glib has strong neuroprotective effects following ischemic stroke and may warrant further testing in future clinical trials for human stroke.

VWF-Cleaving Protease ADAMTS13 Reduces Brain Injury Following Ischemic Stroke in Mice: Essential Role for VWF in Stroke

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 259-259
Author(s):  
Bing-Qiao Zhao ◽  
Anil kumar Chauhan ◽  
Ian S. Patten ◽  
Michael Dockal ◽  
Friedrich Scheiflinger ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Essential Role ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Protective Role ◽  
Artery Occlusion ◽  
Type I ◽  
Deficient Mice

Abstract Ischemic stroke is the second leading cause of death and disability. The only approved therapy available is recombinant tissue plasminogen activator (tPA), but its use remains limited. Therefore, there is a need for an alternative drug. Platelets and their adhesion receptors play a crucial role in modulating infarct size during ischemic stroke. ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) is a plasma metalloprotease that cleaves von Willebrand factor (VWF) an important adhesion molecule for platelets at sites of vascular injury. In patients, an increase in circulating levels of VWF and a decrease in ADAMTS13 activity are considered risk factors for ischemic stroke. By using genetically-modified mice we have previously shown that ADAMTS13 down regulates both thrombosis and inflammation and recombinant human ADAMTS13 down regulates platelet thrombi in injured arterioles. All these processes were dependent on VWF. We therefore hypothesize that ADAMTS13 has a protective role after ischemic stroke. In this study, we show that VWF deficiency or VWF heterozygosity in mice reduces infarct volume by two-fold after focal cerebral ischemia compared to wild-type (WT) in the middle cerebral artery occlusion (MCAO) stroke model. Furthermore, infusion of recombinant human VWF in WT mice not only accelerates thrombosis in the ferric-chloride injured artery model, but also increases infarct volume compared to vehicle-treated controls. These findings suggest an essential role of VWF in modulating infarction after stroke. We also show that ADAMTS13 deficiency in mice results in approximately 20% larger infarcts after cerebral ischemia compared to WT. The larger infarcts observed in ADAMTS13 deficient mice were due to VWF because mice deficient in both ADAMTS13 and VWF had infarct sizes similar to VWF deficient mice. Importantly, infusion of r-human ADAMTS13 immediately before reperfusion (two hour after occlusion) significantly reduced infarct volume (106.2 ± 9.7 mm3 vs 75.8 ± 6.9 mm3, P<0.05). Of note, we observed that ADAMTS13 protein was induced in the ischemic penumbra region of brain after ischemic stroke. Our findings reveal an important role for VWF in modulating infarct volume after ischemic stroke. In addition, recombinant-ADAMTS13 could become a new therapeutic agent for stroke therapy.

scholarly journals Sevoflurane Preconditioning against Focal Cerebral Ischemia

2009 ◽  
Vol 110 (6) ◽  
pp. 1271-1278 ◽  
Author(s):  
Jean-Laurent Codaccioni ◽  
Lionel J. Velly ◽  
Chahrazad Moubarik ◽  
Nicolas J. Bruder ◽  
Pascale S. Pisano ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Cerebral Injury ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Control Group ◽  
Sprague Dawley ◽  
Nissl Staining ◽  
Neuroprotective Effects ◽  
Sevoflurane Preconditioning

