Introduction and Purpose: For efficient development of novel therapeutics in stroke, it is expected to use a non-human primate stroke model that has a similarity in pathophysiology, as well as species to human. However, conventional techniques of MCA occlusion model often need enucleation and occlusion of M1 portion by a transorbital approach, so that it is difficult to evaluate long-term neurological deficits. Here, we show preliminary results which tried to develop a selective embolization model of MCA using cynomolgus monkeys combined with serial PET evaluations of hemodynamics. Subjects and Methods: We used four cynomolgus monkeys and performed experiments under general anesthesia. To produce whole MCA territory or localized branch territory infarction, we placed a thin catheter at Rt M1 or M2 portion under angiography and thereafter occluded the MCA branch by injecting autologous blood clots. The dual-tracer single scan ARG (DARG) method PET was performed to measure CBF, CMRO2 and OEF at pre embolization, and 5min, 3 and 6hours post embolization repeatedly. We defined penumbra regions as regions with elevated OEF (mean value+2SD), thereafter divided the ROI into two subtypes (reversible region: RR or irreversible region: IR) by the final tissue outcome defined by the T2-MRI at 24hours after embolization. For control, we made ROI in normal regions. Neurological symptoms were scored by a monkey stroke scale. Results: All animals showed left hemiparesis, among which two had unilateral spatial neglect, and the other two showed homonymous hemianopia. The infarction volume and neurological score were 9.4±2.4cm3 (account for 26 % of whole brain) and 25±0 in M1 occluded animals (N=2); and 2.8±3.9cm3 (account for 7% of whole brain) and 14±11 in M2 or M3 occluded model (N=1 and 1), however, animals with M1 occlusion both died of cerebral hernia 1day after embolization;. The neurological score was correlated with infarct volume (R=0.869). Even though OEF values did not significantly differ between IR and RR (120% vs. 118%), the IR areas that finally became infarcted, showed lower CBF (70% in RR vs. 55% in IR) and CMRO2 (88% in RR vs. 65% in IR) than those in RR areas that did not. Areas of IR showed variable changes in their time course, whereas RR areas tended to keep lowered in their CBF and CMRO2. Discussions and Conclusion: We presented a less invasive embolization technique in which M1, M2, or M3 portion of MCA was selectively catheterized in cynomolgus monkeys. We confirmed sites of occlusion in MCA branch after each embolization, and suggest that embolization of M1 portion results in large hemispheric infarction so that the animal may hardly survive in later days, whereas embolization of M2 or M3 portion does not affect animal's survival but cause significant neurological deficits that are needed for long-term behavioral evaluation. In addition, we showed time-dependent changes in CBF and CMRO2, especially in a mildly ischemic part within penumbra, suggesting that frequent and serial PET evaluations may be useful to estimate risk of infarction and correlate with the final outcome.
|ジャーナル||Journal of Cerebral Blood Flow and Metabolism|
|出版ステータス||Published - 2007 11月 13|
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