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Despite advances in intravenous thrombolysis and endovascular thrombectomy, numerous acute ischemic stroke survivors continue to experience various disability levels. The nitric oxide (NO) donor, Glyceryl Trinitrate (GTN), has been identified as a potential neuroprotective agent against ischemic damage. We evaluated the safety and feasibility of intravenous GTN in AIS patients. Subsequently, we conducted a secondary analysis to assess for possible efficacy of GTN as a neuroprotectant. We conducted a prospective, double-blind, randomized controlled trial in the Stroke Intervention & Translational Center (SITC) in Beijing Luhe Hospital, Capital Medical University (ChiCTR2100046271). AIS patients within 24 h of stroke onset were evenly divided into GTN or control groups (n = 20 each). The GTN group received intravenous GTN (5 mg in 50 ml saline at a rate of 0.4 mg/h for 12.5 h/day over 2 days), while controls were administered an equivalent volume of 0.9% saline. Both groups followed standard Stroke Guidelines for treatment. Safety measures focused on SBP

BackgroundBrain inflammation plays a key role in ischemia/reperfusion (I/R) injury and is the main cause of “ineffective or futile recanalization” after successful mechanical thrombectomy (MT) in acute ischemic stroke (AIS). One of the primary sources of inflammatory cells after AIS are derived from the spleen. As an innovative and potential neuroprotective strategy after stroke, Remote Administration of Hypothermia (RAH) temporarily suppresses immune activities in the spleen, reduces the release of inflammatory cells and cytokines into blood, and thus reversibly diminishes inflammatory injury in the brain.MethodsThis single-center, prospective, randomized controlled study (RCT) is proposed for AIS patients with anterior circulation large vessel occlusion (LVO). Subjects will be randomly assigned to either the control or intervention groups in a 1:1 ratio (n = 40). Participants allocated to the intervention group will receive RAH on the abdomen above the spleen prior to recanalization until 6 h after thrombectomy. All enrolled patients will receive standard stroke Guideline care. The main adverse events associated with RAH are focal cold intolerance and abdominal pain. The primary outcome will assess safety as it pertains to RAH application. The secondary outcomes include the efficacy of RAH on spleen, determined by spleen volumes, blood inflammatory factor (cells and cytokines), and on brain injury, determined by infarction volumes and poststroke functional outcomes.DiscussionThis study aims to examine the safety and preliminary effectiveness of RAH over the spleen during endovascular therapy in AIS patients. The results of this study are expected to facilitate larger randomized clinical trials and hopefully prove RAH administration confers adjuvant neuroprotective properties in AIS treated with MT.Clinical trial registrationhttps://www.chictr.org.cn/. Identifier ChiCTR 2300077052.

Background: Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection. Methods: A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined. Results: C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α. Conclusion: Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.

Early rehabilitation is crucial in reducing stroke-related disability, but the optimal training model remains unclear. We conducted a trial comparing different initiation timings and intensities of mobilization strategies after stroke. Results showed that early intensive mobilization had favorable outcomes at 3 months post-stroke, while very early intensive mobilization had poorer chances of favorable outcomes. Our investigation into brain injury mechanisms induced by very early exercise within 24 hours of stroke onset aligned with guidelines advising against high-dose very early mobilization. Additionally, we are studying the effects of various exercise intensities and frequencies on early stroke rehabilitation. Integrated rehabilitation models, such as combining remote ischemic conditioning (RIC) with exercise (RICE), hold promise. Our study found RICE to be safe and feasible for early rehabilitation of acute ischemic stroke patients, and further research is underway to determine its efficacy in a larger sample size. Despite extensive research, identifying the most effective early recovery strategies remains a complex challenge, necessitating ongoing work in the field of early rehabilitation after stroke.