Background Preconditioning the brain with volatile anesthetics seems to be a viable option for reducing ischemic cerebral injury. However, it is uncertain whether this preconditioning effect extends over a longer period of time. The purpose of this study was to determine if sevoflurane preconditioning offers durable neuroprotection against cerebral ischemia. Methods Rats (Sprague-Dawley) were randomly allocated to two groups: nonpreconditioned control group (n = 44) and preconditioned group (n = 45) exposed to 2.7 vol% sevoflurane (45 min) 60 min before surgery. Animals in both groups were anesthetized with 3.0 vol% sevoflurane and subjected to transient middle cerebral artery occlusion. After 60 min of awake focal ischemia, the filament was removed. Functional neurologic outcome (range 0-18; 0 = no deficit), cerebral infarct size (Nissl staining), and apoptosis (Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling; cleaved caspase-3 staining) were evaluated at 3, 7, and 14 days after ischemia. Results Sevoflurane preconditioning significantly improved functional outcome and reduced infarct volume (109 +/- 43 vs. 148 +/- 56 mm(3)) 3 days after ischemia compared to the control group. However, after 7- and 14-day recovery periods, no significant differences were observed between groups. The number of apoptotic cells was significantly lower in the preconditioned group than in the control group after 3- and 7-day recovery periods. Fourteen days after ischemia, no differences were observed between groups. Conclusion In this model of transient focal cerebral ischemia, sevoflurane preconditioning induced effective but transient neuroprotective effects. Sevoflurane preconditioning also decreased ischemia-induced apoptosis in a more sustained way because it was observed up to 7 days after injury.

scholarly journals Neuroprotective Effects of Early Hypothermia Induced by Phenothiazines and DHC in Ischemic Stroke

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yun Han ◽  
Xiao-kun Geng ◽  
Hangil Lee ◽  
Fengwu Li ◽  
Yuchuan Ding
Keyword(s):  
Ischemic Stroke ◽  
Brain Damage ◽  
Glucose Transporter ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Ros Production ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Neuroprotective Effects ◽  
Sprague Dawley Rats

Background and Purpose. Studies have shown that interischemia hypothermia is able to reduce the size of myocardial infarctions and improve their clinical outcomes. The present study determined whether interischemia hypothermia induced by the pharmacological approach induced stronger neuroprotection in ischemic brains. Methods. Adult male Sprague Dawley rats were studied in 4 groups: (1) sham; (2) stroke; (3) stroke treated with pharmacological hypothermia before reperfusion (interischemia hypothermia); and (4) stroke treated with pharmacological hypothermia after reperfusion is initiated (inter-reperfusion hypothermia). The combination of chlorpromazine and promethazine with dihydrocapsaicin (DHC) was used to induce hypothermia. To compare the neuroprotective effects of drug-induced hypothermia between the interischemia and inter-reperfusion groups, brain damage was evaluated using infarct volume and neurological deficits at 24 h reperfusion. In addition, mRNA expressions of NADPH oxidase (NOX) subunits (gp91phox, p67phox, p47phox, and p22phox) and glucose transporter subtypes (GLUT1 and GLUT3) were determined by real-time PCR at 6 and 24 h reperfusion. ROS production was measured by flow cytometry assay at the same time points. Results. In both hypothermia groups, the cerebral infarct volumes and neurological deficits were reduced in the ischemic rats. At 6 and 24 h reperfusion, ROS production and the expressions of NOX subunits and glucose transporter subtypes were also significantly reduced in both hypothermia groups as compared to the ischemic group. While there were no statistically significant differences between the two hypothermia groups at 6 h reperfusion, brain damage was significantly further decreased by interischemia hypothermia at 24 h. Conclusion. Both interischemia and inter-reperfusion pharmacological hypothermia treatments play a role in neuroprotection after stroke. Interischemia hypothermia treatment may be better able to induce stronger neuroprotection after ischemic stroke. This study provides a new avenue and reference for stronger neuroprotective hypothermia before vascular recanalization in stroke patients.

Protective Effect of Capparis spinosa Extract Against Focal Cerebral Ischemia-Reperfusion Injury in Rats

2021 ◽  
Vol 21 ◽  
Author(s):  
Hassan Rakhshandeh ◽  
Samira Asgharzade ◽  
Mohammad Bagher Khorrami ◽  
Fatemeh Forouzanfar
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Ischemia Reperfusion Injury ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Public Health Problem ◽  
Artery Occlusion ◽  
Stroke Group ◽  
Capparis Spinosa

