Abstract
Background and PurposeCerebral 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.MethodsMerino-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.ResultsIntracranial 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.ConclusionWe 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.
Highlights
Worldwide, over 15 million people suffer a stroke each year, of which one third will die and one third will remain permanently disabled as a result (Feigin et al, 2017)
We have established that blockade of the receptor for substance P (SP), the tachykinin NK1 receptor (NK1-r), reduces both blood-brain barrier (BBB) permeability and cerebral edema in rodent models of stroke (Turner et al, 2011; Turner and Vink, 2012, 2014) and traumatic brain injury (TBI) (Donkin et al, 2009; Corrigan et al, 2012, 2016), suggesting that this is a common feature of acute brain injury
The excluded animals were unstable throughout the induction of stroke surgery, necessitating repeat boluses of ketamine and diazepam and an increased rate of isoflurane to maintain surgical levels of anesthesia, which resulted in significantly lowered Mean arterial blood pressure (MABP), decreased cerebral perfusion pressure and profound infarct expansion
Summary
Over 15 million people suffer a stroke each year, of which one third will die and one third will remain permanently disabled as a result (Feigin et al, 2017). Cerebral ischemia initiates a cascade of interrelated events precipitating brain tissue injury and cell death (Ayata and Ropper, 2002) Of these secondary injury processes, increased microvascular permeability and loss of structural integrity of the blood-brain barrier (BBB) are key to the development of cerebral edema, a pathological state in which fluid abnormally accumulates in the extracellular space of the cerebral parenchyma, resulting in an overall increase in brain volume. This leads to a subsequent rise in intracranial pressure (ICP), which has devastating consequences including infarct expansion, displacement of brain tissue, tonsillar herniation, and death (Steiner et al, 2001; Raslan and Bhardwaj, 2007; Battey et al, 2014; Kim et al, 2015). 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
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