Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical ...failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the ‘ischaemic cascade’ that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed.
This article is part of the Special Issue entitled ‘Cerebral Ischemia’.
•Discussion of the main animal models used for experimental stroke.•Importance of the ischaemic penumbra.•Acute imaging techniques for identification of the ischaemic penumbra.
Acute hyperglycaemia and chronic hypertension worsen stroke outcome but their impact on collateral perfusion, a determinant of penumbral life span, is poorly understood. Laser-speckle contrast ...imaging (LSCI) was used to determine the influence of these stroke comorbidities on cortical perfusion after permanent middle cerebral artery occlusion (pMCAO) in spontaneously hypertensive stroke prone rats (SHRSP) and normotensive Wistar rats. Four independent studies were conducted. In animals without pMCAO, cortical perfusion remained stable over 180 min. Following pMCAO, cortical perfusion was markedly reduced at 30 min then gradually increased, via cortical collaterals, over the subsequent 3.5 h. In the contralateral non-ischaemic hemisphere, perfusion did not change over time. Acute hyperglycaemia (in normotensive Wistar) and chronic hypertension (SHRSP) attenuated the restoration of cortical perfusion after pMCAO. Inhaled nitric oxide did not influence cortical perfusion in SHRSP following pMCAO. Thus, hyperglycaemia at the time of arterial occlusion or pre-existing hypertension impaired the dynamic recruitment of cortical collaterals after pMCAO. The impairment of collateral recruitment may contribute to the detrimental effects these comorbidities have on stroke outcome.
Stroke-prone spontaneously hypertensive rats (SHRSP) are a highly pertinent stroke model with increased sensitivity to focal ischemia compared with the normotensive reference strain (Wistar-Kyoto ...rats; WKY). Study aims were to investigate temporal changes in the ischemic penumbra in SHRSP compared with WKY.
Permanent middle cerebral artery occlusion was induced with an intraluminal filament. Diffusion- (DWI) and perfusion- (PWI) weighted magnetic resonance imaging was performed from 1 to 6 hours after stroke, with the PWI-DWI mismatch used to define the penumbra and thresholded apparent diffusion coefficient (ADC) maps used to define ischemic damage.
There was significantly more ischemic damage in SHRSP than in WKY from 1 to 6 hours after stroke. The perfusion deficit remained unchanged in WKY (39.9+/-6 mm(2) at 1 hour, 39.6+/-5.3 mm(2) at 6 hours) but surprisingly increased in SHRSP (43.9+/-9.2 mm(2) at 1 hour, 48.5+/-7.4 mm(2) at 6 hours; P=0.01). One hour after stroke, SHRSP had a significantly smaller penumbra (3.4+/-5.8 mm(2)) than did WKY (9.7+/-3.8, P=0.03). In WKY, 56% of the 1-hour penumbra area was incorporated into the ADC lesion by 6 hours, whereas in SHRSP, the small penumbra remained static owing to the temporal increase in both ADC lesion size and perfusion deficit.
First, SHRSP have significantly more ischemic damage and a smaller penumbra than do WKY within 1 hour of stroke; second, the penumbra is recruited into the ADC abnormality over time in both strains; and third, the expanding perfusion deficit in SHRSP predicts more tissue at risk of infarction. These results have important implications for management of stroke patients with preexisting hypertension and suggest ischemic damage could progress at a faster rate and over a longer time frame in the presence of hypertension.
Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether ...stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2∗, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months.
The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle ...exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia. High functional scores in Mincle KO animals using the focal cerebral ischemia model were accompanied by reduced lesion size, fewer infiltrating leukocytes and less neutrophil-derived cytokine production than isogenic controls. Bone marrow chimera experiments revealed that the presence of Mincle in the central nervous system, rather than recruited immune cells, was the critical regulator of a poor outcome following transient middle cerebral artery occlusion. There was no evidence for a direct role for Mincle in microglia or neural activation, but expression in a subset of macrophages resident in the perivascular niche provided new clues on Mincle's role in ischemic stroke.
