Selective intra-arterial brain cooling improves long-term outcomes in a non-human primate model of embolic stroke: Efficacy depending on reperfusion status

Abstract

Nearly all stroke neuroprotection modalities, including selective intra-arterial cooling (SI-AC), have failed to be translated from bench to bed side. Potentially overlooked reasons may be biological gaps, inadequate attention to reperfusion states and mismatched attention to neurological benefits. To advance stroke translation, we describe a novel thrombus-based stroke model in adult rhesus macaques. Intra-arterial thrombolysis with tissue plasminogen activator leads to three clinically relevant outcomes – complete, partial, and no recanalization based on digital subtraction angiography. We also find reperfusion as a prerequisite for SI-AC-induced benefits, in which models with complete or partial reperfusion exhibit significantly reduced infarct volumes, mitigated neurological deficits, improved upper limb motor dysfunction in both acute and chronic stages; however, no further neuroprotection is observed in those without reperfusion. In summary, we discover reperfusion as a crucial regulator of SI-AC-induced neuroprotection and provide insights of long-term functional benefits in behavior and imaging levels. Our findings could be important not only for the translational prerequisite and potential molecular targets, but also for this thrombus-thrombolysis model in monkeys as a powerful tool for further translational stroke studies.

A System for Continuous Pre- to Post-reperfusion Intra-carotid Cold Infusion for Selective Brain Hypothermia in Rodent StrokeModels

“…It should be noted that brain temperature curves in our rat experiments closely resemble those of the (non-stroke) pig or (stroke) canine study [27,28]. Unfortunately, brain temperature has not been measured in the human pilot studies testing cerebral cold infusions during EVT [8][9][10], temperature trends obtained in the primate stroke model were not reported [35], and lacking information on brain temperature probes' penetration depth in the canine stroke model does not allow for comparing species related and brain structure specific cooling rates during ischemia and after reperfusion [28]. In our rat experiments, ICCI decreased ipsilateral striatal temperature much faster compared with ipsilateral cortical temperature (see Fig.…”

“…So far, continuous pre-to post-reperfusion intra-arterial cold infusion was successfully realized only in one canine [28] and one primate stroke model [35]. Use of large animal models might be more attractive when studying thermodynamic effects of ICCI due to their larger gyrencephalic brains compared with the small lissencephalic brains of rodents [5].…”

A Systematic Review and Meta-Analysis of Animal Studies Testing Intra-Arterial Chilled Infusates After Ischemic Stroke

“…The only clinically-established neuroprotective interventions for focal cerebral ischemia are endovascular therapies [i.e., tPA administration, and/or MT; ( 4 )]. To our knowledge, only one study has administered chilled saline in tandem with endovascular therapies, and that was in a non-human primate embolic MCAO model ( 78 ). However, this study did not meet our a priori inclusion criteria because it only investigated the combined effects of IA-SCI + tPA vs. tPA, without a sham IA-SCI or IA-SCI only treatment group.…”

“…This resulted in the exclusion of a few noteworthy studies. First, as mentioned above, Wu et al ( 78 ) conducted a study in non-human primates where tPA-treated animals were compared to tPA + IA-SCI animals, but because this design is relatively unique in the IA-SCI literature, without a sham IA-SCI infusion group and pure IA-SCI treatment group, the results are difficult to compare to existing studies. Caroff et al ( 70 ) performed IA-SCI in canines, but due to a small sample size in their control group, historical controls were used to boost the sample size, ultimately leading to the conclusion that IA-SCI appears to provide benefit in treated animals compared to controls.…”

“…This study represents one of the few IA-SCI studies that we are aware of that have been conducted in non-rodent species. Altogether however, due to the general paucity of non-rodent animal species used in IA-SCI studies, combining these studies via meta-analysis with their relatively unique methodologies [e.g., embolic stroke in ( 78 ), and novel insulated catheter in ( 70 )] would likely add to the already great statistical heterogeneity we observed in our meta-analysis. Nonetheless, those studies certainly add to the growing weight of evidence supporting the use of IA-SCI in focal ischemia.…”