Intracranial Pressure Elevation after Ischemic Stroke in Rats: Cerebral Edema is not the only Cause, and Short-Duration Mild Hypothermia is a Highly Effective Preventive Therapy

Murtha, Lucy A.; McLeod, Damian D.; Pepperall, Debbie; McCann, Sarah; Beard, Daniel J.; Tomkins, Amelia J.; Holmes, William M.; McCabe, Chris; Macrae, I Mhairi; Spratt, Neil J

doi:10.1038/jcbfm.2015.209

Cited by 12 publications

(21 citation statements)

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“…Although a number of studies have reported raised ICP following stroke in small animal models (Beard et al, 2015; Murtha et al, 2015) and large animal species at early time-points (Wells et al, 2015) this study is the first in which ICP was recorded out to 7 days post-stoke in a large gyrencephalic species. Using this model we have successfully characterized the temporal profile and established that ICP peaks at 5–6 days following ovine transient MCAO.…”

Section: Discussionmentioning

confidence: 88%

“…In the clinic, ICP readings of ≥20 mmHg warrant investigation for possible treatment and intervention (Lavinio and Menon, 2011; Battey et al, 2014), as persistently elevated ICP is associated with poor outcome following ischemic stroke, widely accepted as being attributable to the development of edema in the cerebral parenchyma (Ayata and Ropper, 2002). Despite this, conflicting studies have reported an elevation of ICP in the absence of cerebral edema following small ischemic stroke in rats (Beard et al, 2015; Murtha et al, 2015). However, the underlying pathophysiology of increased ICP was not reported and requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Determining the Temporal Profile of Intracranial Pressure Changes Following Transient Stroke in an Ovine Model

et al. 2019

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Background and Purpose Cerebral edema and elevated intracranial pressure (ICP) are the leading cause of death in the first week following stroke. Despite this, current treatments are limited and fail to address the underlying mechanisms of swelling, highlighting the need for targeted treatments. When screening promising novel agents, it is essential to use clinically relevant large animal models to increase the likelihood of successful clinical translation. As such, we sought to develop a survival model of transient middle cerebral artery occlusion (tMCAO) in the sheep and subsequently characterize the temporal profile of cerebral edema and elevated ICP following stroke in this novel, clinically relevant model. Methods Merino-sheep (27M;31F) were anesthetized and subject to 2 h tMCAO with reperfusion or sham surgery. Following surgery, animals were allowed to recover and returned to their home pens. At preselected times points ranging from 1 to 7 days post-stroke, animals were re-anesthetized, ICP measured for 4 h, followed by imaging with MRI to determine cerebral edema, midline shift and infarct volume (FLAIR, T2 and DWI). Animals were subsequently euthanized and their brain removed for immunohistochemical analysis. Serum and cerebrospinal fluid samples were also collected and analyzed for substance P (SP) using ELISA. Results Intracranial pressure and MRI scans were normal in sham animals. Following stroke, ICP rose gradually over time and by 5 days was significantly ( p < 0.0001) elevated above sham levels. Profound cerebral edema was observed as early as 2 days post-stroke and continued to evolve out to 6 days, resulting in significant midline shift which was most prominent at 5 days post-stroke ( p < 0.01), in keeping with increasing ICP. Serum SP levels were significantly elevated ( p < 0.01) by 7 days post-tMCAO. Conclusion We have successfully developed a survival model of ovine tMCAO and characterized the temporal profile of ICP. Peak ICP elevation, cerebral edema and midline shift occurred at days 5–6 following stroke, accompanied by an elevation in serum SP. Our findings suggest that novel therapeutic agents screened in this model targeting cerebral edema and elevated ICP would most likely be effective when administered prior to 5 days, or as early as possible following stroke onset.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Determining the Temporal Profile of Intracranial Pressure Changes Following Transient Stroke in an Ovine Model

et al. 2019

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“…Additionally, the mechanisms of RIPerC with respect to neuroprotection and collateral dynamics remain to be elucidated. Raised intracranial pressure may contribute to collateral failure [86][87][88][89][90] , and may be accelerated in the aged, and the protective effects of RIPerC on the brain and vasculature may act reduce intracranial pressure to preserve collaterals. However, preliminary studies in clinical populations did not identify an effect of RIPerC on intracranial pressure 84 .…”

