scholarly journals An update to the Monro–Kellie doctrine to reflect tissue compliance after severe ischemic and hemorrhagic stroke

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna C. J. Kalisvaart ◽  
Cassandra M. Wilkinson ◽  
Sherry Gu ◽  
Tiffany F. C. Kung ◽  
Jerome Yager ◽  
...  
Keyword(s):  
Brain Regions ◽  
Artery Occlusion ◽  
Density Increase ◽  
Volume Reduction ◽  
Compensatory Mechanisms ◽  
Severe Stroke ◽  
Injured Area ◽  
Tissue Compliance ◽  
Tissue Shrinkage ◽  
Cerebral Artery Occlusion

AbstractHigh intracranial pressure (ICP) can impede cerebral blood flow resulting in secondary injury or death following severe stroke. Compensatory mechanisms include reduced cerebral blood and cerebrospinal fluid volumes, but these often fail to prevent raised ICP. Serendipitous observations in intracerebral hemorrhage (ICH) suggest that neurons far removed from a hematoma may shrink as an ICP compliance mechanism. Here, we sought to critically test this observation. We tracked the timing of distal tissue shrinkage (e.g. CA1) after collagenase-induced striatal ICH in rat; cell volume and density alterations (42% volume reduction, 34% density increase; p < 0.0001) were highest day one post-stroke, and rebounded over a week across brain regions. Similar effects were seen in the filament model of middle cerebral artery occlusion (22% volume reduction, 22% density increase; p ≤ 0.007), but not with the Vannucci-Rice model of hypoxic-ischemic encephalopathy (2.5% volume increase, 14% density increase; p ≥ 0.05). Concerningly, this ‘tissue compliance’ appears to cause sub-lethal damage, as revealed by electron microscopy after ICH. Our data challenge the long-held assumption that ‘healthy’ brain tissue outside the injured area maintains its volume. Given the magnitude of these effects, we posit that ‘tissue compliance’ is an important mechanism invoked after severe strokes.

Abstract WMP41: Neuronal Sirt1 is Required for Resveratrol Preconditioning Induced Ischemic Tolerance

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kevin B Koronowski ◽  
Isa Saul ◽  
Zachary Balmuth-Loris ◽  
Miguel Perez-Pinzon
Keyword(s):  
Knockout Mouse ◽  
Infarct Volume ◽  
Hypoxia Inducible Factor ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Tamoxifen Treatment ◽  
Neurological Score ◽  
Transcription Factor Activation ◽  
Cerebral Artery Occlusion

Introduction: Our previous work demonstrates that resveratrol, a naturally occurring polyphenol, protects against cerebral ischemia when administered 2 or 14 days prior to injury. Resveratrol activates Sirt1, an NAD + -dependent deacylase that regulates cellular metabolism. It has been postulated that neuronal Sirt1 directly mediates this neuroprotection but it remains to be empirically tested. Objective: The objective of this study was to generate an inducible, neuronal-specific Sirt1 knockout mouse and determine whether neuronal Sirt1 is necessary for resveratrol-induced ischemic tolerance. Methods: Twenty to twenty-five gram neuronal-specific Sirt1 knockout mice (Sirt1neu-/-) and WTs were induced with tamoxifen. Mice were randomized for 1) western blot; 2) resveratrol preconditioning (RPC; 10 mg/kg resveratrol i.p.) or vehicle (1.5% DMSO; 0.9% saline) treatment 2 days prior to 60 minute middle cerebral artery occlusion (MCAo); 3) untargeted primary metabolomics by GC-TOF-MS; or 4) transcription factor activation profiling. Twenty-four hours following MCAo, neurological score was used to assess functional outcome and infarct volume was quantified by TTC staining. Results: Tamoxifen treatment removed WT Sirt1 protein from major brain regions but not from heart (Figure 1A, n=3). In WT, RPC reduced infarct volume by 43.7% and improved neurological score by nearly 3 points, however these effects were lost in Sirt1neu-/- (Figure 1B, n=5-9). Compared to WT, metabolic profiles from Sirt1neu-/- displayed significantly altered glycolysis metabolites (Figure 1C, n=8). Activation of hypoxia inducible factor (HIF) was reduced by 48% in Sirt1neu-/- (Figure 1D, n=3). Conclusions: We generated and utilized an inducible, neuronal-specific knockout mouse to demonstrate that neuronal Sirt1 specifically is required for RPC-induced ischemic tolerance. Additionally, Sirt1 regulates glycolysis in the brain, possibly through its interaction with HIF.

