A Modified Transorbital Baboon Model of Reperfused Stroke

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...

Section: Strokementioning

confidence: 99%

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

McEntire

Choudhury

Torres

et al. 2016

“…1 In particular, rodent models have crucial advantages of lower cost, suitability for physiological monitoring, reproducibility of lesion size, and ease of conducting replicate studies. Although Huang et al 2 suggested that the number of animals needed to demonstrate a 50% decrease in infarction volume may be reduced by 41% in their modified transorbital baboon model compared with a previous nonhuman primate stroke model, the coefficient of variation (CV) for infarct volume was still considerably large (62%).…”

mentioning

confidence: 99%

Photothrombotic Middle Cerebral Artery Occlusion and Reperfusion Laser System in Spontaneously Hypertensive Rats

Yao

Sugimori

Fukuda

et al. 2003

Background and Purpose-To establish a less invasive and reproducible focal ischemia model in the rat, we adopted a 2-laser system (ie, photothrombosis and YAG laser-induced reperfusion). Methods-The distal middle cerebral artery (MCA) of spontaneously hypertensive rats was occluded by 568-nm krypton laser and intravenous infusion of the photosensitizing dye rose bengal and was recanalized by 355-nm ultraviolet laser irradiation. Cerebral blood flow was determined by laser-Doppler flowmetry at the penumbral cortex. Infarct volume was determined at 3 days after distal MCA occlusion. Results-Brain temperature determined with infrared thermography was maintained within an acceptable range of approximately 1°C upper shift of the center of brain temperature distribution during krypton or YAG laser irradiation. The average of the values (23 experiments; nϭ163) of coefficient of variation of infarct volume was 21Ϯ6%, indicating high reproducibility of this model. After distal MCA occlusion, cerebral blood flow was decreased to 32Ϯ16% of the control values and was increased to 98Ϯ21% after YAG laser-induced reperfusion. Infarct volume in these rats was 61Ϯ18 mm 3 (coefficient of variationϭ30%; nϭ6). Conclusions-We have characterized a highly reproducible focal ischemia model utilizing a 2-laser system, one to induce thrombotic MCA occlusion and the other to facilitate reperfusion.

“…29 Baboons were anesthetized with 5 mg/kg IM ketamine (Fort Dodge Animal Health). Two 18-gauge peripheral venous catheters were placed, and intravenous fluid administration of 0.9% normal saline was begun.…”

Section: Anesthesiamentioning

confidence: 99%

“…Animals were subjected to middle cerebral artery territory reperfused stroke as previously described by Huang et al 29 Briefly, they underwent orbital exenteration and removal of the posterior-medial orbital wall under the microscope (Super-Lux 40-2 Illuminator, Zeiss). Dura was opened, and the cerebral arteries were identified.…”

Section: Reperfused Strokementioning

confidence: 99%

“…29 Animals were anesthetized with ketamine and sedated with an intravenous pentobarbital bolus and propofol infusion that was titrated to allow independent respiratory function while the airway was maintained with an endotracheal tube. Brain MRI was performed (Signa Advantage, 1.5 T, General Electric) to obtain coronal T2-weighted images with a slice thickness of 3 mm without intervening tissue.…”

Section: Radiographic Imagingmentioning

confidence: 99%

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Ultrarapid, Convection-Enhanced Intravascular Hypothermia

Mack

Huang

Winfree

et al. 2003

Self Cite

Background and Purpose-Hypothermia has been shown to be neuroprotective in a variety of clinical settings.Unfortunately, poor delivery techniques and insufficient data in appropriate preclinical models have hampered its development in human stroke. To address these limitations, we have devised a 10F intravascular catheter capable of rapid systemic cooling of nonhuman primates. Methods-Placed in the inferior vena cava via a transfemoral approach, the catheter was used to induce mild systemic hypothermia 3 hours after the onset of hemispheric stroke in baboons. Results-Cooling was achieved at a rate of 6.3Ϯ0.8°C/h. Target brain temperatures (32.2Ϯ0.2°C) were reached at the same time (47.7Ϯ6.32 minutes) as target esophageal temperatures (32.0Ϯ0.0°C). Hypothermia was maintained for 6 hours in all animals. Animals did not experience the infections, coagulopathy, or cerebral edema commonly seen with surface cooling methods in human stroke. Conclusions-These data suggest that a brief episode of mild core hypothermia instituted at a clinically relevant time point can be achieved in primate stroke and that our intravascular cooling technique provides safe, rapid, and reproducible hypothermia. (Stroke.