Section: Discussionmentioning

confidence: 99%

Improved collateral flow and reduced damage after remote ischemic perconditioning during distal middle cerebral artery occlusion in aged rats

Shuaib

et al. 2020

Sci Rep

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circulation through cerebral collaterals can maintain tissue viability until reperfusion is achieved. However, collateral circulation is time limited, and failure of collaterals is accelerated in the aged. Remote ischemic perconditioning (RIPerC), which involves inducing a series of repetitive, transient peripheral cycles of ischemia and reperfusion at a site remote to the brain during cerebral ischemia, may be neuroprotective and can prevent collateral failure in young adult rats. Here, we demonstrate the efficacy of RIPerC to improve blood flow through collaterals in aged (16-18 months of age) Sprague Dawley rats during a distal middle cerebral artery occlusion. Laser speckle contrast imaging and two-photon laser scanning microscopy were used to directly measure flow through collateral connections to ischemic tissue. Consistent with studies in young adult rats, RIPerC enhanced collateral flow by preventing the stroke-induced narrowing of pial arterioles during ischemia. This improved flow was associated with reduced early ischemic damage in RIPerC treated aged rats relative to controls. Thus, RIPerC is an easily administered, non-invasive neuroprotective strategy that can improve penumbral blood flow via collaterals. Enhanced collateral flow supports further investigation as an adjuvant therapy to recanalization therapy and a protective treatment to maintain tissue viability prior to reperfusion.

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“…It is understood that with high intracranial pressure (ICP), the venous system outflow in the subdural space is modulated similar as the Starling resistor model. In this setting, the high cranial pressure compressed the bridging veins and lacunae before entering dural sinuses and thus decreased venous outflow (Murtha et al, 2015). Although this may help to keep the cortical veins open, prevent abrupt pressure gap between arterial and venous side and therefore maintain the cerebral perfusion, and reduce the disruption of BBB, it may also bring about the risk of increased intracranial hypertension exacerbated by blood retention.…”

Section: The Regulatory Mechanisms Of the Cerebral Venous Systemmentioning

confidence: 99%

Cerebral venous collaterals: A new fort for fighting ischemic stroke?

Tong

Guo

et al. 2018

Progress in Neurobiology

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Stroke therapy has entered a new era highlighted by the use of endovascular therapy in addition to intravenous thrombolysis. However, the efficacy of current therapeutic regimens might be reduced by their associated adverse events. For example, over-reperfusion and futile recanalization may lead to large infarct, brain swelling, hemorrhagic complication and neurological deterioration. The traditional pathophysiological understanding on ischemic stroke can hardly address these occurrences. Accumulating evidence suggests that a functional cerebral venous drainage, the major blood reservoir and drainage system in brain, may be as critical as arterial infusion for stroke evolution and clinical sequelae. Further exploration of the multi-faceted function of cerebral venous system may add new implications for stroke outcome prediction and future therapeutic decision-making. In this review, we emphasize the anatomical and functional characteristics of the cerebral venous system and illustrate its necessity in facilitating the arterial infusion and maintaining the cerebral perfusion in the pathological stroke content. We then summarize the recent critical clinical studies that underscore the associations between cerebral venous collateral and outcome of ischemic stroke with advanced imaging techniques. A novel three-level venous system classification is proposed to demonstrate the distinct characteristics of venous collaterals in the setting of ischemic stroke. Finally, we discuss the current directions for assessment of cerebral venous collaterals and provide future challenges and opportunities for therapeutic strategies in the light of these new concepts.

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Intracranial Pressure Elevation after Ischemic Stroke in Rats: Cerebral Edema is not the only Cause, and Short-Duration Mild Hypothermia is a Highly Effective Preventive Therapy

Cited by 12 publications

References 0 publications

Determining the Temporal Profile of Intracranial Pressure Changes Following Transient Stroke in an Ovine Model

Determining the Temporal Profile of Intracranial Pressure Changes Following Transient Stroke in an Ovine Model

Improved collateral flow and reduced damage after remote ischemic perconditioning during distal middle cerebral artery occlusion in aged rats

Cerebral venous collaterals: A new fort for fighting ischemic stroke?

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