scholarly journals Differential Effects of 17β-Estradiol upon Stroke Damage in Stroke Prone and Normotensive Rats

2004 ◽  
Vol 24 (3) ◽  
pp. 298-304 ◽  
Author(s):  
Hilary V Carswell ◽  
Deborah Bingham ◽  
Kirsty Wallace ◽  
M Nilsen ◽  
David I Graham ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Negative Effects ◽  
Spontaneously Hypertensive ◽  
Endogenous Estrogen ◽  
17Β Estradiol ◽  
Wistar Kyoto Rat ◽  
Wistar Kyoto ◽  
Cerebral Artery Occlusion

We previously reported that during pro-estrus (high endogenous estrogen levels), brain damage after middle cerebral artery occlusion (MCAO) was reduced in stroke-prone spontaneously hypertensive rats (SHRSP) but not in normotensive Wistar Kyoto rat (WKY). In the present study, we examined the effect of exogenous estrogen on brain damage after MCAO in SHRSP and WKY. A 17β-estradiol (0.025mg or 0.25mg, 21 day release) or matching placebo pellet was implanted into ovariectomized WKY and SHRSP (3 to 4 months old) who then underwent distal diathermy-induced MCAO 2 weeks later. Plasma 17β-estradiol levels for placebo and 17β-estradiol groups were as follows: WKY 0.025 mg 16.4 ± 8.5 (pg/mL, mean ± SD) and 25.85 ± 12.6; WKY 0.25 mg 18.2 ± 9.0 and 69.8 ± 27.4; SHRSP 0.25 mg 20.7 ± 8.8 and 81.0 ± 16.9. In SHRSP, infarct volumes at 24 hours after MCAO were similar in placebo and 17β-estradiol groups: SHRSP 0.025 mg 126.7 ± 15.3 mm3 (n = 6) and 114.0 ± 14.1 mm3 (n = 8) (not significant); SHRSP 0.25 mg 113.5 ± 22.3 mm3 (n = 8) and 129.7 ± 26.2 mm3 (n = 7) (not significant), respectively. In WKY, 17β-estradiol significantly increased infarct volume by 65% with 0.025mg dose [36.1 ± 20.7 mm3 (n = 8) and 59.7 ± 19.3 mm3 (n = 8) ( P = 0.033, unpaired t-test)] and by 96% with 0.25 mg dose [55.9 ± 36.4 mm3 (n = 8) and 109.7 ± 6.7 mm3 (n = 4) ( P = 0.017)]. Thus, 17β-estradiol increased stroke damage in normotensive rats with no significant effect in stroke-prone rats. Despite being contrary to our hypothesis, our findings add substance to the recently reported negative effects of 17β-estradiol in clinical studies.

scholarly journals Investigation of Estrogen Status and Increased Stroke Sensitivity on Cerebral Blood Flow after a Focal Ischemic Insult

2000 ◽  
Vol 20 (6) ◽  
pp. 931-936 ◽  
Author(s):  
Hilary V. O. Carswell ◽  
Niall H. Anderson ◽  
James J. Morton ◽  
James McCulloch ◽  
Anna F. Dominiczak ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Internal Control ◽  
Artery Occlusion ◽  
Cumulative Distribution ◽  
Distribution Analysis ◽  
Spontaneously Hypertensive ◽  
Endogenous Estrogen ◽  
Wistar Kyoto ◽  
Cerebral Artery Occlusion

Recently the authors have shown that female stroke-prone spontaneously hypertensive rats (SHRSPs) in proestrus (high endogenous estrogen), sustain more than 20% smaller infarcts after middle cerebral artery occlusion (MCAO) compared with SHRSPs in metestrus (low endogenous estrogen). Because estrogen has vasodilator properties, the authors investigated whether the estrous state influences cerebral blood flow (CBF) after MCAO. CBF was measured 2.5 hours after a distal MCAO by [14C]iodo-antipyrine autoradiography in conscious SHRSPs either in metestrus or in proestrus. There were no significant differences in CBF when analyzed either at predetermined anatomic regions or by cumulative distribution analysis of areas with flow <25 mL/100 g/min. As a positive internal control, the authors compared results in SHRSPs with those in their normotensive reference strain, Wistar Kyoto rat. SHRSPs displayed more severe and widespread ischemia than Wistar Kyoto rats. Thus, the absence of demonstrable CBF differences between estrous states appears to be unrelated to the CBF measurement paradigm. In conclusion, the smaller infarct size afforded in proestrus in SHRSPs is unlikely to be due to an influence on CBF.

