The Stroke-Prone Spontaneously Hypertensive Rat: How Good Is It as a Model for Cerebrovascular Diseases?

Nabika, Toru; Cui, Zong-Hu; Masuda, Junichi

doi:10.1023/b:cemn.0000036402.79129.2f

Cited by 46 publications

(39 citation statements)

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“…It is, instead, similar to brain edema due to malignant hypertension and lacunar infarction, and cerebral hemorrhage caused by arteriosclerosis or hyalinosis of small arteries due to severe hypertension. 34 Besides hypertension, additional genetic factors were implicated in the stroke susceptibility of SHRSP, such as neuronal vulnerability to ischemic insult, dysfunctional blood-brain barrier and arterial histological abnormalities. 34 QTL studies were performed on infarction tissue volume after artificial middle cerebral artery occlusion and stroke latency.…”

Section: Genetic Studies On Hypertension and Cerebral Stroke In Shrspmentioning

confidence: 99%

“…34 Besides hypertension, additional genetic factors were implicated in the stroke susceptibility of SHRSP, such as neuronal vulnerability to ischemic insult, dysfunctional blood-brain barrier and arterial histological abnormalities. 34 QTL studies were performed on infarction tissue volume after artificial middle cerebral artery occlusion and stroke latency. Rubattu et al 35,36 identified QTLs for stroke latency on Chr 1, 4 and 5 in an F2 intercross between SHRSP/Bbb and SHR/Bbb, of which the QTL on Chr 1 was confirmed in congenic strains.…”

Section: Genetic Studies On Hypertension and Cerebral Stroke In Shrspmentioning

confidence: 99%

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The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

et al. 2012

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The stroke-prone spontaneously hypertensive rat (SHRSP) is a unique genetic model of severe hypertension and cerebral stroke. SHRSP, as well as the spontaneously hypertensive rat, the parental strain of SHRSP, has made a tremendous contribution to cardiovascular research. However, the genetic mechanisms underlying hypertension and stroke in these rats have not yet been clarified. Recent studies using whole-genome sequencing and comprehensive gene expression analyses combined with classical quantitative trait loci analyses provided several candidate genes, such as Ephx2, Gstm1 and Slc34a1, which still need further evidence to define their pathological roles. Currently, genome-wide association studies can directly identify candidate genes for hypertension in the human genome. Thus, genetic studies in SHRSP and other rat models must be focused on the pathogenetic roles of 'networks of interacting genes' in hypertension, instead of searching for individual candidate genes. Keywords: cerebral stroke; genetics; hypertension; QTL; SHRSP INTRODUCTIONThe stroke-prone spontaneously hypertensive rat (SHRSP) is a unique genetic model of severe hypertension and cerebral stroke. Two decades have passed since the first pioneering studies on quantitative trait loci (QTLs) of blood pressure (BP) in SHRSP. 1,2 In spite of all efforts, the genetic mechanisms underlying hypertension or cerebral stroke in this rat model remain unknown. During this period, genetic analyses in humans have progressed dramatically. Technologies have made it possible to genotype a large number of samples and analyze an enormous amount of single-nucleotide polymorphism data. Genome-wide association studies (GWAS) that rely on such advanced technologies have revealed a number of loci associated with increased BP in humans. [3][4][5][6][7][8][9][10] Under such circumstance, what is the role of SHRSP and other models in genetic studies of cardiovascular diseases? In this review, we will address this issue and summarize the genetic studies performed thus far in SHRSP.

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Section: Genetic Studies On Hypertension and Cerebral Stroke In Shrspmentioning

confidence: 99%

Section: Genetic Studies On Hypertension and Cerebral Stroke In Shrspmentioning

confidence: 99%

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

et al. 2012

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“…Further, we clearly showed an uneven distribution of DND in CA1. The quantitative evaluation employed here may be useful in the genetic analysis of DND in SHRSP (Nabika et al 2004). In addition, this method is probably useful in the precise evaluation of the effects of medical treatments on the 'ischemia/reperfusion' insult (Qiang et al 1989;Yamashita et al 1993Yamashita et al , 1994.…”

