scholarly journals Neuroprotective mechanisms of erythropoietin in a rat stroke model

2020 ◽  
Vol 11 (1) ◽  
pp. 48-59
Author(s):  
Martin Juenemann ◽  
Tobias Braun ◽  
Nadine Schleicher ◽  
Mesut Yeniguen ◽  
Patrick Schramm ◽  
...  
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Cerebral Edema ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Human Erythropoietin ◽  
Male Wistar Rats ◽  
Cerebral Artery Occlusion

AbstractObjectiveThis study was designed to investigate the indirect neuroprotective properties of recombinant human erythropoietin (rhEPO) pretreatment in a rat model of transient middle cerebral artery occlusion (MCAO).MethodsOne hundred and ten male Wistar rats were randomly assigned to four groups receiving either 5,000 IU/kg rhEPO intravenously or saline 15 minutes prior to MCAO and bilateral craniectomy or sham craniectomy. Bilateral craniectomy aimed at elimination of the space-consuming effect of postischemic edema. Diagnostic workup included neurological examination, assessment of infarct size and cerebral edema by magnetic resonance imaging, wet–dry technique, and quantification of hemispheric and local cerebral blood flow (CBF) by flat-panel volumetric computed tomography.ResultsIn the absence of craniectomy, EPO pretreatment led to a significant reduction in infarct volume (34.83 ± 9.84% vs. 25.28 ± 7.03%; p = 0.022) and midline shift (0.114 ± 0.023 cm vs. 0.083 ± 0.027 cm; p = 0.013). We observed a significant increase in regional CBF in cortical areas of the ischemic infarct (72.29 ± 24.00% vs. 105.53 ± 33.10%; p = 0.043) but not the whole hemispheres. Infarct size-independent parameters could not demonstrate a statistically significant reduction in cerebral edema with EPO treatment.ConclusionsSingle-dose pretreatment with rhEPO 5,000 IU/kg significantly reduces ischemic lesion volume and increases local CBF in penumbral areas of ischemia 24 h after transient MCAO in rats. Data suggest indirect neuroprotection from edema and the resultant pressure-reducing and blood flow-increasing effects mediated by EPO.

Use of mild intraischemic hypothermia versus mannitol to reduce infarct size after temporary middle cerebral artery occlusion in rats

1995 ◽  
Vol 83 (1) ◽  
pp. 93-98 ◽  
Author(s):  
Hiroshi Karibe ◽  
Gregory J. Zarow ◽  
Philip R. Weinstein
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Content Type ◽  
Infarct Area ◽  
Group A ◽  
Group B ◽  
Cerebral Artery Occlusion ◽  
Fine Print

✓ To determine which of two treatments for reducing ischemic injury after temporal focal ischemia is more effective, the effects of mild (33°C) intraischemic hypothermia were compared with those of mannitol, the most commonly used neuroprotective agent. Four groups of Sprague-Dawley rats underwent 1 hour of endovascular middle cerebral artery occlusion followed by 23 hours of normothermic reperfusion. The four experimental groups were as follows: Group A, saline control; Group B, mannitol (25%, 1 g/kg); Group C, hypothermia; and Group D, hypothermia plus man-nitol. Laser-Doppler estimates of cortical blood flow showed that hypothermia did not affect blood flow during ischemia or reperfusion. Mannitol increased cortical blood flow during ischemia and reperfusion under both normothermic and hypothermic conditions (p < 0.05). Neurological deficit was significantly less severe in treated rats (Group B, p < 0.05; Group C or D, p < 0.01) than in controls (Group A). Infarct volume, measured on semiserial Nissl-stained sections, was significantly smaller in treated rats (p < 0.01) than in controls. Infarct volume was also significantly smaller in rats treated with hypothermia than in those treated with mannitol (Group C vs. Group B, p < 0.05); there was no difference between rats treated with mannitol and those treated with mannitol and hypothermia. All three treatments reduced infarct area in the ischemic penumbra; hypothermia with or without mannitol also reduced infarct area in the ischemic core. These results demonstrate that both mild intraischemic hypothermia and mannitol reduce infarct size and neurological deficit: hypothermia reduces infarct size more effectively than mannitol, and mannitol adds no significant protection to hypothermia, whereas hypothermia adds significant protection beyond that afforded by mannitol after brief focal ischemia followed by reperfusion in rats. The results suggest that mild intraischemic hypothermia alone, or in combination with mannitol, may be useful in avoiding ischemic injury from temporary vessel occlusion during cerebrovascular surgery.

scholarly journals Hyperglycaemia does not increase perfusion deficits after focal cerebral ischaemia in male Wistar rats

