Thrombotic Stroke in the Anesthetized Monkey <b><i>(Macaca mulatta)</i></b>: Characterization by MRI – A Pilot Study

Abstract

Background: The lack of a relevant stroke model in large nonhuman primates hinders the development of innova- tive diagnostic/therapeutic approaches concerned with this cerebrovascular disease. Our objective was to develop a novel and clinically relevant model of embolic stroke in the anesthetized monkey that incorporates readily available clinical imaging techniques and that would allow the possibility of drug delivery including strategies of reperfusion. Methods: Thrombin was injected into the lumen of the middle cere- bral artery (MCA) in 12 anesthetized (sevoflurane) male rhesus macaques (Macaca mulatta). Sequential MRI studies (including angiography, FLAIR, PWI, DWI, and gadolinium-enhanced T1W imaging) were performed in a 3T clinical MRI. Physiological and biochemical parameters were monitored throughout the investigations. Results: Once standardized, the surgical procedure induced transient occlusion of the middle cerebral artery in all operated animals. All animals studied showed spontaneous reperfusion, which occurred some time between 2 h and 7 days post-ictus. Eighty percent of the studied animals showed diffusion/perfusion mismatch. The ischemic lesions at 24 h spared both superficial and profound territories of the MCA. Some animals presented hemorrhagic transformation at 7 days post-ictus. Conclusion: In this study, we developed a pre-clinically relevant model of embolic stroke in the anesthetized nonhuman primate.

Spontaneous Reperfusion after In Situ Thromboembolic Stroke in Mice

“…Future studies could include higher doses of thrombin so as to induce more stable occlusion and, hopefully, a more reproducible infarct. Interestingly, implementation of the thrombin injection technique in macaques also resulted in frequently delayed reperfusion, despite a higher dose (800 U for 10 kg) [15].…”

An Enhanced Model of Middle Cerebral Artery Occlusion in Nonhuman Primates Using an Endovascular Trapping Technique

“…This makes the nonhuman primate brain more resistant to stroke induction requiring temporary or permanent elimination of collateral vessels. Published series of stroke and temporary ischemia models have utilized open surgical, endovascular, or mixed techniques 4, 9, 13–16 , many targeting collateral vessels as a means of decreasing cerebral flow. Management of collateral vessels is critical in achieving cerebral blood flow (CBF) below the infarct threshold of approximately 0.12 ml/g per minute.…”

“…Approaches include the surgical introduction of an intraluminal thread from the ECA to the origin of the MCA 4 , injection of autologous clot into the ICA 5 , injection of silk suture into the MCA 6 , transient microcather occlusion of the MCA 7 , permanent MCA occlusion with cyanoacrylate 8 , and combined neurosurgical and endovascular thrombin injection techniques 9 . Ideally, a preclinical cortical stroke model would be reproducible, minimally invasive, minimize pain and distress, spare the deep nuclei, and allow for serial behavioral assessments.…”

Paving the Road to Translation

“…Taken together, the study by Gauberti et al [1] describes a newly developed embolic occlusion model of the distal middle cerebral artery in nonhuman primates (Rhesus monkeys), which shows a dynamically growing cortical infarct within the first 24 h after vessel occlusion resulting in long-lasting functional deficits but no mortality. Although only 3 animals were evaluated over time, the necessary infrastructure may not be readily available to most stroke researchers, and the costs of such experiments are significant, this novel, clinically highly relevant in vivo stroke model may provide an important contribution for breaking the manacles of translational stroke research.…”

“…The paper by Gauberti et al [1] published in the current issue of Cerebrovascular Diseases addresses this problem by presenting a novel model for embolic stroke in Rhesus monkeys, one of the most widely used monkey species in experimental medicine. Following enucleation of the right eye and exposure of the distal middle cerebral artery through a craniectomy of the dorsal orbital wall, the authors used a micropipette to inject thrombin directly into the M1 branch of the middle cerebral artery.…”