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.
SourceAvailable from: Hilary V O Carswell[Show abstract] [Hide abstract]
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
[Show abstract] [Hide abstract]
ABSTRACT: Pre-clinical models of stroke therapeutics depend upon the ability to detect differences in infarct volume as well as in the short- and long-term outcomes of treated animals. Little attention has been paid to interstrain differences in these outcomes and the importance of defining the most appropriate behavioral tests. In this study, we evaluate long-term outcome from stroke in three different rat strains. Lewis, Wistar, and Sprague Dawley (SD) rats were subjected to 2-h middle cerebral artery occlusion and survived for up to 49 days. Behavioral tests were performed weekly. There was continuous assessment of rotational/circling activity in the home cage by use of an automated software program. A separate group of animals was sacrificed at 24 h to determine infarct volume. Infarct volume was similar in all three strains. Mortality was significantly higher in SD rats (P < 0.001). Rotational/circling activity at 24 h was correlated with cortical infarct volume in Wistar and SD rats (ρ = 0.67, P = 0.04 and ρ = 0.72, P = 0.01, respectively). Wistar and SD rats displayed more rotational/circling activity following stroke than Lewis rats, but Lewis rats evidenced more impairment on complex motor tasks like the rotarod. Further, computer automated analysis of rotational activity was more sensitive than subjective assessment, with SD rats showing a preference for clockwise rotations to 49 days after stroke despite normalization of the neurological score after 21 days. There are significant interstrain differences in survival and in the patterns of neurological impairment and recovery after stroke. These differences must be taken into account in pre-clinical studies, but may also be capitalized upon to understand genetic contributions to injury. Finally, computerized assessment of behavior is more sensitive than subjective assessment for detecting behavioral changes.Translational Stroke Research 04/2014; 5(5). DOI:10.1007/s12975-014-0337-y
[Show abstract] [Hide abstract]
ABSTRACT: Small vessel disease (SVD) is a frequent cause of vascular cognitive impairment (VCI), encompassing vascular dementia. SVD is characterised by vasculopathy in deep penetrating arteries, diffuse white matter lesions (seen radiologically as leukoaraiosis) and focal, lacunar infarcts. Risk factors are age and hypertension but the pathogenic mechanism is unknown. Recent systematic reviews assessed experimental models of SVD or VCI. Chronically hypertensive animals (e.g. stroke-prone spontaneously hypertensive rats) display some features of SVD vasculopathy, such as vessel wall thickening. White matter lesions are seen in chronic hypoperfusion states (e.g. carotid occlusion/stenosis models). Small focal infarcts are induced by targeted ischemic challenge (surgical occlusion of a small artery, or stereotaxic endothelin-1 injection). Some degree of cognitive impairment is detectable in most cerebrovascular models, probably reflecting the broad neuroanatomical mapping of cognitive function. Important confounds to be considered in animal models of VCI are somatosensory impairment and hippocampal damage. Advances in clinical understanding will come from targeting specific questions on some aspect of SVD (e.g. vasculopathy, white matter damage) to the appropriate model in vivo. In vivo models of SVD are likely to benefit experimental studies of pathological processes, interactions with other brain disease states (such as Alzheimer disease), and therapeutic strategies.Journal of the neurological sciences 06/2012; 322(1-2):237-40. DOI:10.1016/j.jns.2012.05.046 · 2.32 Impact Factor