2018 ◽  
Vol 2 ◽  
pp. 239821281879482 ◽  
Author(s):  
Lisa A. Thow ◽  
Kathleen MacDonald ◽  
William M. Holmes ◽  
Keith W. Muir ◽  
I. Mhairi Macrae ◽  
...  
Keyword(s):  
Blood Flow ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Arterial Spin Labelling ◽  
Male Wistar Rats ◽  
Cerebral Artery Occlusion ◽  
Spin Labelling

Background: Hyperglycaemia is associated with a worse outcome in acute ischaemic stroke patients; yet the pathophysiological mechanisms of hyperglycaemia-induced damage are poorly understood. We hypothesised that hyperglycaemia at the time of stroke onset exacerbates ischaemic brain damage by increasing the severity of the blood flow deficit. Methods: Adult, male Wistar rats were randomly assigned to receive vehicle or glucose solutions prior to permanent middle cerebral artery occlusion. Cerebral blood flow was assessed semi-quantitatively either 1 h after middle cerebral artery occlusion using 99mTc-D, L-hexamethylpropyleneamine oxime (99mTc-HMPAO) autoradiography or, in a separate study, using quantitative pseudo-continuous arterial spin labelling for 4 h after middle cerebral artery occlusion. Diffusion weighted imaging was performed alongside pseudo-continuous arterial spin labelling and acute lesion volumes calculated from apparent diffusion coefficient maps. Infarct volume was measured at 24 h using rapid acquisition with refocused echoes T2-weighted magnetic resonance imaging. Results: Glucose administration had no effect on the severity of ischaemia when assessed by either 99mTc-HMPAO autoradiography or pseudo-continuous arterial spin labelling perfusion imaging. In comparison to the vehicle group, apparent diffusion coefficient–derived lesion volume 2–4 h post-middle cerebral artery occlusion and infarct volume 24 h post-middle cerebral artery occlusion were significantly greater in the glucose group. Conclusions: Hyperglycaemia increased acute lesion and infarct volumes but there was no evidence that the acute blood flow deficit was exacerbated. The data reinforce the conclusion that the detrimental effects of hyperglycaemia are rapid, and that treatment of post-stroke hyperglycaemia in the acute period is essential but the mechanisms of hyperglycaemia-induced harm remain unclear.

scholarly journals Intraventricular Brain-Derived Neurotrophic Factor Reduces Infarct Size after Focal Cerebral Ischemia in Rats

1997 ◽  
Vol 17 (5) ◽  
pp. 500-506 ◽  
Author(s):  
Wolf-R. Schäbitz ◽  
Stefan Schwab ◽  
Matthias Spranger ◽  
Werner Hacke
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Neurotrophic Factor ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 μg/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls ( P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 ± 27.1 mm3 in BDNF-treated animals and 139.2 ± 56.4 mm3 in controls (mean ± SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 ± 7.1 mm3 in BDNF-treated animals and 37.9 ± 19.8 mm3 in controls (mean ± SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

scholarly journals Transient Middle Cerebral Artery Occlusion by Intraluminal Suture: I. Three-Dimensional Autoradiographic Image-Analysis of Local Cerebral Glucose Metabolism—Blood Flow Interrelationships during Ischemia and Early Recirculation

1997 ◽  
Vol 17 (12) ◽  
pp. 1266-1280 ◽  
Author(s):  
Ludmila Belayev ◽  
Weizhao Zhao ◽  
Raul Busto ◽  
Myron D. Ginsberg
Keyword(s):  
Blood Flow ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Glucose Utilization ◽  
Artery Occlusion ◽  
Ischemic Lesion ◽  
Ischemic Core ◽  
Cerebral Artery Occlusion ◽  
Autoradiographic Image

Using autoradiographic image-averaging strategies, we studied the relationship between local glucose utilization (LCMRglc) and blood flow (LCBF) in a highly reproducible model of transient (2-hour) middle cerebral artery occlusion (MCAO) produced in Sprague-Dawley rats by insertion of an intraluminal suture coated with poly-L-lysine. Neurobehavioral examination at 60 minutes after occlusion substantiated a high-grade deficit in all animals. In two subgroups, LCBF was measured with 14C-iodoantipyrine at either 1.5 hours of MCAO, or at 1 hour of recirculation after suture removal. In two other matched subgroups, LCMRglc was measured with 14C-2-deoxyglucose at 1.5 to 2.25 hours of MCAO, and at 0.75 to 1.5 hours of recirculation after 2 hours of MCAO. Average image data sets were generated for LCBF, LCMRglc, and the LCMRglc/LCBF ratio for each study time. Middle cerebral artery occlusion for 2 hours induced graded LCBF decrements affecting ipsilateral cortical and basal ganglionic regions. After 1 hour of recirculation, LCBF in previously ischemic neocortical regions increased by 40% to 200% above ischemic levels, but remained depressed, on average, at about 40% of control. By contrast, frank hyperemia was noted in the previously ischemic caudoputamen. Mean cortical LCBF values during MCAO correlated highly with their respective LCBF values after 1 hour of recirculation (R = 0.93), suggesting that postischemic LCBF recovery is related to the depth of ischemia. Despite focal ischemia, LCMRglc during ~2 hours of MCAO was preserved, on average, at near-normal levels; but following ~1 h of recirculation, LCMRglc became markedly depressed (on average, 55% of control in previously densely ischemic cortical regions). Regression analysis indicated that this depressed glucose utilization was determined largely by the intensity of antecedent ischemia. By pixel analysis, the ischemic core (defined as LCBF 0% to 20% of control) comprised 33% of the ischemic hemisphere, and the penumbra (LCBF 20% to 40%) accounted for 26%. The penumbra was concentrated at the coronal poles of the ischemic lesion and formed a thin shell around the central ischemic core. During 2 hours of MCAO, the LCMRglc/LCBF ratio within the ischemic penumbra was increased four-fold above normal (average, 179 umol/100 mL). In marked contrast, after ~1 h recirculation, this uncoupling had almost completely subsided. The companion study ( Zhao et al., 1997 ) further analyzes these findings in relation to patterns of infarctive histopathology.

