Association and cosegregation of stroke with impaired endothelium-dependent vasorelaxation in stroke prone, spontaneously hypertensive rats.

116

108

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.)

Section: Discussionmentioning

confidence: 99%

Section: Spontaneous Lesionsmentioning

confidence: 99%

Potential Animal Models of Lacunar Stroke

Bailey

McCulloch

Sudlow

et al. 2009

116

108

“…1,13 Moderate hyperhomocysteinemia, induced by acute methionine loading, produces impaired autoregulatory responses in older humans. 14 When considering the consequences of impairment of normal endothelial function, it is important to recall that genetic analyses have demonstrated cosegregation of endothelial dysfunction with a stroke-prone phenotype, 15 and endothelial dysfunction is emerging as an independent predictor of clinical events including stroke. 16 Levels of circulating homocysteine are determined by multiple mechanisms including genetic and dietary factors.…”

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confidence: 99%

Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction

Faraci

Lentz

2004

209

147

A n elevated circulating concentration of the sulfurcontaining amino acid homocysteine, hyperhomocysteinemia, produces complex changes within the blood vessel wall. In the peripheral circulation, these changes include oxidative stress, proinflammatory effects such as expression of tumor necrosis factor-␣ and inducible nitric oxide (NO) synthase (iNOS), and endothelial dysfunction. [1][2][3][4][5][6] Hyperhomocysteinemia-induced oxidative stress may occur as a result of decreased expression and/or activity of key antioxidant enzymes as well as increased enzymatic generation of superoxide anion (the precursor for multiple reactive oxygen and reactive nitrogen species). 2,4 Do hyperhomocysteinemia-induced changes occur in the cerebral circulation and why are they potentially important? Hyperhomocysteinemia is a an emerging risk factor for carotid artery disease (atherosclerosis) and stroke and is associated with Alzheimer's disease and vascular dementia. 7-11 It was not until relatively recently, however, that experimental studies began to define the impact of hyperhomocysteinemia on cerebral vascular biology and the molecular mechanisms that account for these changes. This work has been facilitated by the development of mouse models with genetic alterations in different components of the homocysteine metabolic pathway (see below).Early work in the cerebral microcirculation observed that acute local administration of a very high concentration of homocysteine (1 mmol/L) in the presence of exogenous Cu 2ϩ produced superoxide-mediated reductions in resting cerebral blood flow (CBF) as well as attenuation of endotheliumdependent and NO-mediated responses. 12 Our group was among the first to show that mild chronic hyperhomocysteinemia produces endothelial dysfunction in the carotid artery. 1,13 Moderate hyperhomocysteinemia, induced by acute methionine loading, produces impaired autoregulatory responses in older humans. 14 When considering the consequences of impairment of normal endothelial function, it is important to recall that genetic analyses have demonstrated cosegregation of endothelial dysfunction with a stroke-prone phenotype, 15 and endothelial dysfunction is emerging as an independent predictor of clinical events including stroke. 16 Levels of circulating homocysteine are determined by multiple mechanisms including genetic and dietary factors. Several genetically altered mice deficient in key enzymes within the homocysteine metabolic pathway have now been developed. 17 These include mice deficient in expression of cystathionine ␤-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR), and methione synthase (MS). 17 All these genetic alterations result in hyperhomocysteinemia, the magnitude of which is dependent on the content of methionine, folate, and choline in the diet. The development of these animals, along with combined dietary interventions, now allows mechanistic studies of effects of mild to moderate hyperhomocysteinemia on the vasculature. We have used these novel genetic models in studies of ...

“…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.…”

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confidence: 99%

New Insights Into Brain Damage in Stroke-Prone Rats

Guerrini

Sironi

Tremoli

et al. 2002

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...