Remote but not Distant: a Review on Experimental Models and Clinical Trials in Remote Ischemic Conditioning as Potential Therapy in Ischemic Stroke

Mollet, Inês G.; Marto, João Pedro; Mendonça, Marcelo; Viana-Baptista, Miguel; Vieira, Helena L.A.

doi:10.1007/s12035-021-02585-6

Cited by 20 publications

(17 citation statements)

References 201 publications

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“…Ischemic stroke, defined as brain, retina or spinal cord infarction, develops in more than 85% of all strokes worldwide. 2 As reported previously, the incidence of stroke is positively associated with patient age; estimates show that approximately 13.7 million individuals suffer from stroke every year globally. 3 , 4 Stroke creates a significant burden on the physical and mental health of patients and also the health-care system.…”

Section: Introductionmentioning

confidence: 71%

Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis

Xie¹,

Zhang²,

Li³

et al. 2022

DDDT

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Background Dihydromyricetin (DHM) exerts protective effects in various brain diseases. The aim of this research was to investigate the biological role of DHM in cerebral ischemia reperfusion (I/R) injury. Methods We generated a rat model of cerebral I/R injury by performing middle cerebral artery occlusion/reperfusion (MCAO/R). The neurological score and brain water content of the experimental rats was then evaluated. The infarct volume and extent of apoptosis in brain tissues was then assessed by 2,3,5-triphenyltetrazolium (TTC) and TdT-mediated dUTP nick end labeling (TUNEL) staining. Hippocampal neuronal cells (HT22) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) and cell counting kit-8 (CCK-8) assays and flow cytometry were performed to detect cell viability and apoptosis. The levels of lipid reactive oxygen species (ROS) and iron were detected and the expression levels of key proteins were assessed by Western blotting. Results DHM obviously reduced neurological deficits, brain water content, infarct volume and cell apoptosis in the brain tissues of MCAO/R rats. DHM repressed ferroptosis and inhibited the sphingosine kinase 1 (SPHK1)/mammalian target of rapamycin (mTOR) pathway in MCAO/R rats. In addition, DHM promoted cell viability and repressed apoptosis in OGD/R-treated HT22 cells. DHM also suppressed the levels of lipid ROS and intracellular iron in OGD/R-treated HT22 cells. The expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM. Moreover, the influence conferred by DHM was abrogated by the overexpression of SPHK1 or treatment with MHY1485 (an activator of mTOR). Conclusion This research demonstrated that DHM repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral I/R injury. Our findings suggest that DHM may be a candidate drug for cerebral I/R injury treatment.

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Section: Introductionmentioning

confidence: 71%

Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis

Xie¹,

Zhang²,

Li³

et al. 2022

DDDT

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“…Several factors have been postulated that may negate the effects of RIC. These include surgical anesthesia, co-morbidities, age, as well as timing, route, and dose of RIC administration 10 , 40 . Many of these factors were pertinent in our trial and may have contributed to the neutral results of our study.…”

Section: Discussionmentioning

confidence: 99%

Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial

Leung

Rizoli

Trypcic

et al. 2023

Sci Rep

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Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

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“…Previous studies have demonstrated that RIC can relieve cerebral ischemia–reperfusion injury in stroke models in animals; however, some researchers believe that the neuroprotective strength of RIC may be inadequate, so it is unclear whether it improves outcomes in patients with EVT. 9 Therefore, we aim to monitor three types of neurological deficit scores (NIHSS, Barthel Index, and mRS) at different follow-up periods to predict outcomes more accurately. The results of this SERIC-EVT study will provide valuable information for further studies.…”

Section: Discussionmentioning

confidence: 99%

“…7 Previous studies have reported that RIC stimulates endogenous protective mechanisms and has a protective role particularly in brain tissue. [8][9][10] In an experimental ischemia-reperfusion model, RIC has been shown to reduce cerebral ischemia-reperfusion injury, inflammatory substances, brain edema, and neuronal apoptosis. 11,12 Thus, RIC might be beneficial for patients who have undergone EVT treatment because cerebral recanalization after ischemia is similar to ischemia-reperfusion models.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of remote ischemic conditioning combined with endovascular thrombectomy for acute ischemic stroke due to large vessel occlusion of anterior circulation: A multicenter, randomized, parallel-controlled clinical trial (SERIC-EVT): Study protocol

Guo

Abuduxukuer

Zhang

et al. 2022

International Journal of Stroke

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Rationale/Aim: Many patients undergoing successful recanalization after endovascular thrombectomy (EVT) do not have a good outcome; additional neuroprotection might benefit this group. Remote ischemic conditioning (RIC) stimulates endogenous protective mechanisms and may have a neuroprotective in acute brain ischemia. The SERIC-EVT trial is investigating the safety and efficacy of RIC for patients with acute ischemic stroke who underwent EVT due to large vessel occlusion of the anterior circulation. Methods: SERIC-EVT is a multicenter, randomized, parallel-controlled, and blinded endpoint clinical trial. Patients are recruited from 10 hospitals in Jilin Province, Northeast China. Patients with anterior circulation acute ischemic stroke undergoing EVT due to large-vessel occlusion are randomized in a 1:1 ratio to RIC or sham-RIC. Participants will receive standard medical treatment and an inflation pressure of 200 mmHg (RIC group) or 60 mmHg (sham-RIC group) twice daily for seven consecutive days. Study outcomes: The primary outcome is the proportion of patients with mRS score of 0–2 on day 90. Secondary outcome measures include the National Institute of Health Stroke Scale, Barthel Index, and mRS scores obtained at 24 h, 7 days, 30±3 days, and 90±3 days post-EVT, recanalization rate, expanded Thrombolysis in Cerebral Infarction score, and symptomatic intracranial hemorrhage post-EVT. Mortality and all adverse events, including skin changes and pain scores, within the first 90 days will be used as safety outcome measures. Sample size estimates: Based on previous studies, we estimate a 14% difference in functional independence (the modified Rankin Score [mRS]≤2) between RIC and sham-RIC groups. Considering a significance level of 5% and power of 80%, and one-fifth of patients lost to follow-up, the planned sample size is 498 patients (249 per group). Discussion: RIC might be a strategy that improves 3-month clinical outcomes in AIS patients who have undergone EVT due to large vessel occlusion of anterior circulation. SERIC-EVT will determine whether this is the case. Clinical Trial Registration: Clinicaltrials.gov, identifier: NCT04977869.

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Remote but not Distant: a Review on Experimental Models and Clinical Trials in Remote Ischemic Conditioning as Potential Therapy in Ischemic Stroke

Cited by 20 publications

References 201 publications

Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis

Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis

Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial

Safety and efficacy of remote ischemic conditioning combined with endovascular thrombectomy for acute ischemic stroke due to large vessel occlusion of anterior circulation: A multicenter, randomized, parallel-controlled clinical trial (SERIC-EVT): Study protocol

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