Abstract W MP81: Excess Salt Increases Infarct Size Produced by Photothrombotic Middle Cerebral Artery Occlusion Without Increasing Blood Pressure in Spontaneously Hypertensive Rats

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Hiroshi Yao ◽  
Toru Nabika
Keyword(s):  
Infarct Size ◽  
Brain Tissue ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Control Group ◽  
Salt Loading ◽  
Ischemic Brain ◽  
Spontaneously Hypertensive ◽  
Ischemic Brain Tissue ◽  
Cerebral Artery Occlusion

Background and Purpose: Cerebral circulation is known to be vulnerable to excess salt (e.g., impaired vasodilation, increased oxidative stress, accelerated spontaneous stroke, and enhanced blood-brain barrier [BBB] disruption). To our knowledge, however, no study has investigated the effects of excess salt on focal ischemic injury. Methods: After 14 days of salt loading or water, spontaneously hypertensive rats (SHR, Izumo strain, n=43) or normotensive Wistar-Kyoto rats (WKY, n=11) were subjected to photothrombotic middle cerebral artery occlusion (MCAO), and infarct volume was determined at 48 h after MCAO. Brain albumin and hemoglobin contents, as indices of BBB disruption, were determined with SELDI-TOF-MS in ischemic brain tissue. Effects of excess salt on the lower limits of cerebral blood flow (CBF) autoregulation were also determined. Results: Two-way analysis of variance confirmed a significant effect of saline on the volumes of drinking in SHR (p=0.000). Resting mean arterial blood pressure (BP) in SHR was 137±15 (S.D.) mmHg and 141±7 mmHg in the salt loading and control groups, respectively. After MCAO, regional CBF, determined with two ways of laser-Doppler flowmetry (one-point measurement or manual scanning), was more steeply decreased in the salt-loaded group than in the control group. In SHR, infarct volume in the salt-loaded group was 112±27 mm3, which was significantly larger than 77±12 mm3 in the control group (p=0.002), while albumin and hemoglobin levels in discrete brain regions were not different between the groups. In WKY, salt loading did not significantly increase infarct size. CBF response to hemorrhagic hypotension (i.e., autoregulation) was not affected by excess salt. Conclusions: We demonstrated that excess salt increased infarct size produced by photothrombotic MCAO without increasing BP in SHR but not in WKY. Excess salt did not deteriorate both vasogenic edema and hemorrhagic transformation of ischemic brain tissue after MCAO. The detrimental effects of excess salt were considered to be the result of compromised CBF in the ischemic brain tissue supplied by collateral circulation. A future study will investigate the mechanisms underlying the salt sensitivity to focal brain ischemia independent of BP changes.

scholarly journals Cortical Negative DC Deflections following Middle Cerebral Artery Occlusion and KCl-Induced Spreading Depression: Effect on Blood Flow, Tissue Oxygenation, and Electroencephalogram

1994 ◽  
Vol 14 (1) ◽  
pp. 12-19 ◽  
Author(s):  
T. Back ◽  
K. Kohno ◽  
K.-A. Hossmann
Keyword(s):  
Blood Flow ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Spreading Depression ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Flow Response ◽  
Eeg Power ◽  
Oxygen Requirements ◽  
Cerebral Artery Occlusion