Section: Discussionmentioning

confidence: 99%

“…As SHRSP is a model of cerebral stroke, the vulnerability to DND may be one of the phenotypic representations of its genetic susceptibility to cerebral stroke (Nabika et al 2004). The quantitative evaluation of DND will promote the study of genetic analysis of DND in this unique model strain.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Delayed Neuronal Death in the Hippocampal Subfields of SHRSP and SHR

et al. 2009

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Transient forebrain ischemia and reperfusion induces delayed neuronal death (DND) in the hippocampal Cornu Ammonis 1 (CA1) subfield of stroke-prone spontaneously hypertensive rat (SHRSP). The vulnerability to DND is potentially related to the genetic susceptibility to stroke in this strain. To elucidate the mechanism of DND in SHRSP, however, it is essential to establish a method for quantitative evaluation of DND, which is not available yet. Male SHRSPs and spontaneously hypertensive rats (SHRs) at 12 weeks of age were used in the experiment. The bilateral common carotid arteries were surgically occluded with aneurysmal clips for 10 min. The brain was taken out 7 days after the experiment of the transient ischemia, and was sliced into serial coronal sections. Quantitative estimation of the number of viable pyramidal cells in the CA1 and CA2/3 subfields was performed based on the stereology with a random and systematic sampling. The transient ischemia and reperfusion (TIR) significantly reduced the number of viable pyramidal cells in CA1 of SHRSP (61000 +/- 20100 in TIR vs. 128500 +/- 21900 in the sham-operation, P < 0.000001 by Student's t-test), while no significant difference was observed in SHR (140300 +/- 30800 in TIR vs. 128200 +/- 16700 in the sham-operation, P = 0.35). Further analysis revealed a dorsal-ventral gradient in the distribution of DND in CA1 of SHRSP with the most severe change in the dorsal area. The quantitative measurement using a stereological method is useful in the precise evaluation of DND in SHRSP. This method can be applied in the studies of effects of medical treatments on the 'ischemia/reperfusion' insult.

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“…The stroke-prone spontaneously hypertensive rat (SHRSP) is a good genetic model for particular types of stroke. These rats develop stroke even when placed on normal diets because of their genetic susceptibility to stroke (31). However, the above-mentioned models represent individual risk factors and a more comprehensive model that incorporates all of these pathologies is needed.…”

Section: █ Conclusionmentioning

confidence: 99%

Searching evidences of stroke in animal models: a review of discrepancies

Kaya

Erdoğan²,

Taşdemiroğlu³

2016

Turkish Neurosurgery

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ABSTRACTcan be replaced with ketone bodies. In total starvation such as global cerebral ischemia, the brain's limited reserves of glycogen and glucose are barely able to fuel normal brain activity up to 5 minutes. It is reported that the energy stores of the brain are equivalent to 20 cl/100 gr (39). In a healthy person, cerebral blood flow (CBF) is autoregulated at 45-50 ml/100gr/min with a mean arterial blood pressure (MABP) of 60-130 mm/Hg (Figure 1). In the cerebral ischemia model, the investigators try to reduce the oxygen and glucose supply of cerebral tissue. This process produces ischemic brain injury via a variety of cellular and molecular mechanisms.There are three major types of ischemic stroke models: global, focal and lacunar. The global ischemic model is produced by occlusion of four (both vertebral and carotid arteries) or two vessels (either both carotid or vertebral arteries) with or without concomittant hypotension during ischemia period (38). In this model, global blood flow is ceased completely, which resembles the condition of cardiac arrest or coronary █ LITERATuRE REvIEw METhODS O ur review method was based on articles dealing with the relations between animal models and clinical trials. By performing a PubMed search, we aimed to identify all relevant papers to call attention to the discrepancy between experimental methodology in animal modeling and clinical experiences. Articles that were referenced by reviewed articles were also evaluated. Data from papers were extracted within the following categories: study design, type of study population, sampling strategy. Articles excluded from the review were studies that were describing surgical techniques, experimental design and methodology. █ An OvERvIEw Of STROkE MODELSThe human adult brain consumes about 8 cal/100 gr/min energy. Normally, almost 100% of glucose is metabolised, but if starved this increases up to 30%, and glucose consumption So far, animal models have helped us better understand the pathophysiology of the ischemic brain damage but they could not contribute so much to clinical practice. The discrepancies in results regarding neuroprotective agents in animal experiments compared to clinical trials have not been solved. Various animal models of ischemic stroke have proven efficacy of many neuroprotective agents without any considerable result in phase III clinical trials.As is well known, stroke-related focal cerebral ischemia or cardiac arrest related global cerebral ischemia are major causes of disability and death among human subjects. Animal models are essential to evaluate the therapeutic approaches for humans.In this review, we will try to answer two important questions: 1) Which factors endanger the reliability of experimental studies of stroke on animal models? 2) How can we design our experiments to reflect the neurorestoration and/or neuroprotection mechanisms following ischemic injury, when it comes to human disease?

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The Stroke-Prone Spontaneously Hypertensive Rat: How Good Is It as a Model for Cerebrovascular Diseases?

Cited by 46 publications

References 19 publications

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

Quantitative Analysis of Delayed Neuronal Death in the Hippocampal Subfields of SHRSP and SHR

Searching evidences of stroke in animal models: a review of discrepancies

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