Adenosine and cerebral capillary perfusion and blood flow during middle cerebral artery occlusion

1989 ◽  
Vol 257 (5) ◽  
pp. H1656-H1662
Author(s):  
M. Anwar ◽  
H. R. Weiss
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Capillary Perfusion ◽  
Arterial Blood ◽  
Cerebral Artery Occlusion

The effects of adenosine on regional cerebral blood flow and indexes of the total and perfused microvascular bed were studied after 1 h of middle cerebral artery occlusion in the anesthetized rat. Iodo[14C]antipyrine was used to determine cerebral blood flow. Fluorescein isothiocyanate-dextran was used to study the perfused microvasculature, and an alkaline phosphatase stain was used to identify the total bed. Mean arterial blood pressure was significantly reduced by adenosine. Cerebral blood flow increased significantly by 75%, except in the flow-restricted cortex where flow averaged 28 +/- 15 (SD) ml.min-1.100 g-1 in control and 34 +/- 33 ml.min-1.100 g-1 in adenosine-treated animals. No significant regional structural differences were observed within the microvascular beds of the two groups. The percentage of the microvascular volume perfused increased significantly in all brain regions in the adenosine-treated rats, including the flow-restricted cortex. The percent perfused arteriolar volume in the flow-restricted cortex was 30 +/- 12% in control and 95 +/- 3% in adenosine-treated animals. Similar values for the capillary bed were 22 +/- 10% in control and 54 +/- 3% in adenosine-treated rats. These results indicate a maintenance of flow with a reduction in diffusion distances in the flow-restricted cortex after treatment with adenosine.

Persistent Phosphorylation of Synaptic Proteins following Middle Cerebral Artery Occlusion

2002 ◽  
Vol 22 (9) ◽  
pp. 1107-1113 ◽  
Author(s):  
Shohei Matsumoto ◽  
Mehrdad Shamloo ◽  
Atsushi Isshiki ◽  
Tadeusz Wieloch
Keyword(s):  
Cell Signaling ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Ischemic Brain ◽  
Aberrant Cell ◽  
Synaptosomal Fraction ◽  
Cerebral Artery Occlusion

Transient cerebral ischemia following 1 to 2 hours of middle cerebral artery occlusion (MCAO) in the rat leads to infarction, which can be diminished by synaptic transmission modulators, implying aberrant cell signaling in the pathogenetic process. The authors report here changes in the levels of tyrosine phosphorylated proteins (PTyr) and calcium calmodulin kinase II (CaMKII) phosphorylation of Thr 286, in synaptosomal, particulate, and cytosolic fractions of different cortical areas following 1 or 2 hours of MCAO, or 2 hours of MCAO followed by 2 hours of reperfusion. At the end of 2-hour MCAO, PTyr, and in particular the pp180, indicative of NR2A/B subunit, increased in the synaptosomal fraction in less ischemic areas while it decreased in more severe ischemic regions. During reperfusion, phosphorylation increased at least 2-fold in all reperfused areas. During 2 hours of MCAO, the phosphorylation of CaMKII increased 8- to 10-fold in the synaptosomal fraction in all ischemic brain regions. During reperfusion, the phospho-CaMKII levels remained elevated by approximately 300% compared with the contralateral hemisphere (control). There was no increase in phospho-CaMKII in the cytosolic fraction at any time during or following ischemia in any of the brain regions examined. The authors conclude that both tyrosine kinase coupled pathways, as well as CaMKII-mediated cellular processes associated with synaptic activity, are strongly activated during and particularly following MCAO. These results support the hypothesis that aberrant cell signaling may contribute to ischemic cell death and dysfunction, and that selective modulators of cell signaling may be targets for pharmacological intervention against ischemic brain damage.

