Proteinuria Precedes Cerebral Edema in Stroke-Prone Rats

Blezer, Erwin L. A.; Schurink, Merel; Nicolay, Klaas; Bär, P.R.; Jansen, Gerard H.; Koomans, Hein A.; Joles, Jaap A.

doi:10.1161/01.str.29.1.167

Cited by 35 publications

(42 citation statements)

References 27 publications

(25 reference statements)

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“…73 The only model that mimics both microvessel and parenchymal changes is the spontaneous stroke in SHRSPs. 60,74 This species is highly inbred and may therefore be of limited relevance, but the microvascular and brain morphological features are so similar to those described in humans that it is hard to ignore. In this model, the initiating step appears to be BBB disruption, 52,60,75 which leads to parenchymal perivascular edema-related damage in white matter 60 and arteriolar damage.…”

Section: Discussionmentioning

confidence: 99%

Potential Animal Models of Lacunar Stroke

Bailey

McCulloch

Sudlow

et al. 2009

Stroke

116

108

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Background and Purpose-Lacunar ischemic stroke accounts for 25% of all ischemic strokes, but the exact etiology is unknown. Numerous pathophysiologies have been proposed, including atheroma and endothelial dysfunction. Models of any of these pathological features would aid understanding of the etiology and help develop treatments for lacunar stroke. We therefore aimed to assess the relevance of all available potential animal models of lacunar stroke. Methods-We systematically reviewed the published literature for animal models that could represent lacunar stroke using validated search strategies. We included studies that could represent an aspect of lacunar stroke as well as those aiming to model conditions with potentially similar pathology and extracted data on species, induction method, and resulting brain and vessel lesions. Results-From 5670 papers, 41 studies (46 papers) met inclusion criteria representing over 10 different classes of stroke induction. Important data like infarct size and animal numbers were often missing. Many models' infarcts were too large or affected the cortex. Emboli mostly caused cortical but not small subcortical lesions. Most models focused on creating ischemic lesions in brain tissue. Only one (spontaneous lesions in spontaneously hypertensive stroke-prone rats) also mimicked small vessel pathology. Here, the precursor to small vessel and brain damage was blood-brain barrier failure. Conclusion-Some animal models produce small subcortical infarcts, but few mimic the human small vessel pathology.Models of small vessel disease could help improve understanding of human lacunar disease, particularly to clarify factors associated with the small vessel morphological changes preceding brain damage. Much lacunar stroke may arise after blood-brain barrier disruption. (Stroke. 2009;40:e451-e458.)

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Section: Discussionmentioning

confidence: 99%

Potential Animal Models of Lacunar Stroke

Bailey

McCulloch

Sudlow

et al. 2009

Stroke

116

108

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“…With bovine albumin as a standard, 24-h urine protein was measured according to Bradford. Proteinuria (protein levels Ն40 mg/day) predicts the appearance of brain abnormalities in SHRSP (Blezer et al, 1998;Guerrini et al, 2002) and was used to schedule the frequency of MRI investigations. The SHRSP underwent MRI every week until 24-h proteinuria exceeded 40 mg/day, then every other day until brain damage was observed and every day for 3 days afterwards.…”

Section: Methodsmentioning

confidence: 99%

Anti-Inflammatory Effects of AT1 Receptor Blockade Provide End-Organ Protection in Stroke-Prone Rats Independently from Blood Pressure Fall

Sironi¹,

Guerrini²,

Banfi³

et al. 2004

J Pharmacol Exp Ther

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Spontaneously hypertensive stroke-prone rats (SHRSP) develop hypertension and systemic inflammation, with subsequent brain and renal disorders and early death. We tested the hypothesis that valsartan, an angiotensin II type 1 (AT1) receptor antagonist, exerts protective effects in SHRSP through its anti-inflammatory properties, even in the absence of a blood pressure-lowering effect. SHRSP fed a high-salt diet were treated with vehicle or valsartan (1-10 mg/kg/day). The vehicletreated rats developed hypertension, proteinuria, progressive kidney disease, and, 40 Ϯ 5 days from the beginning of the treatment, brain damage as visualized by magnetic resonance imaging. Rats treated with 1 mg/kg/day valsartan developed brain damage after 61 Ϯ 3 days (p Ͻ 0.01 versus vehicletreated rats). No damage showed after 100 days in 80% of the rats treated with 10 mg/kg/day. Valsartan treatment preserved renal structure, by preventing the infiltration of inflammatory cells, and lowered renal expression of monocyte chemoattractant protein-1, transforming growth factor-␤1, and interleukin-1␤, compared with vehicle-treated SHRSP. Urinary excretion of acute-phase proteins increased in the latter but remained negligible in the drug-treated animals. Furthermore, valsartan exerted protective effects also when given after established proteinuria. In SHRSP, blockade of AT1 receptor with valsartan prevents the development of proteinuria, delays the appearance of brain damage, preserves renal structure, and increases survival under stressful conditions. Valsartan exerts its beneficial effects independently of any blood pressure fall and by means of broad anti-inflammatory actions both at local and at systemic levels. These observations indicate that the administration of AT1 receptor antagonists may be useful in pathological situations in which an anti-inflammatory effect is required.