In the periphery of ischemic brain lesions, transient spreading depression-like direct current (DC) deflections occur that may be of pathophysiological importance for determining the volume of the ischemic infarct. The effect of these deflections on cerebral blood flow, tissue oxygen tension, and electrophysiology was studied in rats submitted to intraluminal thread occlusion of the middle cerebral artery (MCA) and compared with the changes following potassium chloride (KCl)-induced spreading depression of intact animals. Immediately after MCA occlusion, cortical laser–Doppler flow (LDF) in the periphery of the MCA territory sharply decreased to 35 ± 14% of control (mean ± SD; p < 0.05), tissue Po2 declined from 28 ± 4 to 21 ± 3 mm Hg (p < 0.05), and EEG power fell to ∼80% of control. During 7-h occlusion, 3–11 DC deflections with a mean duration of 5.2 ± 4.8 min occurred at irregular intervals, and EEG power gradually declined to 66 ± 16% of control (p < 0.05). During the passage of DC deflections, LDF did not change, but Po2 further declined to 19 ± 4 mm Hg (p < 0.05). KCl-induced depolarizations of intact rats were significantly shorter (1.4 ± 0.5 min; p < 0.05) and were accompanied by a 43% increase in LDF (p < 0.05) and a slight but significant increase in tissue Po2 from 22 ± 4 to 25 ± 4 mm Hg (p < 0.05). The comparison of periinfarct and KCl-induced depolarizations demonstrates that oxygen requirements are not coupled to an appropriate flow response in the periinfarct zone with severely reduced blood flow. The resulting episodes of relative hypoxia could explain the previously documented relationship between the number of depolarizations and infarct volume.

scholarly journals Effect of 20-HETE Inhibition on Infarct Volume and Cerebral Blood Flow after Transient Middle Cerebral Artery Occlusion

2008 ◽  
Vol 29 (3) ◽  
pp. 629-639 ◽  
Author(s):  
Marija Renic ◽  
Judith A Klaus ◽  
Tomohiro Omura ◽  
Naoya Kawashima ◽  
Michihito Onishi ◽  
...  
Keyword(s):  
At Risk ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Dienoic Acid ◽  
Artery Occlusion ◽  
Area At Risk

This study examined the effects of an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis, N-(3-chloro-4-morpholin-4-yl)phenyl- N'-hydroxyimido formamide (TS-011), on infarct volume, volume at risk, cerebral blood flow (CBF), and levels of cytochrome P450 (CYP450) eicosanoids in the brain after transient occlusion of the middle cerebral artery (t-MCAO) in rats. TS-011 (0.1 mg/kg, iv) reduced cortical infarct volume by approximately 70% and total infarct volume by 55%. TS-011 had no effect on the volume at risk or CBF during or up to 30 mins after the ischemic period. TS-011 reduced the delayed fall in CBF seen 2 h after reperfusion. The levels of CYP450 eicosanoids were similar in the ischemic and contralateral hemispheres after t-MCAO. TS-011 reduced 20-HETE levels in cerebral tissue by 80% but had no effect on the levels of EETs. Administration of another 20-HETE inhibitor, HET0016 (0.01 to 1.0 mg/kg, iv) or a 20-HETE antagonist 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (10 mg/kg, iv) also reduced infarct size. These results indicate that inhibitors of the synthesis or vasoconstrictor effects of 20-HETE reduce infarct size in rats after cerebral ischemia. The effects of TS-011 are not associated with changes in the area at risk or CBF and may be because of a potential protective effect in neurons subjected to ischemic stress.

scholarly journals Effect of combined therapy with hyperbaric oxygen and an antioxidant on infarct volume after permanent focal cerebral ischemia

2007 ◽  
pp. 369-373
Author(s):  
G Acka ◽  
A Sen ◽  
Z Canakci ◽  
S Yildiz ◽  
A Akin ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Hyperbaric Oxygen ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Combined Therapy ◽  
Artery Occlusion ◽  
Control Group ◽  
Male Wistar Rats ◽  
Cerebral Artery Occlusion ◽  
Reduce Infarct Volume

The aim of the present study was to evaluate the efficiency of combination of hyperbaric oxygen (HBO) and an antioxidant on permanent focal cerebral ischemia. Male Wistar rats underwent permanent middle cerebral artery occlusion (MCAO). Then, animals were randomly assigned to one of four groups: the control group (n=9) received no treatment, HBO group (n=9) was treated for 90 min at 2.5 absolute atmosphere for 3 days, the U-74389G group (n=8) received single U-74389G injection (3 mg/kg), the HBO + U-74389G group (n=8) received both HBO and U-74389G treatments. Treatments were initiated within the first 10 min after MCAO. After 3 days, the infarct volumes in rat brains were measured. The infarct ratios were 25.6+/-6.5 % for the control group, 21.9+/-6.4 % for the HBO group, 15.7+/-5.7 % for U-74389G group and 12.5+/-3.8 % for HBO + U74389G group. The infarct volumes were significantly reduced in rats treated with U-74389G (p<0.05) and combination therapy (p<0.05). HBO failed to reduce infarct volume significantly. We concluded that 1) U-74389G is more beneficial than HBO on permanent MCAO in rats, and 2) a combined therapy failed to significantly improve infarct volume more than either single treatment.

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