scholarly journals Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct

2021 ◽  
Author(s):  
Zhenzhou Li ◽  
Heather L McConnell ◽  
Teresa L Stackhouse ◽  
Martin M Pike ◽  
Wenri Zhang ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Neurovascular Coupling ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Stroke Patients ◽  
Natural Inhibitor ◽  
Cerebral Artery Occlusion ◽  
Infarct Border ◽  
Capillary Dilation

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ~75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-HETE, either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of EP4 receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying neurovascular coupling impairment after stroke. Our results suggest that the brain's energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.

Abstract T P39: Leptomeningeal Collaterals in Patients with Proximal Middle Cerebral Artery Occlusion are Associated with Milder Stroke and Better Functional Outcome after Fibrinolysis

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Charlotte R Trampedach ◽  
Christian Ovesen ◽  
Anders F Christensen ◽  
Hanne K Christensen
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Acute Ischemia ◽  
Stroke Severity ◽  
Severe Stroke ◽  
Proximal Middle Cerebral Artery ◽  
Time Of Admission ◽  
Cerebral Artery Occlusion

Background: Proximal middle cerebral artery occlusions (M1 occlusion) are often but not always associated with severe stroke and poor outcome. The presence of leptomeningeal collaterals can potentially reduce the acute ischemia and thus reduce stroke severity. Occlusions and collaterals can be assessed using computed tomography angiography (CTA). Collaterals were scored according to the amount of collateral supply filling the occluded middle cerebral artery territory. We assessed the hypothesis that leptomeningeal collaterals covariates with National Institutes of Health Stroke Scale (NIHSS) at time of admission and with three month outcome after acute ischaemic stroke. Method: Fifty-eight patients - subsequently diagnosed with a M1 occlusion on CTA - were admitted within 4.5 hours after symptom onset between May 2009 and December 2011. All patients were scored according to NIHSS at time of admittance by a stroke-neurologist. Occlusions and leptomeningeal collaterals were evaluated on the nonenhanced CT and CTA. All patients received fibrinolysis. Outcome was assessed by modified Rankin Scale (mRS) at 3 months. Results: Fifty-eight patients with a M1 occlusion were included into the analysis (57% female, 43% male, mean age 70 years, range 42-93 years). There was no correlation between age and collateral score. Median NIHSS at time of admittance was 15 (range 3-25), which correlated to the collateral score (r= -0.422, p=0.001). Median mRS at 3 months was 3 (range 0-6) and a correlation with the collateral score was present (r=-0.361, p=0.007). Conclusion: Leptomeningeal collaterals on CT angiography in patients with a proximal middle cerebral artery occlusion relate to lower NIHSS on admission as well as less handicap three months after fibrinolysis treatment.

Abstract TP275: Brain Cell Volume Reductions After Severe Ischemic and Hemorrhagic Strokes in Rat

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Anna C Kalisvaart ◽  
Cassandra M Wilkinson ◽  
Tiffany F Kung ◽  
Yonglie Ma ◽  
Ian R Winship ◽  
...  
Keyword(s):  
Cell Volume ◽  
Cortical Thickness ◽  
Brain Regions ◽  
Volume Density ◽  
Volume Reduction ◽  
Separate Experiment ◽  
Compensatory Mechanisms ◽  
Cellular Density ◽  
Sham Procedure ◽  
Cellular Volume

