Abstract
Development of new stroke therapies requires animal models that recapitulate the pathophysiological and functional consequences of ischemic brain damage over time-frames relevant to the therapeutic intervention. This is particularly relevant for the rapidly developing area of stem cell therapies, where functional replacement of circuitry will require maturation of transplanted human cells over months. An additional challenge is the establishment of models of ischemia with stable behavioral phenotypes in chronically immune-suppressed animals to allow for long-term survival of human cell grafts. Here we report that microinjection of endothelin-1 into the sensorimotor cortex of athymic rats results in ischemic damage with a sustained deficit in function of the contralateral forepaw that persists for up to 9 months. The histological post-mortem analysis revealed chronic and diffuse atrophy of the ischemic cortical hemisphere that continued to progress over 9 months. Secondary atrophy remote to the primary site of injury and its relationship with long-term cognitive and functional decline is now recognized in human populations. Thus, focal cortical infarction in athymic rats mirrors important pathophysiological and functional features relevant to human stroke, and will be valuable for assessing efficacy of stem cell based therapies.
Highlights
Pre-clinical development of new therapies for stroke is critically dependent on animal models of ischemic brain damage that produce functional impairments relevant to human stroke outcomes
Dunnett’s multiple comparisons tests: NeuN density: Saline mean ± SEM = 2687 ±, n = 6; ET-1 1 week mean ± SEM = 1896 ±, n = 4; ET-1 3 weeks mean ± SEM = 2995 ±, n = 4; ET-1 24 weeks mean ± SEM = 2688 ±, n = 5; ET-1 36 weeks mean ± SEM = 2852 ±, n-5; p-value = 0.0708; p-value = 0,7365; p-value = 0.999; p-value = 0.9486]. These results show that focal ischemic damage to the frontal cortex through injection of ET-1 can result in impairment of forelimb function that persists for up to 9 months
Gross motor co-ordination, assessed on the accelerating rotarod, was significantly impaired in the acute phase, 1 week after ischemia, but recovered to be similar to control levels at subsequent testing beyond 4 weeks. This is consistent with other pre-clinical studies in various rodent stroke models reporting rapid and sometimes complete recovery in rotarod performance between 4 and 14 days after ischemia (Hunter et al, 2000; Zhang et al, 2000; Bouet et al, 2007)
Summary
Pre-clinical development of new therapies for stroke is critically dependent on animal models of ischemic brain damage that produce functional impairments relevant to human stroke outcomes The stability of these impairments and sensitivity to different behavioral tests can vary widely depending on the nature of the ischemic event, the timing of the testing after damage and the animal species and strain (Carmichael and Chesselet, 2002; Schaar et al, 2010; Trueman et al, 2016). Functional deficits targeted by new therapies should be stable over a time-course relevant to the therapeutic mechanism and distinguishable from those that resolve spontaneously and independently of any treatment This presents particular challenges for stem cell therapies, which aim to restore function in stroke patients through intra-cerebral transplantation of cells that can replace damaged neuronal circuitry. Transient functional deficits limited to the acute phase after stroke, such as gross motor function assessed by rotarod performance in certain rodent stroke models (Hunter et al, 2000; Zhang et al, 2000; Bouet et al, 2007), are unsuitable as tests of the potential benefit of cell replacement
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