Background: Ischemic stroke is a serious public health problem. Despite extensive research focusing on the area, little is known about novel treatments. Objective: In this study, we aimed to investigate the effects of Capparis spinosa (C. spinosa) extract in the middle cerebral artery occlusion (MCAO) model of ischemic stroke. Methods: Wistar rats underwent 30-min MCAO-induced brain ischemia followed by 24 h of reperfusion. C. spinose was administrated orally once a day for 7 days before the induction of MCAO. The neurologic outcome, infarct volume (TTC staining), histological examination, and markers of oxidative stress, including total thiol content and malondialdehyde (MDA) levels, were measured 24 hr. after the termination of MCAO. Results: Pretreatment with C. spinosa, reduced neurological deficit score, histopathological alterations, and infarct volume in treated groups compared to stroke group. Furthermore, pretreatment with C. spinosa extract significantly reduced the level of MDA with concomitant increases in the levels of thiol in the brain tissues compared with the stroke group. Conclusion: Our study demonstrates that C. spinosa extract effectively protects MCAO injury through attenuation of suppressing oxidative stress.

scholarly journals A novel indication of platonin, a therapeutic immunomodulating medicine, on neuroprotection against ischemic stroke in mice

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Joen-Rong Sheu ◽  
Zhih-Cherng Chen ◽  
Thanasekaran Jayakumar ◽  
Duen-Suey Chou ◽  
Ting-Lin Yen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Infarct Volume ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Occlusion Time ◽  
Oxide Synthase ◽  
Cerebral Artery Occlusion

Abstract Thrombosis and stroke are major causes of disability and death worldwide. However, the regular antithrombotic drugs may have unsatisfactory results and side effects. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers and some acute inflammation. Here, we explored the neuroprotective effects of platonin against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in mice. Platonin(200 μg/kg) substantially reduced cerebral infarct volume, brain edema, neuronal cell death and neurological deficit scores, and improved the MCAO-reduced locomotor activity and rotarod performance. Platonin(5–10 μM) potently inhibited platelet aggregation and c-Jun NH2-terminal kinase (JNK) phosphorylation in collagen-activated platelets. The antiaggregation effect did not affect bleeding time but increased occlusion time in platonin(100 and 200 μg/kg)-treated mice. Platonin(2–10 μM) was potent in diminishing collagen- and Fenton reaction-induced ∙OH formation. Platonin(5–10 μM) also suppressed the expression of nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β, and JNK phosphorylation in lipopolysaccharide-stimulated macrophages. MCAO-induced expression of 3-nitrotyrosine and Iba1 was apparently attenuated in platonin(200 μg/kg)-treated mice. In conclusion, platonin exhibited remarkable neuroprotective properties against MCAO-induced ischemia in a mouse model through its antiaggregation, antiinflammatory and antiradical properties. The observed therapeutic efficacy of platonin may consider being a novel medcine against ischemic stroke.

Abstract TP116: Effect of Voluntary Physical Activity on Circulating LG3 and Its Impact on Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ifechukwude Joachim Biose ◽  
Katie E Salmeron ◽  
Anthony Parker ◽  
Ann Stowe ◽  
Gregory Bix
Keyword(s):  
Physical Activity ◽  
Ischemic Stroke ◽  
Infarct Volume ◽  
Exercise Group ◽  
Artery Occlusion ◽  
Control Group ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Voluntary Physical Activity ◽  
Wheel Activity

