A New Model of Cortical Stroke in the Rhesus Macaque

Abstract

Primate models are essential tools for translational research in stroke but are reportedly inconsistent in their ability to produce cortical infarcts of reproducible size. Here, we report a new stroke model using a transorbital, reversible, two-vessel occlusion approach in male rhesus macaques that produces consistent and reproducible cortical infarcts. The right middle cerebral artery (distal to the orbitofrontal branch) and both anterior cerebral arteries were occluded with vascular clips. Bilateral occlusion of the anterior cerebral artery was critical for reducing collateral flow to the ipsilateral cortex. Reversible ischemia was induced for 45, 60, or 90 mins (n = 2/timepoint) and infarct volume and neurologic outcome were evaluated. The infarcts were located predominantly in the cortex and increased in size with extended duration of ischemia determined by T 2 -weighted magnetic resonance imaging . Infarct volume measured by 2,3,5-triphenyl tetrazolium chloride and cresyl violet staining corroborated magnetic resonance imaging results. Neurologic deficit scores worsened gradually with longer occlusion times. A subset of animals (n = 5) underwent 60 mins of ischemia resulting in consistent infarct volumes primarily located to the cortex that correlated well with neurologic deficit scores. This approach offers promise for evaluating therapeutic interventions in stroke.

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

“…Various NHP models of stroke have been reported using different surgical techniques in the marmosets: 15,31 African green monkey, 26 baboon, 17,32 macaques, 20,21,[33][34][35][36] and squirrel monkeys. 16 However, to date, there has been less emphasis on outcome measures and disabilities relevant to daily living activities, such as dexterous movements.…”

“…Another species with less collateralization is Macaca fascicularis, 20,37 while the baboon (Papio anubis) and rhesus (Macaca Mulatta) exhibit collateralization that requires occluding other segments of the MCA. 21,[38][39][40] Studies have previously reported the correlation between functional outcome and size of the infarct. [41][42][43] In the squirrel monkey, focal stroke induced by vascular coagulation using a bipolar electrocoagulator in M1 hand area of the cortex produced motor deficits according to the extent of the injury.…”

“…Nonhuman primate (NHP) models offer an assessment of complex physiological, immunologic, biochemical, and behavioral outcomes most similar to those of humans. [14][15][16][17][18][19][20][21][22][23][24] These outcome measures complement those from other animal models by improving our understanding…”

An Integrated Stroke Model with a Consistent Penumbra for the Assessment of Neuroprotective Interventions

“…These data on primates demonstrate that the 1- or 2-VO strategy is particularly limited in terms of generating infarcted lesions of consistent size. In contrast, using a modified 3-VO method (both anterior cerebral arteries and the MCA distal to the orbitofrontal branch) for 1 h produced moderate-sized infarcted lesions in the cortex (25.8 ± 2.1%, IVC: 8.1%, n = 5), with no mortality at 48 h in rhesus macaques [59]. Thus, the consequences of 1-, 2-, and 3-VO in both rodents and primates are similar.…”

Rectal Prolapse Associated with Recurrent Diarrhea in a Laboratory Cynomolgus Monkey (Macaca fascicularis)

“…was premedicated intramuscularly with ketamine (10 mg/kg) and atropine (0.04 mg/kg). The animal was then intubated and maintained under general anesthesia using 1.5% isoflurane vaporized in 100% oxygen (West et al, 2009). The prolapsed rectum was surgically removed and then a purse-string suture was placed in the anus.…”