Standards and pitfalls of focal ischemia models in spontaneously hypertensive rats: With a systematic review of recent a
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REVIEW
Open Access
Standards and pitfalls of focal ischemia models in spontaneously hypertensive rats: With a systematic review of recent articles Hiroshi Yao1* and Toru Nabika2
Abstract We reviewed the early development of various focal ischemia models in spontaneously hypertensive rats (SHR), and summarized recent reports on this topic. Among 6 focal ischemia models established in divergent substrains of SHR, distal middle cerebral artery occlusion is the most frequently used and relevant method of focal ischemia in the light of penumbra concept. We performed an online PubMed search (2001–2010), and identified 118 original articles with focal ischemia in SHR. Physiological parameters such as age, body weight, and even blood pressure were often neglected in the literature: the information regarding the physiological parameters of SHR is critical, and should be provided within the methodology section of all articles related to stroke models in SHR. Although the quality of recent studies on neuroprotective strategy is improving, the mechanisms underlying the protection should be more clearly recognized so as to facilitate the translation from animal studies to human stroke. To overcome the genetic heterogeneity in substrains of SHR, new approaches, such as a huge repository of genetic markers in rat strains and the congenic strategy, are currently in progress. Keywords: Focal ischemia, Hypertension, Experimental, Genetics, Animal Models, Cerebrovascular disease, Stroke
Introduction Almost 50 years have passed since the spontaneously hypertensive rats (SHR) were established [1]. In the present review, we will focus on the early development of focal ischemia models in SHR, and provide a critical systematic review on recent reports on SHR stroke models. SHR are one of the most widely used genetic models for hypertension. Hypertension is a major risk factor for stroke and most other cardiovascular diseases, and therefore SHR are relevant to stroke research. SHR were initially obtained by selective inbreedings from the Wistar-Kyoto rats (WKY) with the highest blood pressure. The stroke prone SHR (SHRSP) were established from the A substrain of the SHR, and the other 2 substrains (B and C) are resistant to spontaneous stroke [2]. The B substrain corresponds to SHR/Izm (Izumo). SHR
were sent to the National Institute of Health (NIH) at the F13 generation in 1966. The advantages of using SHR in contrast to normotensive rats in stroke research are: (1) presence of comorbidity (i.e., hypertension), (2) reproducible and adequate-sized infarction after distal middle cerebral artery occlusion (MCAO) alone, and (3) a similar therapeutic time window and cerebral blood flow (CBF) threshold for infarction to normotensive rats [3,4]. Shortcomings are: (1) SHR and SHRSP are expensive, (2) high mortality in aged SHR and SHRSP, and (3) resistance to therapy. Another confounding problem with using SHR in stroke research is that SHR and WKY from different sources are genetically heterogeneous [5-7]. Because WKY are rarely used for fo
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