Stroke Therapy Research Articles

Potensi Citicoline sebagai Terapi Neuroproteksi dan Neuroregenerasi pada Stroke Iskemik Akut

Ischemic stroke, caused by a blockage in the brain’s blood vessels, is a critical emergency that requires immediate treatment. This study examined the efficacy of citicoline as an adjunct therapy to improve outcomes in acute ischemic stroke. A comprehensive search of four databases (Cochrane Library, ScienceDirect, PubMed, and Google Scholar) was conducted, identifying a total of 5265 articles. Three clinical trials were selected for critical appraisal. Agarwal demonstrated a larger reduction in stroke infarct volume in the citicoline group (4.22 cm3) compared to the placebo group (2.63 cm3) (p=0.483). On day 90, the citicoline group exhibited superior results in mRS scores of 0-2 (p=0.732), NIHSS scores of 0-2 (p=0.934), Barthel index ≥95 (p=0.564), and patient mortality (p=0.468). Seifaddini’s study revealed improved peak systolic velocity and mean arterial flow velocity in the cerebrovascular system. Enrico’s study showed improved mean short afferent latency inhibition in the cholinergic circuits of the citicoline group (p=0.004). Citicoline proves effective as an adjuvant neuroprotective and neuroregenerative therapy for acute ischemic stroke.

RE-OPEN: Randomised trial of biosimilar TNK versus TPA during endovascular therapy for acute ischaemic stroke due to large vessel occlusions

RationaleRapid and timely treatment with intravenous thrombolysis and endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS) and large vessel occlusion (LVO) significantly improves patient outcomes. Bridging therapy is...

Recombinant Human Heavy Chain Ferritin Nanoparticles Serve as ROS Scavengers for the Treatment of Ischemic Stroke.

Ischemic stroke is a high-incidence disease that threatens human well-being. The potent neuroprotective effects render reactive oxygen species (ROS) scavengers potential agents for acute ischemic stroke therapy. Challenges such as inadequate permeability across the blood-brain barrier (BBB), limited half-life, and adverse effects hinder the widespread utilization of small molecule and inorganic ROS scavengers. Thus, there is an urgent demand for efficacious neuroprotective agents targeting ischemic stroke. Our study discovered the superoxide dismutase (SOD)-mimetic activity of recombinant human heavy chain ferritin (rHF) nanoparticles expressed from Escherichia coli (E. coli). Subsequent investigations delved into the ROS-scavenging proficiency of rHF within neural cells, its therapeutic efficacy against ischemic stroke, and the elucidation of its neuroprotective mechanisms. rHF protein nanoparticles were expressed in E. coli and purified via size-exclusion chromatography. The superoxide anion (•O2-) scavenging SOD-mimetic activity of rHF nanoparticles was measured using a SOD detection kit. The ROS scavenging ability and protection effects against oxidative damage of rHF nanoparticles were studied in H2O2-induced PC12 cells. Therapeutic effects and neuroprotective mechanisms of rHF against ischemic stroke were investigated with transient middle cerebral artery occlusion (MCAO) reperfusion mice model. rHF nanoparticles can eliminate excessive ROS in nerve cells and alleviate oxidative damage. The results of animal experiments demonstrated that rHF nanoparticles passed across BBB, reduced infarct areas in brain tissue, and lowered the neurological deficit score of ischemia-reperfusion model mice. Additionally, rHF nanoparticles mitigated neuronal apoptosis and ferroptosis, suppressed microglial activation, maintained oxygen homeostasis, and exhibited negligible organ toxicity. rHF nanoparticle could be developed as a new ROS scavenger for nerve cells and has therapeutic potential as a drug for cerebral ischemia-reperfusion injury.

Cathodal bilateral transcranial direct-current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia-reperfusion injury.

Non-invasive transcranial direct-current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se-dependent signalling in rat cerebral ischaemia-reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct-current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen-glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R-insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R-insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality-control signalling, vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4), in OGD/R-insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS- and BtDCS-induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. KEY POINTS: Cathodal bilateral transcranial direct-current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra. Se plays a crucial role in cerebral ischaemia injury. Direct-current stimulation reduces mitochondria injury and blocks the reduction of vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4) in oxygen-glucose deprivation reoxygenation-insulted neurons following coculturing with astrocytes. Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia.

A One-Stone-Two-Birds Strategy of Targeting Microbubbles with "Dual" Anti-Inflammatory and Blood-Brain Barrier "Switch" Function for Ischemic Stroke Treatment.

