Multicentre translational Trial of Remote Ischaemic Conditioning in Acute
						Ischaemic Stroke (TRICS): protocol of multicentre, parallel group,
						randomised, preclinical trial in female and male rat and mouse from the
						Italian Stroke Organization (ISO) Basic Science networkMulticentre
						translational Trial of Remote Ischaemic Conditioning in Acute Ischaemic
						Stroke (TRICS): protocol of multicentre, parallel group, randomised,
						preclinical trial in female and male rat and mouse fro

Tettamanti, Mauro; Beretta, Simone; Pignataro, Giuseppe; Fumagalli, Stefano; Perego, Carlo; Sironi, Luigi; Pedata, Felicita; Amantea, Diana; Bacigaluppi, Marco; Vinciguerra, Antonio; Valente, Alessia; Diamanti, Susanna; Mariani, Jacopo; Viganò, Martina; Santangelo, Francesco; Zoia, Chiara Paola; Rogriguez-Menendez, Virginia; Castiglioni, Laura; Rzemieniec, Joanna; Dettori, Ilaria; Bulli, Irene; Coppi, Elisabetta; Gullotta, Giorgia Serena; Bagetta, Giacinto; Martino, Gianvito; Ferrarese, Carlo; Simoni, M.G. De

doi:10.1136/bmjos-2020-100063

Cited by 7 publications

(15 citation statements)

References 22 publications

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“…Briefly, vessel occlusion was accomplished by introducing a silicone-coated nylon filament (diameter: 0.23 mm, Doccol Corporation, Redlands, CA, USA) into the internal carotid artery (ICA) for 10–11 mm from its bifurcation from the common carotid artery, whereby a moderate resistance was indicative of proximal MCAo at the level of the Willis circle. In addition to correct positioning of the filament, animals were considered ischemic, and hence included in the study, if presenting >3 of the following deficits assessed after 45 min MCAo: ellipsoidal shape of the palpebral fissure, lateral extension of one or both ears, asymmetric body bending or laterally extending limbs [ 70 ]. To allow reperfusion, the filament was withdrawn 1 h after MCAo.…”

Section: Methodsmentioning

confidence: 99%

“…Neurological deficits were assessed 48 h after MCAo or SHAM surgery using the dichotomized De Simoni composite neuroscore to evaluate the general and focal neurological dysfunctions caused by the ischemic insult. Briefly, the total score ranges from 0 (healthy) to 56 (the worst performance in all the 13 categories) and represents the sum of six general deficits (fur (0–2), ears (0–2), eyes (0–4), posture (0–4), spontaneous activity (0–4) and epileptic behaviour (0–12)) and seven focal deficits (body asymmetry (0–4), gait (0–4), climbing (0–4), circling behaviour (0–4), forelimb symmetry (0–4), compulsory circling (0–4) and whisker response (0–4)) [ 70 , 71 , 72 , 73 ].…”

Section: Methodsmentioning

confidence: 99%

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Characterization of the Involvement of Tumour Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse

Santo

Russa

Greco³

et al. 2023

IJMS

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The identification of novel targets to modulate the immune response triggered by cerebral ischemia is crucial to promote the development of effective stroke therapeutics. Since tumour necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, is involved in the regulation of immune and stromal cell functions in acute neurodegeneration, we aimed to characterize its involvement in ischemic stroke. Transient middle cerebral artery occlusion (1 h MCAo, followed by 6 to 48 of reperfusion) in mice resulted in a significant elevation in cerebral TSG-6 protein levels, mainly localized in neurons and myeloid cells of the lesioned hemisphere. These myeloid cells were clearly infiltrating from the blood, strongly suggesting that brain ischemia also affects TSG-6 in the periphery. Accordingly, TSG-6 mRNA expression was elevated in peripheral blood mononuclear cells (PBMCs) from patients 48 h after ischemic stroke onset, and TSG-6 protein expression was higher in the plasma of mice subjected to 1 h MCAo followed by 48 h of reperfusion. Surprisingly, plasma TSG-6 levels were reduced in the acute phase (i.e., within 24 h of reperfusion) when compared to sham-operated mice, supporting the hypothesis of a detrimental role of TSG-6 in the early reperfusion stage. Accordingly, systemic acute administration of recombinant mouse TSG-6 increased brain levels of the M2 marker Ym1, providing a significant reduction in the brain infarct volume and general neurological deficits in mice subjected to transient MCAo. These findings suggest a pivotal role of TSG-6 in ischemic stroke pathobiology and underscore the clinical relevance of further investigating the mechanisms underlying its immunoregulatory role.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterization of the Involvement of Tumour Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse

Santo

Russa

Greco³

et al. 2023

IJMS

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“…Neurological deficits were assessed 24h after MCAo or SHAM surgery, or 72h after PC by using the dichotomized De Simoni composite neuroscore that allows to evaluate the general and focal neurological dysfunctions caused by the ischemic insult ( 51 , 52 ). Briefly, total score ranges from 0 (healthy) to 56 (the worst performance in all the 13 categories) and represents the sum of 6 general deficits (fur [0-2], ears [0-2], eyes [0-4], posture [0-4], spontaneous activity [0-4], and epileptic behavior [0-12]) and 7 focal deficits (body asymmetry [0-4], gait [0-4], climbing [0-4], circling behavior [0-4], forelimb symmetry [0-4], compulsory circling [0-4], and whisker response [0-4].…”

