Dataset Information

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.

SUBMITTER: Wu D

PROVIDER: S-EPMC7851312 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Wu Di D Fu Yongjuan Y Wu Longfei L Huber Mitchell M Chen Jian J Yao Tianqi T Zhang Mo M Wu Chuanjie C Song Ming M He Xiaoduo X Li Sijie S Zhang Yongbiao Y Li Shengli S Ding Yuchuan Y Ji Xunming X

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20201001 4

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 pla ...[more]

PMID: 32710291

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Project description:Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo.

Project description:BackgroundClinically ineffective reperfusion (CIR) refers to the discrepancy between successful reperfusion and a favorable functional outcome in patients with large vessel occlusion (LVO) stroke after endovascular treatment (EVT). The Improving Neuroprotective Strategy for Ischemic Stroke with Sufficient Recanalization after Thrombectomy by Intra-arterial Cocktail Therapy (INSIST-CT) trial aimed to explore the safety, feasibility, and efficacy of intra-arterial cocktail therapy using argatroban, dexamethasone, and edaravone in patients who achieved sufficient reperfusion after EVT.MethodsIn this prospective, single-arm, pilot study, eligible patients with anterior circulation LVO who achieved sufficient reperfusion after EVT were enrolled in the INSIST-CT trial. Consecutive patients who met the inclusion/exclusion criteria were included in the control group retrospectively. In the INSIST-CT group, argatroban, dexamethasone, and edaravone were continuously administered for 30 min into the culprit artery after sufficient recanalization. The primary endpoint was the proportion of favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-2 at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage (sICH). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses were performed to account for multiple confounders.ResultsA total of 30 patients were included in the INSIST-CT group, and 261 patients were included in the control group. The proportion of the patients with the primary endpoint was 60% in the INSIST-CT group and 55.9% in the control group (unadjusted odds ratio [OR] 1.18, 95% CI 0.55-2.61, p = 0.67; adjusted OR 1.42, 95% CI 0.62-3.26, p = 0.41). No significant difference in sICH at 48 h after treatment was observed between the two groups (unadjusted OR 0.96, 95% CI 0.15-3.56, p = 0.96; adjusted OR 0.82 95% CI 0.17-3.97, p = 0.809). Similar results were observed after the PSM and IPTW analyses.ConclusionIn anterior circulation, LVO patients who achieved sufficient reperfusion after EVT, bridging intra-arterial cocktail therapy with argatroban, dexamethasone, and edaravone may be safe and feasible. However, it did not improve the 90-day functional outcomes. A numerically higher probability of a favorable outcome in the INSIST-CT group suggests the potential promise of this cocktail therapy in reducing clinically ineffective reperfusion.Clinical trial registrationClinicalTrials.gov, NCT04202549.

Dataset Information

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

Publications

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

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