Inflammation is considered to be the main target of the development of new stroke therapies. There are three key issues in the treatment of stroke inflammation: the first one is how to overcome the blood-brain barrier (BBB) to achieve drug delivery, the second one is how to select drugs to treat stroke inflammation, and the third one is how to achieve targeted drug delivery. In this study, we constructed hydrocortisone-phosphatidylserine microbubbles and combined them with ultrasound (US)-targeted microbubble destruction technology to successfully open the BBB to achieve targeted drug delivery. Phosphatidylserine on the microbubbles was used for its "eat me" effect to increase the targeting of the microvesicles. In addition, we found that hydrocortisone can accelerate the closure of the BBB, achieving efficient drug delivery while reducing the entry of peripheral toxins into the brain. In the treatment of stroke inflammation, it was found that hydrocortisone itself has anti-inflammatory effects and can also change the polarization of microglia from the harmful pro-inflammatory M1 phenotype to the beneficial anti-inflammatory M2 phenotype, thus achieving dual anti-inflammatory effects and enhancing the anti-inflammatory effects in ischemic areas after stroke, well reducing the cerebellar infarction volume by inhibiting the inflammatory response after cerebral ischemia. A confocal microendoscope was used to directly observe the polarization of microglial cells in living animal models for dynamic microscopic visualization detection showing the advantage of being closer to clinical work. Taken together, this study constructed a multifunctional targeted US contrast agent with the function of "one-stone-two-birds", which can not only "on-off" the BBB but also have "two" anti-inflammatory functions, providing a new strategy of integrated anti-inflammatory targeted delivery and imaging monitoring for ischemic stroke treatment.

Treatment Effects of Acetazolamide on Ischemic Stroke: A Meta-Analysis and Systematic Review

BackgroundIschemic stroke significantly contributes to high mortality and disability rates. Cerebral edema is a common consequence of ischemic stroke and can lead to aggravation or even death. Current treatment strategies are limited to decompressive craniectomy and the intravascular administration of hypertonic drugs, which have significant side effects. Acetazolamide (ACZ) plays a therapeutic role in cerebral edema by inhibiting aquaporin-4 (AQP-4) and improving collateral circulation. This study aimed to perform a meta-analysis and systematic review of ACZ therapy for ischemic stroke and evaluate its efficacy in animal models. MethodsWe searched Embase, Cochrane Library, PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Database, and Chinese Biomedical Literature Database until April 2023 for studies on ACZ in ischemic animal models. The quality of the animal trials was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Stroke. ResultsAfter screening 376 articles, only five studies were included. We found that ACZ reduced brain edema in cerebral ischemia 24 h after onset(SMD,-2.00 ;95% CI,-3.57 to -0.43 ,p=0.01). ACZ also inhibited AQP-4 expression 24 h after onset( SMD=-1.46,;95% CI, -2.01 to -0.91,p<0.001). Brain edema and AQP-4 expression also showed a declining trend on the third day after onset, although there were not enough data to support this. The effect of ACZ on brain ischemia in animals’ neurological function is uncertain because of the limited research data. ConclusionsACZ inhibited AQP-4 and alleviated brain edema after ischemic stroke in the early stages but seemingly couldn’t improve the neurological function.

Senescence and SASP Are Potential Therapeutic Targets for Ischemic Stroke.

Aging is a known co-morbidity of ischemic stroke with its risk and severity increasing every year past 55+. While many of the current stroke therapies have shown success in reducing mortality, post-stroke morbidity has not seen the same substantial reduction. Recently, the involvement of cellular senescence and SASP in brain injury and neurological degeneration has been recognized. Ischemic injury causes oxidative stress and mitochondrial damage that induces senescence through the activation of p21 and p16 pathways, ultimately leading to synthesis and release of senescence-associated secretory phenotype (SASP). This ischemic event causes stress-induced premature senescence (SIPS), aging the brain decades beyond the standard biological age due to an increase in senescent cells in the ischemic core and ipsilateral hemisphere. Therefore, therapies that target the senescent cells and SASP, including senolytics, senomorphic drugs, stem cell therapies, and other cell-specific interventions, may be a new path for stroke treatment.

Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury

Homoeostatic regulation of the acid–base balance is essential for cellular functional integrity. However, little is known about the molecular mechanism through which the acid–base balance regulates cellular responses. Here, we report that bicarbonate ions activate a G protein-coupled receptor (GPCR), i.e., GPR30, which leads to Gq-coupled calcium responses. Gpr30-Venus knock-in mice reveal predominant expression of GPR30 in brain mural cells. Primary culture and fresh isolation of brain mural cells demonstrate bicarbonate-induced, GPR30-dependent calcium responses. GPR30-deficient male mice are protected against ischemia-reperfusion injury by a rapid blood flow recovery. Collectively, we identify a bicarbonate-sensing GPCR in brain mural cells that regulates blood flow and ischemia–reperfusion injury. Our results provide a perspective on the modulation of GPR30 signalling in the development of innovative therapies for ischaemic stroke. Moreover, our findings provide perspectives on acid/base sensing GPCRs, concomitantly modulating cellular responses depending on fluctuating ion concentrations under the acid–base homoeostasis.