Background: Raised intracranial pressure (ICP) following severe strokes can impede blood flow to the brain, causing injury or death. There are compensatory mechanisms regulating ICP, but they are often inadequate. Interestingly, our recent observations in intracerebral hemorrhage (ICH) suggest that a volume reduction in remaining brain may serve a compensatory role after large strokes. We observed neurons well outside the hematoma reduce their volume and intercellular space 7 days after the bleed. Here, we tested the hypotheses that this volume reduction would occur sooner in both ischemic and hemorrhagic insults. Methods: Rats received either an ICH via stereotaxic infusion of collagenase or a sham procedure. Euthanasia and perfusion fixation occurred either 1 (N=12), 3 (N=12), or 7 (N=12) days following the ICH. Following histological processing, cellular volume, density, and cortical thickness were assessed with stereological techniques in representative brain regions such as hippocampus, striatum, and primary somatosensory cortex (S1). In a separate experiment, rats received either a middle cerebral artery occlusion (MCAO) via intraluminal suture occlusion (N=8), or a sham procedure (N=7). Rats were euthanized and perfusion fixed 1 day following the MCAO, with brains processed and assessed as described above. Results: After ICH, the decrease in neuronal volume (up to 60%) compared to shams had the largest effect one day following the insult in hippocampal layers CA1 and CA3 (p<0.0001), striatum (p<0.001), and S1 (p<0.05). The largest increase in cellular density occurred one day following the insult in CA1 and CA3 (p<0.0001), and striatum (p<0.001). Cortical thickness was significantly decreased on day 1 (p<0.0001). Following MCAO, cellular volume was significantly decreased compared to shams in areas CA1 (p<0.01) and S1 (p<0.05). Cellular density was significantly increased compared to shams in areas CA1 and S1 (p<0.01), and striatum (p<0.05). Discussion: Our data challenges the assumption that ‘healthy’ brain tissue outside the injured area maintains its volume after stroke. Given the magnitude of cell volume reductions, we posit that this is an important intracranial compliance mechanism invoked after severe strokes.

scholarly journals Immunohistochemical Detection of Leukemia Inhibitory Factor After Focal Cerebral Ischemia in Rats

2000 ◽  
Vol 20 (4) ◽  
pp. 661-668 ◽  
Author(s):  
Shigeaki Suzuki ◽  
Kortaro Tanaka ◽  
Shigeru Nogawa ◽  
Daisuke Ito ◽  
Tomohisa Dembo ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Leukemia Inhibitory Factor ◽  
Defense Mechanism ◽  
Focal Cerebral Ischemia ◽  
Lectin Histochemistry ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Inhibitory Factor ◽  
Infarct Core ◽  
Cerebral Artery Occlusion

The cytokine leukemia inhibitory factor (LIF) modulates neuronal function during development and promotes neuronal survival after peripheral nerve injury, but little is known about LIF expression after cerebral ischemia. In the present study, the localization of LIF protein was immunohistochemically examined in rats after 3.5, 12, 24, 48, and 96 hours of reperfusion following 1.5 hours of middle cerebral artery occlusion (MCAO) induced by the intraluminal suture method. Double-staining immunohistochemistry with microtubule-associated protein-2 (MAP2), glial fibrillary acidic protein (GFAP), lectin histochemistry, and interleukin (IL) 6 was also performed. The sham group and immunosorption test did not show any clear LIF immunoreactivity. Definite LIF immunoreactivity was first detected after 12 hours of reperfusion in each of the brain regions examined: ischemic core, periinfarct region, and contralateral cortex. However, expression of LIF was most prominent in the periinfarct region at each time point, peaked at 24 hours, and then gradually declined until 96 hours of reperfusion. Some LIF-positive neurons in the periinfarct region expressed IL-6. At 96 hours of reperfusion, GFAP-labeled astrocytes around the infarct core also expressed LIF protein. Induction of LIF mRNA and protein was also confirmed by reverse transcription polymerase chain reaction and western blot analysis, respectively. These findings suggest that LIF expression in ischemically threatened neurons may reflect a repair or defense mechanism against the ischemic insult.

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