Abstract Background We aimed to investigate the risk factors of early neurological deterioration (END) after intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and the relationship between END and poor 3-month functional outcomes. Methods Patients who accepted intravenous recombinant rt-PA were enrolled continuously. END was defined as an increase in National Institute of Health Stroke (NIHSS) score ≥ 4 points or death within 24 hours after intravenous thrombolysis. The modified Rankin Scale (mRS) score was recorded to evaluate the functional outcome of stroke, and the poor 3-month prognosis was defined as an mRS score ≥ of 3. Univariate and multivariate analyses were used to analyze the risk factors of END. The relation between END and 3-month functional outcome was analyzed by multivariate logistic regression analysis. Results A total of 1107 patients (mean age, 63.42 ± 11.33 years; 673 males) were included in the final analysis, and 81(7.32%) patients had END. In multivariate analysis, the serum glucose level was significantly associated with END; the odds ratio was 1.10 (95% CI 1.03 to 1.18, p = 0.004). The multivariate logistic analysis showed END has a notable association with the poor 3-month functional recovery even after adjusting for confounding factors; the adjusted OR was 8.25 (95% CI 3.77 to 18.03, p

The impact of stroke, currently the second leading cause of death worldwide, continues to worsen, and even those that survive can have persistent neurological deficits. A potentially significant implication may be due to hyperglycemia, found in one-third of all acute ischemic stroke (AIS) patients. However, prior studies reported conflicting information about the impact of hyperglycemia on poststroke prognosis, likely due to different measurements of stress-induced hyperglycemia. The glucose-to-glycated hemoglobin ratio is an index of stress-induced hyperglycemia after AIS that better quantifies acute changes in blood glucose, as opposed to absolute variations in glucose levels. Moderate blood glucose reductions might counteract the negative effects of hyperglycemia and glycemic control medications can also play a role in neuroprotection. The liver is the main organ that functions to maintain energy and glucose metabolism and the effects of AIS can reach far peripheral organs, including the liver. In this review, we highlighted the mechanism responsible for acute poststroke hyperglycemia, a hepatic inflammatory pathway that results in hepatic gluconeogenesis and reduced hepatic insulin sensitivity. Hepatitis cascades lead to hepatic gluconeogenesis, and targeted therapy with antihyperglycemic drugs has the potential to improve stroke prognosis and recovery.

ObjectiveThis study assesses whether stress-induced hyperglycemia is a predictor of poor outcome at 3 months for patients with acute ischemic stroke (AIS) treated by endovascular treatment (EVT) and impacted by their previous blood glucose status.MethodsThis retrospective study collected data from 576 patients with AIS due to large vessel occlusion (LVO) treated by EVT from March 2019 to June 2022. The sample was composed of 230 and 346 patients with and without diabetes mellitus (DM), respectively, based on their premorbid diabetic status. Prognosis was assessed with modified Rankin Scale (mRS) at 3-month after AIS. Poor prognosis was defined as mRS>2. Stress-induced hyperglycemia was assessed by fasting glucose-to-glycated hemoglobin ratio (GAR). Each group was stratified into four groups by quartiles of GAR (Q1–Q4). Binary logistic regression analysis was used to identify relationship between different GAR quartiles and clinical outcome after EVT.ResultsIn DM group, a poor prognosis was seen in 122 (53%) patients and GAR level was 1.27 ± 0.44. These variables were higher than non-DM group and the differences were statistically significant (p < 0.05, respectively). Patients with severe stress-induced hyperglycemia demonstrated greater incidence of 3-month poor prognosis (DM: Q1, 39.7%; Q2, 45.6%; Q3, 58.6%; Q4, 68.4%; p = 0.009. Non-DM: Q1, 31%; Q2, 32.6%; Q3, 42.5%; Q4, 64%; p < 0.001). However, the highest quartile of GAR was independently associated with poor prognosis at 3 months (OR 3.39, 95% CI 1.66–6.96, p = 0.001), compared to the lowest quartile in non-DM patients after logistic regression. This association was not observed from DM patients.ConclusionThe outcome of patients with acute LVO stroke treated with EVT appears to be influenced by premorbid diabetes status. However, the poor prognosis at 3-month in patients with DM is not independently correlated with stress-induced hyperglycemia. This could be due to the long-term damage of persistent hyperglycemia and diabetic patients’ adaptive response to stress following acute ischemic damage to the brain.