Physical activity (PA) is neuroprotective. However, the mechanism for the benefit of PA prior to ischemic stroke is not well understood. Circulating LG3 levels, a 25-kDa protein fragment of brain extracellular matrix proteoglycan (perlecan), increases with PA in humans. We showed that LG3 significantly reduces infarct volume following ischemic stroke. The aim of this study is to assess whether LG3 concentration increases with voluntary physical activity in mice and to determine how circulating LG3 concentration, prior to ischemic stroke, influences outcomes. Male mice (C57BL/6J, 8-9 weeks old, 21–24 g) were randomized into sedentary control group (individually housed in motorized running wheel cages with applied brakes) and an exercise group with access to running wheels. Blood draws were collected via submental method on day 1, 7, 14 and 20 of wheel activity prior to middle cerebral artery occlusion (MCAO), to evaluate LG3 concentration in serum. Following three weeks of voluntary PA or sedentary condition, 25 mice (sedentary n=13, exercise n=12) underwent transient distal MCAO for 60 min and were recovered for three days. In another study, 29 mice (sedentary n=15, exercise n=14) underwent transient proximal MCAO for 60 min. Calf muscles (soleus and gastrocnemius) and brain samples were collected for histology, protein analysis, and infarct volume assessment. We show that voluntary PA significantly reduces ischemic lesion volume compared to sedentary controls, following distal MCAO (15.2±8 vs 5.3±2 mm 3 ; P<0.0001, Figure 1). The analysis of LG3 concentration, neurofunction, as well as brain and muscle samples are currently ongoing. We expect that the findings will link LG3 concentration to the volume of exercise as well as the neuroprotection it confers in the setting of ischemic stroke.

scholarly journals Rapid Tolerance to Focal Cerebral Ischemia in Rats is Attenuated by Adenosine A1 Receptor Antagonist

2002 ◽  
Vol 22 (2) ◽  
pp. 161-170 ◽  
Author(s):  
Michiko Nakamura ◽  
Kazuhiko Nakakimura ◽  
Mishiya Matsumoto ◽  
Takefumi Sakabe
Keyword(s):  
Receptor Antagonist ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Induced Tolerance ◽  
Cerebral Artery Occlusion

Two types of ischemic tolerance in the brain, rapid and delayed, have been reported in terms of the interval between the conditioning and test insults. Although many reports showed that delayed-phase neuroprotection evoked by preconditioning is evident after 1 week or longer, there have been a few investigations about rapidly induced tolerance, and the reported neuroprotective effects become ambiguous 7 days after the insults. The authors examined whether this rapid ischemic tolerance exists after 7 days of reperfusion in a rat focal ischemic model, and investigated modulating effects of the adenosine A1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine). Preconditioning with 30 minutes of middle cerebral artery occlusion reduced infarct volume 7 days after 180 minutes of subsequent focal ischemia given after 1-hour reperfusion. The rapid preconditioning also improved neurologic outcome. These beneficial effects were attenuated by pretreatment of 0.1 mg/kg DPCPX, which did not influence the infarct volume after conditioning (30 minutes) or test (180 minutes) ischemia when given alone. The results show that preconditioning with a brief focal ischemia induces rapid tolerance to a subsequent severe ischemic insult, the effect of which is still present after 7 days of reperfusion, and that the rapid ischemic tolerance is possibly mediated through an adenosine A1 receptor–related mechanism.

scholarly journals Neuroprotective Effects of a Novel Nitrone, NXY-059, after Transient Focal Cerebral Ischemia in the Rat

1999 ◽  
Vol 19 (7) ◽  
pp. 778-787 ◽  
Author(s):  
Satoshi Kuroda ◽  
Ryoichi Tsuchidate ◽  
Maj-Lis Smith ◽  
Kirk R. Maples ◽  
Bo K. Siesjö
Keyword(s):  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Recovery Period ◽  
Artery Occlusion ◽  
Transfer Constant ◽  
Neuroprotective Effects ◽  
Transient Focal Cerebral Ischemia ◽  
Therapeutic Opportunity ◽  
Cerebral Artery Occlusion ◽  
Antiischemic Effect

Recent results have demonstrated that the spin trapping agent α-phenyl- N- tert-butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle cerebral artery occlusion, even when given 1 to 3 hours after the start of recirculation. In the current study, the authors assessed the effect of NXY-059, a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30, 3.0, or 30 mg · kg−1 followed by 0.30, 3.0, or 30 mg · kg−1 · h−1 for 24 or 48 hours. Dose–response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg · kg−1 had a small and 30 mg · kg-i a marked effect on infarct volume. At equimolar doses (3.0 mg · kg−1 for NXY-059 and 1.4 mg · kg−1 for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained when a recovery period of 7 days was allowed. The window of therapeutic opportunity for NXY-059 was 3 to 6 hours after the start of recirculation. Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively. This fact, and the pronounced antiischemic effect of NXY-059, suggest that the delayed events leading to infarction may be influenced by reactions occurring at the blood–endothelial interface.