scholarly journals Impact of Age and Sex on α-Syn (α-Synuclein) Knockdown-Mediated Poststroke Recovery

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3138-3141
Author(s):  
Bharath Chelluboina ◽  
Taehee Kim ◽  
Suresh L. Mehta ◽  
Joo-Yong Kim ◽  
Saivenkateshkomal Bathula ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Critical Role ◽  
Artery Occlusion ◽  
Motor Deficits ◽  
Ischemic Brain ◽  
Therapeutic Opportunity ◽  
Interfering Rna ◽  
Cerebral Artery Occlusion ◽  
Age And Sex

Background and Purpose: Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age. Methods: Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion. Results: α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited. Conclusions: α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex.

scholarly journals Upregulation of TACE/ADAM17 after Ischemic Preconditioning is Involved in Brain Tolerance

2002 ◽  
Vol 22 (11) ◽  
pp. 1297-1302 ◽  
Author(s):  
Antonio Cárdenas ◽  
María A. Moro ◽  
Juan C. Leza ◽  
Esther O'Shea ◽  
Antoni Dávalos ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Brain Damage ◽  
Cerebral Artery ◽  
Ischemic Preconditioning ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Tnf Α ◽  
Cerebral Artery Occlusion

A short ischemic event (ischemic preconditioning [IPC]) can result in a subsequent resistance to severe ischemic injury (ischemic tolerance [IT]). Although tumor necrosis factor-α (TNF-α) contributes to the brain damage, its expression and neuroprotective role in models of IPC have also been described. However, the role of TNF-α convertase (TACE) in IPC and IT is not known. Using in vitro models, the authors previously demonstrated that TACE is upregulated after ischemic brain damage. In the present study, the authors used a rat model of transient middle cerebral artery occlusion as IPC to investigate TACE expression, its involvement in TNF-α release, and its role in IT. Western blot analysis showed that TACE expression is increased after IPC. Ischemic preconditioning caused TNF-α release, an effect that was blocked by the selective TACE inhibitor BB-1101 (10 mg · kg−1 · day−1; SHAM, 1,050 ± 180; IPC, 1,870 ± 290; IPC + BB, 1,320 ± 260 ng/mg; n = 4, P < 0.05). Finally, IPC produced a reduction in infarct volume, which was inhibited by treatment with BB-1101 and with anti–TNF-α (10 μg/5 doses; SHAM + permanent middle cerebral artery occlusion [pMCAO], 335 ± 20; IPC + pMCAO, 244 ± 14; IPC + BB + pMCAO, 300 ± 6; IPC + anti-TNF + pMCAO, 348 ± 22 mm3; n = 6–10, P < 0.05). Taken together, these data demonstrate that TACE is upregulated after IPC, plays a major role in TNF-α shedding in IPC, and has a neuroprotective role in IT.

scholarly journals ACE Inhibition Reduces Infarction in Normotensive but Not Hypertensive Rats: Correlation with Cortical ACE Activity

2010 ◽  
Vol 30 (8) ◽  
pp. 1520-1526 ◽  
Author(s):  
Michelle J Porritt ◽  
Michelle Chen ◽  
Sarah SJ Rewell ◽  
Rachael G Dean ◽  
Louise M Burrell ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Infarct Volume ◽  
Ace Inhibition ◽  
Artery Occlusion ◽  
Spontaneously Hypertensive ◽  
Beneficial Effects ◽  
Wky Rats ◽  
Ace Activity ◽  
Wistar Kyoto

Angiotensin-converting enzyme (ACE) inhibition can reduce stroke risk by up to 43% in humans and reduce the associated disability, and hence understanding the mechanism of improvement is important. In animals and humans, these effects may be independent of the blood pressure-lowering effects of ACE inhibition. Normotensive (Wistar–Kyoto (WKY)) and hypertensive (spontaneously hypertensive rat (SHR)) animals were treated with the ACE inhibitors ramipril or lisinopril for 7 or 42 days before 2 hours of transient middle cerebral artery occlusion (MCAo). Blood pressure, serum ACE, and blood glucose levels were measured and stroke infarct volume was recorded 24 hours after stroke. Despite greater reductions in blood pressure, infarct size was not improved by ACE inhibition in hypertensive animals. Short-term ACE inhibition produced only a modest reduction in blood pressure, but WKY rats showed marked reductions in infarct volume. Long-term ACE inhibition had additional reductions in blood pressure; however, infarct volumes in WKY rats did not improve further but worsened. WKY rats differed from SHR in having marked cortical ACE activity that was highly sensitive to ACE inhibition. The beneficial effects of ACE inhibition on infarct volume in normotensive rats do not correlate with changes in blood pressure. However, WKY rats have ACE inhibitor-sensitive cortical ACE activity that is lacking in the SHR.