ObjectiveRehabilitation is essential in reducing stroke disability and should be performed as early as possible. Exercise is an established and effective rehabilitation method; however, its implementation has been limited as its very early use exacerbates cerebral injury and is restricted by patients' unstable conditions and disabilities. Remote ischemic conditioning (RIC) is a passive and accessible therapy in acute phases of stroke and appears to have similar neuroprotective effects as exercise. This study assessed the safety and feasibility of the novel rehabilitation strategy—early RIC followed by exercise (RICE) in acute ischemic stroke (AIS).MethodsWe conducted a single-center, double-blinded, randomized controlled trial with AIS patients within 24 h of stroke onset or symptom exacerbation. All enrolled patients were randomly assigned, at a ratio of 1:1, to either the RICE group or the sham-RICE group (sham RIC with exercise). Each group received either RIC or sham RIC within 24 h after stroke onset or symptom exacerbation, once a day, for 14 days. Both groups started the exercise routine on day 4, twice daily, for 11 total days. The safety endpoints included clinical deterioration, recurrence of stroke, hemorrhagic transformation, complications, and adverse events resulting from RICE during hospitalization. The efficacy endpoints [Modified Rankin Scale (mRS) score, National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index, and walking ability] were evaluated at admission and 90 days after stroke onset.ResultsForty AIS patients were recruited and completed the study. No significant differences in baseline characteristics were found between the two groups, which included risk factors, stroke severity at admission, pre-morbid disability, and other special treatments. No significant differences were found in the safety endpoints between two groups. Excellent recovery (mRS 0–2) at 3 months was obtained in 55% of the patients with RICE as compared 40% in sham group, but it did not reach a significant level.ConclusionsRICE was safe and feasible for AIS patients, and seems to be a promising early stroke rehabilitation. The results of this study suggest a need for a future randomized and controlled multicenter trial with a larger sample size to determine the efficacy of RICE.

Branch atheromatous disease (BAD) is a subtype of ischemic stroke caused by perforating arteries occlusion due to proximal atherosclerosis of the arteries. Early neurological deterioration and recurrent stereotyped transient ischemic attacks are typical clinical manifestations of BAD. The optimal treatment for BAD has not been determined. This article explores a possible mechanism of BAD and effective treatment measures to prevent early progression and attack of transient ischemic events. This article explains the current status of intravenous thrombolysis, tirofiban, and argatroban for BAD and subsequent prognosis.

Background: Despite intravenous thrombolysis and endovascular therapy for acute ischemic stroke (AIS), many survivors still have varying degrees of disability. Glyceryl trinitrate (GTN), a nitric oxide (NO) donor, has been previously reported to induce neuroprotection after AIS. The use of GTN to reduce brain damage after stroke remains yet to be elucidated. This study was designed to explore the safety, feasibility, and preliminary efficacy of intravenous administration of GTN after AIS.Methods: A prospective randomized controlled trial is proposed with AIS patients. Participants will be randomly allocated to GTN group and control group with a 1:1 ratio (n = 40). Both groups will be treated with standard therapies according to the current stroke guidelines. Participants allocated to the GTN group will receive intravenous administration of GTN (5 mg GTN in 50 ml saline at a rate of 0.4 mg/h that is continued for 12.5 h/day for 2 days) within 24 h of symptom onset. Participants allocated to the control group will receive intravenous administration at equal capacity of 0.9% normal saline (NS) (total 50 ml/day at 4 ml/h that is continued for 12.5 h/day for 2 days). The primary outcome is safety [systolic blood pressure (SBP)