scholarly journals Adenosine kinase determines the degree of brain injury after ischemic stroke in mice

2011 ◽  
Vol 31 (7) ◽  
pp. 1648-1659 ◽  
Author(s):  
Hai-Ying Shen ◽  
Theresa A Lusardi ◽  
Rebecca L Williams-Karnesky ◽  
Jing-Quan Lan ◽  
David J Poulsen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Adenosine Kinase ◽  
Cerebral Injury ◽  
Induced Tolerance ◽  
Cerebral Artery Occlusion

Adenosine kinase (ADK) is the major negative metabolic regulator of the endogenous neuroprotectant and homeostatic bioenergetic network regulator adenosine. We used three independent experimental approaches to determine the role of ADK as a molecular target for predicting the brain's susceptibility to ischemic stroke. First, when subjected to a middle cerebral artery occlusion model of focal cerebral ischemia, transgenic fb-Adk-def mice, which have increased ADK expression in striatum (164%) and reduced ADK expression in cortical forebrain (65%), demonstrate increased striatal infarct volume (126%) but almost complete protection of cortex (27%) compared with wild-type (WT) controls, indicating that cerebral injury levels directly correlate to levels of ADK in the CNS. Second, we demonstrate abrogation of lipopolysaccharide (LPS)-induced ischemic preconditioning in transgenic mice with brain-wide ADK overexpression (Adk-tg), indicating that ADK activity negatively regulates LPS-induced tolerance to stroke. Third, using adeno-associated virus-based vectors that carry Adk-sense or -antisense constructs to overexpress or knockdown ADK in vivo, we demonstrate increased (126%) or decreased (51%) infarct volume, respectively, 4 weeks after injection into the striatum of WT mice. Together, our data define ADK as a possible therapeutic target for modulating the degree of stroke-induced brain injury.

Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia

1996 ◽  
Vol 85 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Marin B. Marinov ◽  
Kimberly S. Harbaugh ◽  
P. Jack Hoopes ◽  
Harold J. Pikus ◽  
Robert E. Harbaugh
Keyword(s):  
Infarct Size ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Suture Technique ◽  
Neuroprotective Effects ◽  
Tetrazolium Chloride ◽  
Content Type ◽  
Fine Print

✓ The known cytoprotective properties of MgSO4 led the authors to study its effects on infarct size in rats when administered intraarterially before reversible focal ischemia. Following an intracarotid infusion of MgSO4 in the amount of 30 mg/kg (24 animals), 90 mg/kg (18 animals), or an equal volume of vehicle (23 animals), middle cerebral artery occlusion was produced in rats by means of an intraluminal suture technique. Reperfusion occurred after 1.5 (42 animals) or 2 hours (23 animals) of ischemia. Automated, volumetric measurements of 2′,3′,5′-triphenyl-2H-tetrazolium chloride—stained coronal brain sections demonstrated a statistically significant decrease in infarct size for MgSO4 treatment groups compared to controls. Cytoprotection was greater in animals subjected to 1.5 hours of ischemia (28.4% reduction in infarct volume, p ≤ 0.001, Student's t-test), than in those having 2 hours of ischemia (19.3% reduction, p < 0.05). Animals given 90 mg/kg MgSO4 prior to 1.5 hours of ischemia (12 animals) showed a 59.8% reduction in infarct volume compared to controls (11 animals, p < 0.001) and a 43.1% reduction compared to the 30 mg/kg group (11 animals, p < 0.001). Analysis of variance demonstrated the statistically significant effects of MgSO4 doses on infarct volume across all groups (F = 22.95, p < 0.0001). The neuroprotective effect of intraarterial MgSO4 in this model is robust, dose dependent, and related to the duration of ischemia. The compound may be valuable for limiting infarction if given intraarterially before induction of reversible ischemia during cerebrovascular surgery.

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