Stroke-prone rats exhibit prolonged behavioral deficits without increased brain injury: an indication of disrupted post-stroke brain recovery of function.
ABSTRACT Stroke-prone rat strains exhibit an increased stroke risk and sensitivity, and reduced endogenous mechanisms of ischemic brain tolerance. This experiment provides a comparative, serial evaluation of neurological deficits and brain injury following middle cerebral artery occlusion/permanent focal stroke in this high-risk strain. Stroke-prone spontaneously hypertensive (SHR-SP), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were evaluated over 28 days using magnetic resonance imaging (MRI), histopathology, and neurobehavioral testing. T2- and diffusion weighted-MRI was performed after 1, 10 and 28 days to measure the degree of stroke-induced brain injury. Normotensive WKY rats receiving the same stroke and other SHR-SP rats receiving sham surgery were used for control comparisons. Functional deficits were scored after 1, 4, 11, 18 and 28 days. The degree of brain infarction/injury was practically identical in hypertensive and stroke-prone rats. WKY rats exhibited significantly smaller infarcts (P<0.05), with neurological function recovering quickly to normal by day 11 in this strain. Functional deficits persisted longer in hypertensive rats, with function recovering to normal by day 18 (P<0.05). Functional deficits in SHR-SP rats persisted the longest, and were observed even after 28 days (P<0.05). This increased and prolonged neurologic dysfunction exhibited by SHR-SP compared to SHR rats, while exhibiting practically identical degrees of brain injury/infarction, reflects the increased stroke risk and sensitivity of this strain and suggests a reduced SHR-SP brain plasticity following injury. Therefore, the stroke-prone rat provides an enhanced and prolonged functional deficit model that can be used to elucidate those mechanisms/novel targets critical to longitudinal neurobehavioral recovery post-stroke.
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ABSTRACT: Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. Pathologically, three lesions are seen: small vessel arteriopathy, lacunar infarction, and diffuse white matter injury (leukoaraiosis). Appropriate experimental models would aid in understanding these pathologic states and also in preclinical testing of therapies. The objective was to perform a systematic review of animal models of SVD and determine whether these resemble four key clinicopathologic features: (1) small, discrete infarcts; (2) small vessel arteriopathy; (3) diffuse white matter damage; (4) cognitive impairment. Fifteen different models were included, under four categories: (1) embolic injuries (injected blood clot, photochemical, detergent-evoked); (2) hypoperfusion/ischaemic injury (bilateral common carotid occlusion/stenosis, striatal endothelin-1 injection, striatal mitotoxin 3-NPA); (3) hypertension-based injuries (surgical narrowing of the aorta, or genetic mutations, usually in the renin-angiotensin system); (4) blood vessel damage (injected proteases, endothelium-targeting viral infection, or genetic mutations affecting vessel walls). Chronic hypertensive models resembled most key features of SVD, and shared the major risk factors of hypertension and age with human SVD. The most-used model was the stroke-prone spontaneously hypertensive rat (SHR-SP). No model described all features of the human disease. The optimal choice of model depends on the aspect of pathophysiology being studied.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 08/2008; 28(12):1877-91. DOI:10.1038/jcbfm.2008.91 · 5.34 Impact Factor
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ABSTRACT: To identify if the stroke-prone spontaneously hypertensive rat (SHRSP) exhibits impaired functional recovery after stroke compared with its normotensive reference strain, the Wistar Kyoto rat (WKY). In study 1, a 2-mm distal middle cerebral artery occlusion (middle cerebral artery occlusion) was performed in both strains and recovery assessed using a 33-point neurological score. Because SHRSPs displayed much larger infarcts than WKYs, study 2 and study 3 involved extending the length of middle cerebral artery (MCA) occlusion in the WKY to increase the volume and distribution of infarction to comparable levels with SHRSP. Animals were assessed with the neurological score, tapered beam walk, and cylinder tests. In study 1, infarct volume (expressed as a percent of contralateral hemisphere) was WKY 13.1+/-3% and SHRSP 19.8+/-1%. Initial neurological deficit was greater (WKY 25+/-1, SHRSP 22+/-1, out of a possible 33) and subsequent recovery was poorer in SHRSP. In studies 2 and 3, infarct volume and distribution (study 2, WKY 21.8+/-1.3%, SHRSP 22.9+/-3%; study 3, WKY 17.2+/-2%, SHRSP 16.5+/-3%) and initial neurological deficit at 2 hours after middle cerebral artery occlusion (study 2 WKY 23+/-1, SHRSP 22+/-2; study 3 WKY 25+/-1 and SHRSP 23+/-1; mean+/-SEM) were comparable between strains. However, whereas WKY recovered toward normal scores, SHRSP scored significantly lower 2 weeks (study 2) and 4 weeks (study 3) after middle cerebral artery occlusion. Beam walk data revealed long-term impairment in SHRSP contralateral limb use, compared with WKY, at days 3, 7, and 28 (P<0.05). SHRSP exhibit impaired functional recovery after stroke compared with WKY.Stroke 01/2005; 36(1). DOI:10.1161/01.STR.0000149629.32525.b7 · 6.02 Impact Factor
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ABSTRACT: To determine how cytokine transport systems at the blood-brain barrier (BBB) participate in stroke progression and recovery, we generated a mouse model of transient middle cerebral artery occlusion (tMCAO). After 1 h of occlusion followed by nearly complete reperfusion, the neurological deficits lasted more than a week as shown by several behavioral tests. Despite the prominent infarct area indicated by reduced cerebral perfusion and confirmed by vital staining, the volume of distribution of (131)I-albumin in various brain regions was not significantly altered over time (12 h to 14 days). In sharp contrast, the blood-to-brain permeation of 125I-TNFalpha was significantly increased 5 days after tMCAO. Furthermore, excess unlabeled TNFalpha abolished this enhanced 125I-TNFalpha uptake. Thus, not only did the known saturable transport system for TNFalpha persist, but it functioned at a higher capacity in tMCAO mice. Upregulation of TNFR1 and TNFR2 partially explains the increased transport, as mRNA for both receptors showed the most pronounced increase (15-fold and 30-fold, respectively) in the ischemic hemisphere 5-7 days after tMCAO. However, even in the hemisphere contralateral to the ischemia induced by stroke, there was increased TNFalpha transport. The bilateral increase in 125I-TNFalpha entry from blood to brain suggests that TNFalpha trafficking in cerebral endothelial cells is influenced by global mediators in addition to the transporting receptors. Given the known multiple modulatory effects of TNFalpha after stroke, the results indicate that the TNFalpha transport system at the BBB facilitates neuroplasticity and plays an important role in stroke recovery.Experimental Neurology 04/2006; 198(1):222-33. DOI:10.1016/j.expneurol.2005.11.020 · 4.62 Impact Factor