Minimally invasive neuroradiologic model of preclinical transient middle cerebral artery occlusion in canines

Abstract

Stroke is currently the third leading cause of death in the United States, with approximately 780,000 Americans affected by a new or recurring stroke each year. Although a variety of therapeutic approaches have shown promise in small-animal models of stroke, the vast majority of clinical trials to test the efficacy of such modalities have failed. To bridge the translational gap between laboratory and clinical research, we developed a preclinical model of acute ischemic stroke in dogs. Using a minimally invasive endovascular approach, a platinum coil was intravascularly guided through the vertebrobasilar system under C-arm fluoroscopy to occlude the M1 segment of the middle cerebral artery (MCA) for 1 h. The approach included femoral artery catheterization to access the MCA and therefore eliminated the occurrence of head trauma associated with other preclinical stroke models relying on transorbital or craniectomy approaches. After 1 h of focal MCA ischemia, the coil was retrieved to cause reperfusion, which was verified by arteriograms. At 24 h, T2-weighted coronal magnetic resonance (MR) images were acquired and processed for three-dimensional reconstruction of the brain and its vasculature. Infarction, limited to the area at risk, was noted. Two independent observers calculated the mean percentage hemispherical lesion volumes as follows: observer 1, 30.9 ؎ 2.1%; observer 2, 31.2 ؎ 4.3%. Infarctaffected changes in histology were determined by hematoxylin and eosin as well as by Fluoro-Jade staining. This work reports the successful development of a powerful preclinical model of stroke that lends itself to the study of biologic mechanisms as well as to testing experimental therapeutics.imaging ͉ therapeutics ͉ vascular ͉ stroke ͉ ischemia

Tocotrienol Vitamin E Protects against Preclinical Canine Ischemic Stroke by Inducing Arteriogenesis

“…As a result, rodent stroke models have been criticized for the anatomical disparity between small and large mammalian brains, large variability in infarct volumes, and inaccurate methods of inducing and confirming arterial occlusion (Gerriets et al, 2004). These considerations develop a compelling rationale to engage a translational relevant preclinical approach to test the therapeutic efficacy of TE natural vitamin E (Rink et al, 2008). As compared with the lissencephalic brain of rodents, the size and anatomical feature set of the canine brain closely mimics that of humans.…”

“…The minimally invasive, endovascular approach to achieve middle cerebral artery occlusion (MCAO) in canines was performed as previously described (Rink et al, 2008). Briefly, the anesthetized canine (1.5% to 2.0% isoflurane) underwent bilateral femoral artery access with five French sheaths (ArrowGE Healthsystems, Waukesha, WI, USA) from which 4-Fr and 5-Fr guide catheters (Boston Scientific, Natick, MA, USA) were used to provide access to the basilar artery system and for routine contrast (Omnipaque) visualization of the middle cerebral artery (MCA) territories.…”

“…Indeed, we have demonstrated that orally supplemented aTCT protects against stroke-induced lesion in the brain of spontaneously hypertensive rats (Khanna et al, 2005b). As small animal studies are recognized to be of limited reliability to predict success for stroke therapeutics in clinical trials (Kidwell et al, 2001), we developed a minimally invasive preclinical canine model (Rink et al, 2008) to test the efficacy of a tocotrienolenriched (TE) supplement in a randomized, blind, placebo (PBO)-controlled setting. Angiography, enabled in our large animal setting, helped elucidate that prophylactic TE supplementation improves collateral blood flow to the stroke-affected territory during stroke.…”

An endovascular canine stroke model: middle cerebral artery occlusion with autologous clots followed by ipsilateral internal carotid artery blockade

“…Second, the cerebrovascular structure and brain volume of canines are suitable for routine radiological methodology, which permits a minimally invasive approach, a direct and targeted arterial embolization and real-time visualization of occlusion. 1,2 In addition, magnetic resonance imaging (MRI) provides an accurate way to follow the progression of stroke models in serial images. [10][11][12][13] However, strokes in humans and canine models are highly heterogeneous both clinically and radiographically.…”

“…[1][2][3][4] The understanding of pathophysiology of stroke and testing any therapeutic regimen make an ideal and reproducible model of stroke necessary. Considering limitations in cerebral infarction animal models generated by other groups (eg, different cerebrovascular anatomy between small animal and human being, translational barriers between experimental and clinical studies, and ethical and economic issues in nonhuman primates), this canine ischemic stroke model has emerged as an ideal option in clinical research 1,2,5-10 with many advantages.…”