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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.

SUBMITTER: Wu D

PROVIDER: S-EPMC7308521 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

| S-EPMC7851312 | biostudies-literature

Phenotype Shifting in Astrocytes Account for Benefits of Intra-Arterial Selective Cooling Infusion in Hypertensive Rats of Ischemic Stroke.

Project description:The translational failure of neuroprotective therapies in stroke may be influenced by the mismatch of existing comorbidities between animal models and patients. Previous studies found that single-target neuroprotective agents reduced infarction in Sprague-Dawley but not in spontaneously hypertensive rats. It is of great interest to explore whether multi-target neuroprotectants and stroke models with comorbidities should be used in further translational researches. Ischemic stroke was induced in normotensive or hypertensive rats by 90- or 120-min middle cerebral artery occlusion (MCAO) and reperfusion. Intra-Arterial Selective Cooling Infusion (IA-SCI) was started at the onset of reperfusion for 30 minutes. Acute neurological deficits, infarct volumes, gene expression and markers of A1-like and A2-like astrocytes were evaluated. In further analysis, TNFα and IL-1α were administrated intracerebroventricularly, phenotype shifting of astrocytes and infarct volumes were assessed. Normobaric oxygen treatment, as a negative control, was also assessed in hypertensive rats. IA-SCI led to similar benefits in normotensive rats with 120-min MCAO and hypertensive rats with both 90-min and 120-min MCAO, including mitigated functional deficit and reduced infarct volumes. IA-SCI shifted astrocyte phenotypes partly by downregulating A1-like astrocytes and upregulating A2-like astrocytes in both RNA and protein levels. Upregulated A1-type astrocyte markers levels, induced by intracerebroventricular injection of TNFα and IL-1α, were closely related to increased infarct volumes in hypertensive rats, despite receiving IA-SCI treatment. In addition, infarct volumes and A1/A2-like genes were not affected by normobaric oxygen treatment. IA-SCI reduced infarction in both normotensive and hypertensive rats. Our results demonstrated the neuroprotective effects of IA-SCI in hypertensive rats may be related with phenotype shifting of astrocytes.

| S-EPMC9130426 | biostudies-literature

miRNAs involved in regulating embolic stroke recovery following spontaneous reperfusion

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-12-09 | GSE46269 | GEO

miRNAs involved in regulating embolic stroke recovery following spontaneous reperfusion

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-09 | E-GEOD-46269 | biostudies-arrayexpress

microRNAs involved in regulating embolic stroke recovery following spontaneous reperfusion [mRNA]

2013-12-09 | GSE46267 | GEO

microRNAs involved in regulating embolic stroke recovery following spontaneous reperfusion [miRNA]

2013-12-09 | GSE46266 | GEO

microRNAs involved in regulating embolic stroke recovery following spontaneous reperfusion [mRNA]

Project description:To date, miRNA and mRNA expression studies on cerebral ischemia in both human and animal models have focused mainly on acute phase of ischemic stroke. In this study, we present the roles played by microRNAs in the spontaneous recovery phases in cerebral ischemia using rodent stroke models. In this study presented here, Middle Cerebral Artery Occlusion stroke model was established by using embolus and the brain samples of stroke model were harvestd at 0hrs, 3hrs, 6hrs, 12hrs, 24hrs, 48hrs, 72hrs, 120hrs and 168hrs. RNAs were extracted from these samples and microRNA array and mRNA array were performed.

2013-12-09 | E-GEOD-46267 | biostudies-arrayexpress

microRNAs involved in regulating embolic stroke recovery following spontaneous reperfusion [miRNA]

Project description:To date, miRNA expression studies on cerebral ischemia in both human and animal models have focused mainly on acute phase of ischemic stroke. In this study, we present the roles played by microRNAs in the spontaneous recovery phases in cerebral ischemia using rodent stroke models. In this study presented here, Middle Cerebral Artery Occlusion stroke model was established by using embolus and the brain samples of stroke model were harvested at 0hrs, 3hrs, 6hrs, 12hrs, 24hrs, 48hrs, 72hrs, 120hrs and 168hrs. RNAs were extracted from these samples and microRNA array and mRNA array were performed.

2013-12-09 | E-GEOD-46266 | biostudies-arrayexpress

Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model.

Project description:Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes.Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.

| S-EPMC8756475 | biostudies-literature

The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy.

Project description:Background and purposeReperfusion following intra-arterial stroke therapy is associated with improved clinical outcomes. However, the degree of reperfusion needed to achieve successful outcomes is unknown. The purpose of this analysis was to determine whether the degree of reperfusion has an impact on final infarct volumes and clinical outcomes.Materials and methodsA retrospective analysis identified 88 consecutive patients who underwent intra-arterial therapy for acute anterior circulation stroke. Reperfusion was graded by using the TICI scale into none (TICI 0 or 1), partial (TICI 2a), or near-complete (TICI 2b/3). Baseline characteristics were compared. For each of these groups, we compared discharge disposition and final infarct volumes.ResultsNear-complete, partial, and no reperfusion occurred in 44.3%, 26.1%, and 29.6% of patients, respectively. Baseline characteristics were similar across all 3 groups. The median NIHSS score was 15. Significant differences in discharge disposition were seen, with 41.0% of the TICI 2b/3 group discharged home versus 17.4% of TICI 2a and 7.7% of TICI 0/1. In-hospital mortality was 12.8% for TICI 2b/3 compared with 39.1% for TICI 2a and 34.6% for TICI 0/1. Patients with near-complete reperfusion were significantly more likely to have infarct volumes ≤70 mL (OR = 12.1; 95% CI, 2.7-54.2), compared with patients with partial reperfusion (OR = 2.2; 95% CI, 0.5-9.6).ConclusionsSignificant differences exist in outcomes and infarct volumes between partial (TICI 2a) and near-complete (TICI 2b/3) reperfusion following intra-arterial stroke therapy. Further trials should separately report these groups to facilitate comparison among treatment paradigms.

| S-EPMC7966350 | biostudies-literature

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