Permanent Middle Cerebral Artery Occlusion in Sheep: A Novel Large Animal Model of Focal Cerebral Ischemia

Boltze, Johannes; Förschler, Annette; Nitzsche, Björn; Waldmin, D; Hoffmann, Anke; Boltze, Christiane; Dreyer, Antje; Goldammer, Axel; Reischauer, A.; Härtig, Wolfgang; Geiger, Kathrin; Barthel, Henryk; Emmrich, Frank; Gille, Uwe

doi:10.1038/jcbfm.2008.89

Cited by 86 publications

(98 citation statements)

References 26 publications

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“…9,10 There has been a concerted effort in developing relevant large animal models. 11,12 Interspecies comparison suggests that cerebral venous angioarchitecture in large animals is closer to that of humans 13 ; nevertheless, such models remain relatively underdeveloped. Nonhuman primate (NHP) models offer an assessment of complex physiological, immunologic, biochemical, and behavioral outcomes most similar to those of humans.…”

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confidence: 99%

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke

McEntire

Choudhury

Torres

et al. 2016

Stroke

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The World Health Organization reports that stroke claims 6.2 million lives each year. There are ≈5.4 million stroke survivors with ≈80% requiring hand therapy. 1 The estimated economic burden for stroke exceeds $56.8 billion per year in the United States alone.Acute thrombolysis has a significant impact on the management of stroke, 2,3 with a therapeutic window that may extend ≤6 hours with intra-arterial delivery. 4 Yet only a minority of stroke victims benefit, and the majority experience progression of ischemia associated with neurological disabilities.Animal models that recapitulate human disabilities and disease pathology remain an unmet need in stroke research. There has been a tremendous advance in developing rodent experimental model stroke (reviewed in Durukan and Tatlisumak 5 and Carmichael 6 ). However, the lack of success in developing neuroprotective therapies in small animal models for stroke 7,8 prompted recommendations for additional research and development in large animal models with physiological, structural, and functional traits closer to those of humans before clinical trials.9,10 There has been a concerted effort in developing relevant large animal models. 11,12 Interspecies comparison suggests that cerebral venous angioarchitecture in large animals is closer to that of humans 13 ; nevertheless, such models remain relatively underdeveloped. Nonhuman primate (NHP) models offer an assessment of complex physiological, immunologic, biochemical, and behavioral outcomes most similar to those of humans.14-24 These outcome measures complement those from other animal models by improving our understanding Background and Purpose-Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans. In this study, we characterize the African green monkey model of focal ischemia reperfusion with a defined syndrome, impaired dexterous movements. Methods-Cerebral ischemia was induced by transient occlusion of the M3 segment of the left middle cerebral artery.Motor and cognitive functions after stroke were evaluated using the object retrieval task with barrier-detour. Postmortem magnetic resonance imaging and histopathology were performed to map and characterize the infarct. Results-The middle cerebral artery occlusion consistently produced a necrotic infarct localized in the sensorimotor cortex in the middle cerebral artery territory. The infarction was reproducible and resulted in significant loss of fine motor function characterized by impaired dexterity. No significant cognitive impairment was detected. Magnetic resonance imaging and histopathology demonstrated consistent and significant loss of tissue on the left parietal cortex by the central sulcus covering the sensorimotor area. The results sug...

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confidence: 99%

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke

McEntire

Choudhury

Torres

et al. 2016

Stroke

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“…used to target antigens on cancer cells for clinical diagnosis and therapy, based on the fact that some antigens expressed on cancer cells surface reflect malignant behaviors invasion, metastasis, and neo-vascularization (1)(2)(3)(4)(5). Molecular imaging of antibodies in the whole body will enable us to prescribe the appropriate antibody therapy in terms of dose and the timing of administration.…”

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In vivo far-red luminescence imaging of a biomarker based on BRET from Cypridina bioluminescence to an organic dye

Mino²,

Akimoto³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We aimed to develop a far-red luminescence imaging technology for visualization of disease specific antigens on cell surfaces in a living body. First, we conjugated a far-red fluorescent indocyanine derivative to biotinylated Cypridina luciferase. This conjugate produced a bimodal spectrum that has long-wavelength bioluminescence emission in the far-red region as a result of bioluminescence resonance energy transfer. To generate a far-red luminescent probe with targeting and imaging capabilities of tumors, we then linked this conjugate to an anti-human Dlk-1 monoclonal antibody via the biotin-avidin interaction. This far-red luminescent probe enabled us to obtain high-resolution microscopic images of live, Dlk-1-expressing Huh-7 cells without an external light source, and to monitor the accumulation of this probe in tumor-bearing mice. Thus this far-red luminescent probe is a convenient analytical tool for the evaluations of monoclonal antibody localization in a living body.Cypridina luciferase ͉ far-red luminescent probe ͉ luciferin ͉ tumor A n increasing number of monoclonal antibodies have been used to target antigens on cancer cells for clinical diagnosis and therapy, based on the fact that some antigens expressed on cancer cells surface reflect malignant behaviors invasion, metastasis, and neo-vascularization (1-5). Molecular imaging of antibodies in the whole body will enable us to prescribe the appropriate antibody therapy in terms of dose and the timing of administration. Fluorescence imaging (FLI) and bioluminescence imaging (BLI) have played an important role in molecular imaging in small animals (6-8). Photon detection is affordable and easy to use compared with radioisotope imaging. BLI is achieved with a luciferin-luciferase reaction in the presence of molecular oxygen. However, most bioluminescence spectra are in the visible region, overlapping with the absorption spectrum of hemoglobin, attenuating the bioluminescence intensity in live animals. Recently, a ''self-illuminating quantum dot probe'' was developed to improve the light penetration based on bioluminescence resonance energy transfer (BRET) between the bioluminescence of Renilla luciferase and quantum dots (9). The multivalent conjugation of Renilla luciferase to single dots allowed for highly efficient BRET between luciferase and quantum dots. However, the large size of the conjugate may cause problems in metabolism and localization in vivo (10).BRET is a natural phenomenon observed in marine organisms. Green fluorescent protein, for example, is a well-known energy acceptor in the bioluminescence of Renilla luciferase and aequorin. BRET between the bioluminescence of Renilla luciferase and green fluorescent protein mutants has been used to study protein interactions (11). Recently several far-red fluorescent protein variants showing emission maxima around 650 nm were developed for in vivo imaging (12), but have not been well characterized as energy acceptors for BRET systems. On the other hand, the organic dyes indocyanine and its derivat...

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“…; therefore, in the future it may be advantageous to study cerebral ischemia more frequently in large mammals such as sheep (162) or swine (163). However, the availability and cost of animals may limit the number of these kinds of experiments.…”

Section: Inflammation and Infection: Risk Factors And Disease Consequmentioning

confidence: 99%

Modeling Risk Factors and Confounding Effects in Stroke

2016

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Most research to date has used experimental models in rodents which fail to mimic the underlying causes of stroke in patients or the primary confounding factors. Available data indicate that factors such as atherosclerosis, hypertension, obesity, diabetes, age, and inflammation have a major influence on outcome. These findings suggest that we need to rethink the preclinical data that are required before selection of candidate interventions for clinical trials in stroke.

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Permanent Middle Cerebral Artery Occlusion in Sheep: A Novel Large Animal Model of Focal Cerebral Ischemia

Cited by 86 publications

References 26 publications

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke

In vivo far-red luminescence imaging of a biomarker based on BRET from Cypridina bioluminescence to an organic dye

Modeling Risk Factors and Confounding Effects in Stroke

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