Ischemic stroke is a leading cause of death and disability worldwide, but there are no effective, widely applicable stroke therapies. Systemic hypothermia is an international mainstay of postcardiac arrest care, and the neuroprotective benefits of systemic hypothermia following cerebral ischemia have been proven in clinical trials, but logistical issues hinder clinical acceptance. As a novel solution to these logistical issues, the application of local endovascular infusion of cold saline directly to the infarct site using a microcatheter has been put forth. In small animal models, the procedure has shown incredible neuroprotective promise on the biochemical, structural, and functional levels, and preliminary trials in large animals and humans have been similarly encouraging. In addition, the procedure would be relatively cost-effective and widely applicable. The administration of local endovascular hypothermia in humans is relatively simple, as this is a normal part of endovascular intervention for neuroendovascular surgeons. Therefore, it is expected that this new therapy could easily be added to an angiography suite. However, the neuroprotective efficacy in humans has yet to be determined, which is an end goal of researchers in the field. Given the potentially massive benefits, ease of induction, and cost-effective nature, it is likely that local endovascular hypothermia will become an integral part of endovascular treatment following ischemic stroke. This review outlines relevant research, discusses neuroprotective mechanisms, and discusses possibilities for future directions.

Background: Following an acute ischemic stroke (AIS), rapidly initiated reperfusion therapies [i. e., intravenous thrombolysis (IVT) and endovascular treatment (EVT)] demonstrate robust clinical efficacy. However, only a subset of these patients can benefit from these therapies due to their short treatment windows and potential complications. In addition, many patients despite successful reperfusion still have unfavorable outcomes. Thus, neuroprotection strategies are urgently needed for AIS patients. Chlorpromazine and promethazine (C+P) have been employed in clinical practice for antipsychotic and sedative purposes. A clinical study has also shown a neuroprotective effect of C+P on patients with cerebral hemorrhage and subarachnoid hemorrhage. The safety, feasibility, and preliminary efficacy of intravenous administration of C+P in AIS patients within 24 h of onset will be elucidated.Methods: A prospective randomized controlled trial is proposed with AIS patients. Participants will be randomly allocated to an intervention group and a control group with a 1:1 ratio (n = 30) and will be treated with standard therapies according to the current stroke guidelines. Participants allocated to the intervention group will receive intravenous administration of C+P (chlorpromazine 50 mg and promethazine 50 mg) within 24 h of symptom onset. The primary outcome is safety (mainly hypotension), while the secondary outcomes include changes in functional outcome and infarction volume.Discussions: This study on Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-like Effect in Stroke (RICHES) will be the first prospective randomized controlled trial to ascertain the safety, feasibility, and preliminary efficacy of intravenous C+P as a neuroprotection strategy in AIS patients. These results will provide parameters for future studies, provide insights into treatment effects, and neuroprotection with phenothiazine in AIS.Clinical Trial Registration:www.chictr.org.cn, identifier: ChiCTR2000038727.

Objective: Very early mobilization was thought to contribute to beneficial outcomes in stroke-unit care, but the optimal intervention strategy including initiation time and intensity of mobilization are unclear. In this study, we sought to confirm the rehabilitative effects of different initiation times (24 vs. 48 h) with different mobilization intensities (routine or intensive) in ischemic stroke patients within three groups.Materials and Methods: We conducted a randomized and controlled trial with a blinded follow-up assessment. Patients with ischemic stroke, first or recurrent, admitted to stroke unit within 24 h after stroke onset were recruited. Eligible subjects were randomly assigned (1:1:1) to 3 groups: Early Routine Mobilization in which patients received < 1.5 h/d out-of-bed mobilization within 24–48 h after stroke onset, Early Intensive Mobilization in which patients initiated ≥3 h/d mobilization at 24–48 h after the stroke onset, and Very Early Intensive Mobilization in which patients received≥3 h/d mobilization within 24 h. The modified Rankin Scale score of 0–2 was used as the primary favorable outcome.Results: We analyzed 248 of the 300 patients (80 in Early Routine Mobilization, 82 in Very Early Intensive Mobilization and 86 in Early Intensive Mobilization), with 52 dropping out (20 in Early Routine Mobilization, 18 in Very Early Intensive Mobilization and 14 in Early Intensive Mobilization). Among the three groups, the Early Intensive Mobilization group had the most favorable outcomes at 3-month follow-up, followed by patients in the Early Routine Mobilization group. Patients in Very Early Intensive Mobilization received the least odds of favorable outcomes. At 3 month follow up, 53.5%, (n = 46) of patients with Early Intensive Mobilization showed a favorable outcome (modified Rankin Scale 0–2) (p = 0.041) as compared to 37.8% (n = 31) of patients in the Very Early Intensive Mobilization.Conclusions: Post-stroke rehabilitation with high intensity physical exercise at 48 h may be beneficial. Very Early Intensive Mobilization did not lead to a favorable outcome at 3 months.Clinical Trial Registration:www.chictr.org.cn, identifier ChiCTR-ICR-15005992.

