An animal model of capsular infarct: Endothelin-1 injections in the rat

Small white-matter infarcts of the internal capsule are clinically prevalent but underrepresented among currently available animal models of ischemic stroke. In particular, the assessment of long-term outcome, a primary end point in clinical practice, has been challenging due to mild deficits and the rapid and often complete recovery in most experimental models. We, therefore, sought to develop a focal white-matter infarction model that can mimic the lasting neurologic deficits commonly observed in stroke patients. The potent vasoconstrictor endothelin-1 (n = 24) or vehicle (n = 9) was stereotactically injected into the internal capsule at one of three antero-posterior levels (1, 2, or 3 mm posterior to bregma) in male Sprague-Dawley rats. Endothelin-injected animals showed highly focal (~1 mm 3 ) and reproducible ischemic infarcts, with severe axonal and myelin loss accompanied by cellular infiltration when examined 2 and 4 weeks after injection. Only those rats injected with endothelin-1 at the most posterior location developed robust and pure-motor deficits in adhesive removal, cylinder and foot-fault tests that persisted at 1 month, without detectable sensory impairments. In summary, we present an internal capsule stroke model optimized to produce lasting pure-motor deficits in rats that may be suitable to study neurologic recovery and rehabilitation after white-matter injury.

Section: Discussionmentioning

confidence: 99%

“…11 The ET-1 model has been used to produce capsular lesions in rats. 12,13 However, deficits have been mild and short-lasting, limiting the usefulness of such models for recovery paradigms.…”

Section: Introductionmentioning

confidence: 99%

Lasting Pure-Motor Deficits after Focal Posterior Internal Capsule White-Matter Infarcts in Rats

Blasi

Whalen

Ayata

2015

“…The direct injection of vasoconstrictor agents into the subcortical white matter has been used to induce focal white-matter stroke both in rats and in mice. [35][36][37] For example, when endothelin-1 is injected into the internal capsule in rats, tissue necrosis and demyelination occur in 14 days, which eventually causes sensorimotor deficits. 35 Also in mice, microinjection of endothelin-1 into the subcortical white matter produces an infarct core as in human subcortical stroke, which accompanies with oligodendrocyte apoptosis, myelin loss, axonal fiber loss, and activation of microglia/ macrophages.…”

Section: Rat/mouse Model Of Focal Injection Of Vasoconstrictormentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

“…Although many studies of therapeutic strategies have been performed using cortical infarct models, only a few studies have investigated subcortical capsular infarcts (SCIs), owing to a lack of pertinent rodent models for capsular infarct. [6][7][8] Specifically, to investigate motor deficits and their recovery after a stroke, a portion of the motor pathway from the motor cortex to the medullary pyramid should be selectively destroyed or modified to create animal models that have motor impairment. However, most of these models involve damage within the gray matter of the cortex, and only a few studies have attempted to damage the white matter to develop a stroke model.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 Only a few models have been successful in manifesting a persistent and marked sensorimotor deficit after SCI. [6][7][8] During the last decade, it has been a challenge to create a persistent SCI model. Several methods have been developed and tested, including occlusion of the middle cerebral artery, occlusion of the anterior choroidal artery, and injection of the vasoconstrictive peptide endothelin-1 into the PLIC.…”

Section: Introductionmentioning

confidence: 99%

A Rat Model of Photothrombotic Capsular Infarct with a Marked Motor Deficit: A Behavioral, Histologic, and microPET Study

Kim

et al. 2014

We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n ¼ 38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[ 18 F]-fluoro-D-glucose ([ 18 F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for 43 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery.