Reperfusion plus Selective Intra-arterial Cooling (SI-AC) Improve Recovery in a Nonhuman Primate Model of Stroke

Abstract

Early reperfusion is increasingly prioritized in ischemic stroke care, but outcomes remain suboptimal. Therefore, there is an urgent need to find neuroprotective approaches that can be combined with reperfusion to maximize efficacy. Here, the neuroprotective mechanisms behind therapeutic hypothermia were evaluated in a monkey model of ischemic stroke. Focal ischemia was induced in adult rhesus monkeys by placing autologous clots in the middle cerebral artery. Monkeys were treated with tissue plasminogen activator (t-PA) alone or t-PA plus selective intra-arterial cooling (SI-AC). Serial MRI scans and functional deficit were evaluated after ischemia. Histopathology and immunohistochemistry analysis were performed after the final MRI scan. t-PA plus SI-AC treatment led to a higher rate of MRI tissue rescue, and significantly improved neurologic deficits and daily activity scores compared with t-PA alone. In peri-infarct areas, higher fractional anisotropy values and greater fiber numbers were observed in models receiving t-PA plus SI-AC. Histological findings indicated that myelin damage, spheroids, and spongiosis were significantly ameliorated in models receiving SI-AC treatment. White matter integrity was also improved by SI-AC based on immunochemical staining. Our study demonstrates that SI-AC can be effectively combined with t-PA to improve both structural and functional recovery in a monkey model of focal ischemia. These findings provide proof-of-concept that it may be feasible to add neuroprotective agents as adjunctive treatments to reperfusion therapy for stroke.

Selective Brain Cooling: A New Horizon of Neuroprotection

“…We believe that some of the beneficial effects of this method could be due to mechanical flushing, increasing vessel patency and promoting vasorelaxation and hemodilution. This protocol also showed advantages in monkey stroke models and patients with stroke ( 80 ). Interestingly, several animal studies have reported that the combination of cold saline and magnesium sulfate (acting as an N -methyl- d -aspartate receptor antagonist that prevents excitotoxic cell damage) or low-dose albumin (improving microcirculation with multiple neuroprotective properties) has greater neuroprotective advantages than cold saline alone ( 81 ).…”

Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

“…Intermittent positive pressure ventilation was performed for monkeys with a fixed respiratory rate. Non-invasive blood pressure, electrocardiogram, heart rate, oxygen saturation, blood gas, and rectal temperature were monitored ( Wu et al, 2020a , b , c ).…”

Improving Large Animal Ischemic Stroke Models for Translational Studies in the Era of Recanalization

“…Collecting baseline and series of anatomical imaging permits the longitudinal assessments of brain atrophy and white matter tractography integrity. 20 Salvaged tissue or diffusion lesion reversal has been explored in monkey models after stroke onset. 21 Another advantage is to biopsy brain tissue based on imaging identification of the target, which can facilitate molecular analyses.…”