Section: Methodsmentioning

confidence: 99%

Section: Assessment Of Infarct Size Edema and Neurological Deficitsmentioning

confidence: 99%

Ischemic Preconditioning Modulates the Peripheral Innate Immune System to Promote Anti-Inflammatory and Protective Responses in Mice Subjected to Focal Cerebral Ischemia

et al. 2022

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The development of tolerance triggered by a sublethal ischemic episode (preconditioning, PC) involves a complex crosstalk between neurons, astrocytes and microglia, although the role of the peripheral immune system in this context is largely unexplored. Here, we report that severe cerebral ischemia caused by transient middle cerebral artery occlusion (MCAo) in adult male mice elevates blood counts of inflammatory neutrophils and monocytes, and plasma levels of miRNA-329-5p. These inflammatory responses are prevented by ischemic PC induced by 15 min MCAo, 72h before the severe insult (1h MCAo). As compared with sham-operated animals, mice subjected to either ischemic PC, MCAo or a combination of both (PC+MCAo) display spleen contraction. However, protein levels of Ym1 (a marker of polarization of myeloid cells towards M2/N2 protective phenotypes) are elevated only in spleen from the experimental groups PC and PC+MCAo, but not MCAo. Conversely, Ym1 protein levels only increase in circulating leukocytes from mice subjected to 1h MCAo, but not in preconditioned animals, which is coincident with a dramatic elevation of Ym1 expression in the ipsilateral cortex. By immunofluorescence analysis, we observe that expression of Ym1 occurs in amoeboid-shaped myeloid cells, mainly representing inflammatory monocytes/macrophages and neutrophils. As a result of its immune-regulatory functions, ischemic PC prevents elevation of mRNA levels of the pro-inflammatory cytokine interleukin (IL)-1β in the ipsilateral cortex, while not affecting IL-10 mRNA increase induced by MCAo. Overall, the elevated anti-inflammatory/pro-inflammatory ratio observed in the brain of mice pre-exposed to PC is associated with reduced brain infarct volume and ischemic edema, and with amelioration of functional outcome. These findings reaffirm the crucial and dualistic role of the innate immune system in ischemic stroke pathobiology, extending these concepts to the context of ischemic tolerance and underscoring their relevance for the identification of novel therapeutic targets for effective stroke treatment.

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“…The Italian Stroke Organization (ISO) Basic Science Network, a nationwide network that promotes translational research on acute ischemic stroke, has launched a multicenter translational research program on RIC. This program provides for a multi-center pre-clinical study of experimental ischemic stroke ( 27 ) and a multi-center randomized phase II clinical trial on remote ischemic conditioning in patients with acute stroke within 9 h of onset who are not candidates for recanalization therapies (TRICS-9).…”

Section: Introduction and Rationalementioning

confidence: 99%

Multi-Center Randomized Phase II Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies (TRICS-9): Study Design and Protocol

et al. 2021

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Aim: To assess the efficacy of remote ischemic conditioning (RIC) in patients with ischemic stroke within 9 h of onset, that are not candidates for recanalization therapies.Sample Size Estimates: A sample size of 80 patients (40 in each arm) should yield 80% power to detect a 20% difference in early neurological improvement at 72 h at p = 0.05, two sided.Methods and Design: TRICS-9 is a phase II, multicenter, controlled, block randomized, open-label, interventional clinical trial. Patients recruited in Italian academic hospitals will be randomized 1:1 to either RIC plus standard medical therapy or standard medical therapy alone. After randomization, RIC will be applied manually by four alternating cycles of inflation/deflation 5 min each, using a blood pressure cuff around the non-paretic arm.Study Outcomes: The primary efficacy outcome is early neurological improvement, defined as the percent change in the National Institute of Health Stroke Scale (NIHSS) at 72 h in each arm. Secondary outcomes include early neurologic improvement at 24 and 48 h, disability at 3 months, rate of symptomatic intracerebral hemorrhage, feasibility (proportion of patients completing RIC), tolerability after RIC and at 72 h, blood levels of HIF-1α, and HSP27 at 24 h and 72 h.Discussion/Conclusion: RIC in combination with recanalization therapies appears to add no clinical benefit to patients, but whether it is beneficial to those that are not candidates for recanalization therapies is still to be demonstrated. TRICS-9 has been developed to elucidate this issue.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT04400981.

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Cited by 7 publications

References 22 publications

Characterization of the Involvement of Tumour Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse

Characterization of the Involvement of Tumour Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse

Ischemic Preconditioning Modulates the Peripheral Innate Immune System to Promote Anti-Inflammatory and Protective Responses in Mice Subjected to Focal Cerebral Ischemia

Multi-Center Randomized Phase II Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies (TRICS-9): Study Design and Protocol

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