Estrogen as a Neuroprotectant in Stroke Hurn, Patricia D.; Macrae, I. Mhairi
Journal of Cerebral Blood Flow & Metabolism,
04/2000, Letnik:
20, Številka:
4
Journal Article, Book Review
Recenzirano
Odprti dostop
Recent evidence suggests that reproductive steroids are important players in shaping stroke outcome and cerebrovascular pathophysiologic features. Although women are at lower risk for stroke than ...men, this native protection is lost in the postmenopausal years. Therefore, aging women sustain a large burden for stroke, contrary to a popular misconception that cancer is the main killer of women. Further, the value of hormone replacement therapy in stroke prevention or in improving outcome remains controversial. Estrogen has been the best studied of the sex steroids in both laboratory and clinical settings and is considered increasingly to be an endogenous neuroprotective agent. A growing number of studies demonstrate that exogenous estradiol reduces tissue damage resulting from experimental ischemic stroke in both sexes. This new concept suggests that dissecting interactions between estrogen and cerebral ischemia will yield novel insights into generalized cellular mechanisms of injury. Less is known about estrogen's undesirable effects in brain, for example, the potential for increasing seizure susceptibility and migraine. This review summarizes gender-specific aspects of clinical and experimental stroke and results of estrogen treatment on outcome in animal models of cerebral ischemia, and briefly discusses potential vascular and parenchymal mechanisms by which estrogen salvages brain.
Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to ...improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).
Poststroke hyperglycemia is associated with a poor outcome yet clinical management is inadequately informed. We sought to determine whether clinically relevant levels of hyperglycemia exert ...detrimental effects on the early evolution of focal ischemic brain damage, as determined by magnetic resonance imaging, in normal rats and in those modeling the ‘metabolic syndrome’. Wistar Kyoto (WKY) or fructose-fed spontaneously hypertensive stroke-prone (ffSHRSP) rats were randomly allocated to groups for glucose or vehicle administration before permanent middle cerebral artery occlusion. Diffusion-weighted imaging was carried out over the first 4 hours after middle cerebral artery occlusion and lesion volume calculated from apparent diffusion coefficient maps. Infarct volume and immunostaining for markers of oxidative stress were measured in the fixed brain sections at 24 hours. Hyperglycemia rapidly exacerbated early ischemic damage in both WKY and ffSHRSP rats but increased infarct volume only in WKY rats. There was only limited evidence of oxidative stress in hyperglycemic animals. Acute hyperglycemia, at clinically relevant levels, exacerbates early ischemic damage in both normal and metabolic syndrome rats. Management of hyperglycemia may have greatest benefit when performed in the acute phase after stroke in the absence or presence of comorbidities.
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.
In rodent stroke models, investigation of deficits in spatial memory using the Morris watermaze may be confounded by coexisting sensory or motor impairments. To target memory specifically, we devised ...a watermaze protocol to minimize the impact of sensory and motor impairments in female Lister-hooded rats exposed to proximal electrocoagulation of the middle cerebral artery (MCAO). Rats were trained in a reference-memory task comprising 4 trials/day; trial 1 being a probe trial (platform absent for the first 60 seconds). Training ended once animals reached a strict criterion based on the probe-trial performance. Memory retention was tested 1, 7, and 28 days later. The MCAO did not affect the number of days to reach criterion during acquisition or the time spent in target quadrant during retention testing, compared with sham or unoperated rats. However, MCAO rats showed slightly poorer accuracy in crossing the platform location and increased thigmotactic swimming compared with controls. Our results show that spatial memory deficits are minimal in this rodent stroke model, and suggest that previously published watermaze impairments are attributable to sensory and motor deficits but not memory deficits. We recommend using probe trials and training to a predetermined performance criterion in future studies assessing watermaze memory deficits in rodent stroke models.
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