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“…Twenty-four-hour urinary protein concentrations were measured according to Bradford (Bio-Rad Laboratories, Milan, Italy), with bovine albumin being used as a standard. Proteinuria (protein levels Ն40 mg/d) predicts the appearance of brain abnormalities in SHRSP 11,12 and was used to schedule the frequency of the MRI investigations. Systolic arterial blood pressure was measured in conscious rats by means of tail-cuff plethysmography (PB Recorder 8006, Ugo Basile), after warming to 37°C.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…15 Ischemic lesions can also be detected by means of T2-weighted (T2W) MRI, but only in the advanced stage of the disease. Generally, ADC values decrease in the first hours 11 but no analysis has been made of the evolution of MRI parameters in the follow-up period. To the best of our knowledge, ADC images have only been used in 1 study evaluating the chronic stage of the disease in SHRSP, 16 but no information is available concerning this parameter at the time of the onset of brain damage and during the early stages.…”

mentioning

confidence: 99%

New Insights Into Brain Damage in Stroke-Prone Rats

Guerrini

Sironi

Tremoli

et al. 2002

Stroke

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Background and Purpose-The spontaneously hypertensive stroke-prone rat (SHRSP) is an animal model for a complex form of cerebrovascular pathology. MRI provides an efficient and noninvasive tool for studying the time course of brain damage. The aim of this study was to gain new insights into the pathological phenomena responsible for the occurrence of brain injury in SHRSP with the use of the apparent diffusion coefficient of water (ADC), one of the most efficient MRI parameters for detecting brain abnormalities. To this end, the pattern of ADC variation observed in SHRSP was compared with that of focal ischemia induced in both SHRSP and Sprague-Dawley rats. Methods-Four groups of animals were studied: SHRSP developing spontaneous brain lesions fed with a salt-loaded (nϭ15, group 1) or standard diet (nϭ3, group 2) and Sprague-Dawley rats (nϭ8, group 3) and SHRSP (nϭ8, group 4) with permanent middle cerebral artery occlusion. ADC maps and T2-weighted images of brains were performed by MRI. After the rats were killed, the brains were removed and histologically processed. Results-There was no decrease in ADC during spontaneous stroke in the SHRSP fed with a normal or salt-enriched diet, while both the SHRSP and Sprague-Dawley rats with middle cerebral artery occlusion showed a marked decrease that lasted for 24 to 48 hours. Conclusions-Cerebral ischemia cannot be considered a major factor in the onset of spontaneous brain lesions in SHRSP, which show only vasogenic edema after the beginning of the damage with no evidence of metabolic impairment. Key Words: animal models Ⅲ brain injuries Ⅲ diffusion Ⅲ magnetic resonance imaging Ⅲ middle cerebral artery occlusion Ⅲ rats T he spontaneous hypertensive stroke-prone rat (SHRSP) is generally considered a good experimental model for studying the hypertensive damage leading to stroke, 1,2 but the similarity between SHRSP and human stroke is still a matter of debate. 3,4 The model has been used to study vascular and brain tissue alterations both structurally and functionally, [5][6][7][8] and the relationship between histopathological findings and behavioral or metabolic abnormalities (eg, increased aggressiveness, hypokinesia or hyperkinesia, blood-brain barrier damage, proteinuria, a sudden loss of body weight) has also been extensively investigated. 1,9 -12 However, less information is available concerning the onset of the spontaneous brain damage and the mechanisms responsible for the development of brain abnormalities. 12 The morphological and histopathological investigations directed at the characterization of the brain lesion in SHRSP did not univocally clarify the pathogenesis of the damage. In fact, the term stroke is not univocally adopted in literature that concerns SHRSP studies, and there is ambiguity regarding whether this term is used to mean hemorrhage, infarct, or hemorrhagic infarct. 2,3,[5][6][7] This is in part due to the difficulty of precisely predicting the timing and the location of the spontaneous brain lesions, in turn making their systematic study i...

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Proteinuria Precedes Cerebral Edema in Stroke-Prone Rats

Cited by 35 publications

References 27 publications

Potential Animal Models of Lacunar Stroke

Potential Animal Models of Lacunar Stroke

Anti-Inflammatory Effects of AT1 Receptor Blockade Provide End-Organ Protection in Stroke-Prone Rats Independently from Blood Pressure Fall

New Insights Into Brain Damage in Stroke-Prone Rats

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