Acute ischemic stroke (AIS) not only affects the brain but also has significant implications for peripheral organs through neuroendocrine regulation. This reciprocal relationship influences overall brain function and stroke prognosis. Recent research has highlighted the importance of poststroke liver changes in determining patient outcomes. In our previous study, we investigated the relationship between stroke and liver function. Our findings revealed that the prognostic impact of stress‑induced hyperglycemia in patients undergoing acute endovascular treatment for acute large vessel occlusion is closely related to their preexisting diabetes status. We found that the liver contributes to stress hyperglycemia after AIS by increasing hepatic gluconeogenesis and decreasing hepatic insulin sensitivity. These changes are detrimental to the brain, particularly in patients without diabetes. Furthermore, we examined the role of bilirubin, a byproduct of hepatic hemoglobin metabolism, in stroke pathophysiology. Our results demonstrated that blood bilirubin levels can serve as predictors of stroke severity and may hold therapeutic potential for reducing oxidative stress‑induced stroke injury in patients with mild stroke. These results underscore the potential role of the liver in the oxidative stress response following AIS, paving the way for further investigation into liver‑targeted therapeutic strategies to improve stroke prognosis and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (CSVD) is not only associated with an increased risk of intracranial hemorrhage (ICH) in patients on oral anticoagulation, but also associated with an increased risk of ischemic stroke. Limited data support the benefits of direct, non-Vitamin K antagonist oral anticoagulants (direct oral anticoagulants [DOACs]) in acute ischemic stroke (AIS) or transient ischemic attack (TIA) patients with nonvalvular atrial fibrillation (AF) and CSVD. We aimed to evaluate the effectiveness and safety of DOACs in AIS or TIA with AF and CSVD. Patients and Methods: We conducted a retrospective study with consecutive patients who experienced AIS or TIA with AF and CSVD from January 1, 2017 to December 31, 2019 in the Stroke Center at Beijing Luhe Hospital, Capital Medical University. Patients are followed for 12 months by outpatient visits or telephone interviews. The safety endpoint of this study was symptomatic ICH (sICH), while the efficacy endpoint was recurrent ischemic events (AIS or TIA). Patients in the DOACs group were compared with patients in the warfarin group using Chi-square tests or the continuity correction Chi-square tests. The safety and efficacy endpoint was progression-free survival assessed by the log-rank test. Results: A total of 542 patients were finally included in this study (353 in the DOACs group and 189 in the warfarin group). There were no significant differences in vascular risk factors, NIH Stroke Scale score at baseline, and CHA2DS2-VASc score between the two groups. There were no significant differences in recurrent events between the two groups (P = 0.68). Patients in the DOACs group showed lower risks of sICH (P = 0.03) and a shorter hospital stay (P = 0.03) compared to patients in the warfarin group followed over 12 months. Conclusion: DOACs were associated with lower risks of sICH and similar risks of the recurrent ischemic event as compared to the warfarin group with AF and CSVD. Patients in the DOACs group had shorter hospital stay when compared to patients in the warfarin group. DOACs may be a better option than warfarin for AIS or TIA patients with AF and CSVD for secondary prevention. [ABSTRACT FROM AUTHOR]