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 Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage

2017 ◽  
Vol 38 (6) ◽  
pp. 1060-1069 ◽  
Author(s):  
Abraham Cisneros-Mejorado ◽  
Miroslav Gottlieb ◽  
Asier Ruiz ◽  
Juan C Chara ◽  
Alberto Pérez-Samartín ◽  
...  
Keyword(s):  
Brain Damage ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Atp Release ◽  
Artery Occlusion ◽  
Ruthenium Red ◽  
Ischemic Brain ◽  
Knock Out ◽  
Cerebral Artery Occlusion ◽  
Cortical Slices

Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia.

scholarly journals Penumbra Detection using PWI/DWI Mismatch MRI in a Rat Stroke Model with and without Comorbidity: Comparison of Methods

2012 ◽  
Vol 32 (9) ◽  
pp. 1765-1777 ◽  
Author(s):  
Emma Reid ◽  
Delyth Graham ◽  
M Rosario Lopez-Gonzalez ◽  
William M Holmes ◽  
I Mhairi Macrae ◽  
...  
Keyword(s):  
Artery Occlusion ◽  
Anatomical Location ◽  
Lesion Volume ◽  
Spatial Assessment ◽  
Spontaneously Hypertensive ◽  
Diffusion Weighted ◽  
Volumetric Assessment ◽  
Apparent Diffusion ◽  
Wistar Kyoto ◽  
Cerebral Artery Occlusion

Perfusion-diffusion (perfusion-weighted imaging (PWI)/diffusion-weighted imaging (DWI)) mismatch is used to identify penumbra in acute stroke. However, limitations in penumbra detection with mismatch are recognized, with a lack of consensus on thresholds, quantification and validation of mismatch. We determined perfusion and diffusion thresholds from final infarct in the clinically relevant spontaneously hypertensive stroke-prone (SHRSP) rat and its normotensive control strain, Wistar-Kyoto (WKY) and compared three methods for penumbra calculation. After permanent middle cerebral artery occlusion (MCAO) (WKY n=12, SHRSP n=15), diffusion-weighted (DWI) and perfusion-weighted (PWI) images were obtained for 4 hours post stroke and final infarct determined at 24 hours on T2 scans. The PWI/DWI mismatch was calculated from volumetric assessment (perfusion deficit volume minus apparent diffusion coefficient (ADC)-defined lesion volume) or spatial assessment of mismatch area on each coronal slice. The ADC-derived lesion growth provided the third, retrospective measure of penumbra. At 1 hour after MCAO, volumetric mismatch detected smaller volumes of penumbra in both strains (SHRSP: 31±50 mm3, WKY: 22±59 mm3, mean±s.d.) compared with spatial assessment (SHRSP: 36±15 mm3, WKY: 43±43 mm3) and ADC lesion expansion (SHRSP: 41±45 mm3, WKY: 65±41 mm3), although these differences were not statistically significant. Spatial assessment appears most informative, using both diffusion and perfusion data, eliminating the influence of negative mismatch and allowing the anatomical location of penumbra to be assessed at given time points after stroke.

scholarly journals No Role for Interleukin-18 in Acute Murine Stroke-Induced Brain Injury

2003 ◽  
Vol 23 (5) ◽  
pp. 531-535 ◽  
Author(s):  
Rachel D. Wheeler ◽  
Herve Boutin ◽  
Omar Touzani ◽  
Giamal N. Luheshi ◽  
Kiyoshi Takeda ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Brain Damage ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Interleukin 18 ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion

There is now extensive evidence to show that the cytokine interleukin-1 (IL-1) contributes directly to reversible and permanent ischemic brain damage in rodents. Because interleukin-18 (IL-18) shares many structural and functional similarities with IL-1, the authors tested the hypothesis that IL-18 contributes directly to ischemic brain damage in mice exposed to focal, reversible (15-minute or 30-minute) middle cerebral artery occlusion. IL-18 expression was not induced acutely by middle cerebral artery occlusion, and deletion of the IL-18 gene (IL-18 knockout mice) did not affect infarct volume. The present results suggest that IL-18 does not contribute to acute ischemic brain damage.

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