The Relevance of Reperfusion Stroke Therapy for miR-9-3p and miR-9-5p Expression in Acute Stroke-A Preliminary Study.

Reperfusion stroke therapy is a modern treatment that involves thrombolysis and the mechanical removal of thrombus from the extracranial and/or cerebral arteries, thereby increasing penumbra reperfusion. After reperfusion therapy, 46% of patients are able to live independently 3 months after stroke onset. MicroRNAs (miRNAs) are essential regulators in the development of cerebral ischemia/reperfusion injury and the efficacy of the applied treatment. The first aim of this study was to examine the change in serum miRNA levels via next-generation sequencing (NGS) 10 days after the onset of acute stroke and reperfusion treatment. Next, the predictive values of the bioinformatics analysis of miRNA gene targets for the assessment of brain ischemic response to reperfusion treatment were explored. Human serum samples were collected from patients on days 1 and 10 after stroke onset and reperfusion treatment. The samples were subjected to NGS and then validated using qRT-PCR. Differentially expressed miRNAs (DEmiRNAs) were used for enrichment analysis. Hsa-miR-9-3p and hsa-miR-9-5p expression were downregulated on day 10 compared to reperfusion treatment on day 1 after stroke. The functional analysis of miRNA target genes revealed a strong association between the identified miRNA and stroke-related biological processes related to neuroregeneration signaling pathways. Hsa-miR-9-3p and hsa-miR-9-5p are potential candidates for the further exploration of reperfusion treatment efficacy in stroke patients.

Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress.

Stroke is a major contributor to global mortality and disability. While reperfusion is essential for preventing neuronal death in the penumbra, it also triggers cerebral ischemia-reperfusion injury, a paradoxical injury primarily caused by oxidative stress, inflammation, and blood-brain barrier disruption. An oxidative burst inflicts marked cellular damage, ranging from alterations in mitochondrial function to lipid peroxidation and the activation of intricate signalling pathways that can even lead to cell death. Thus, given the pivotal role of oxidative stress in the mechanisms of cerebral ischemia-reperfusion injury, the reinforcement of the antioxidant defence system has been proposed as a protective approach. Although this strategy has proven to be successful in experimental models, its translation into clinical practice has yielded inconsistent results. However, it should be considered that the availability of numerous antioxidant molecules with a wide range of chemical properties can affect the extent of injury; several groups of antioxidant molecules, including polyphenols, carotenoids, and vitamins, among other antioxidant compounds, can mitigate this damage by intervening in multiple signalling pathways at various stages. Multiple clinical trials have previously been conducted to evaluate these properties using melatonin, acetyl-L-carnitine, chrysanthemum extract, edaravone dexborneol, saffron, coenzyme Q10, and oleoylethanolamide, among other treatments. Therefore, multi-antioxidant therapy emerges as a promising novel therapeutic option due to the potential synergistic effect provided by the simultaneous roles of the individual compounds.

Blood-Brain Barrier-Penetrating and Lesion-Targeting Nanoplatforms Inspired by the Pathophysiological Features for Synergistic Ischemic Stroke Therapy.

Ischemic stroke is a dreadful vascular disorder that poses enormous threats to the public health. Due to its complicated pathophysiological features, current treatment options after ischemic stroke attack remains unsatisfactory. Insufficient drug delivery to ischemic lesions impeded by the blood-brain barrier (BBB) largely limits the therapeutic efficacy of most anti-stroke agents. Herein, inspired by the rapid BBB penetrability of 4T1 tumor cells upon their brain metastasis and natural roles of platelet in targeting injured vasculatures, a bio-derived nanojacket is developed by fusing 4T1 tumor cell membrane with platelet membrane, which further clothes on the surface of paeonol and polymetformin-loaded liposome to obtain biomimetic nanoplatforms (PP@PCL) for ischemic stroke treatment. The designed PP@PCL could remarkably alleviate ischemia-reperfusion injury by efficiently targeting ischemic lesion, preventing neuroinflammation, scavenging excess reactive oxygen species (ROS), reprogramming microglia phenotypes, and promoting angiogenesis due to the synergistic therapeutic mechanisms that anchor the pathophysiological characteristics of ischemic stroke. As a result, PP@PCL exerts desirable therapeutic efficacy in injured PC12 neuronal cells and rat model of ischemic stroke, which significantly attenuates neuronal apoptosis, reduces infarct volume, and recovers neurological functions, bringing new insights into exploiting promising treatment strategies for cerebral ischemic stroke management.

New Perspectives in Neuroprotection for Ischemic Stroke

The constant failure of new neuroprotective therapies for ischemic stroke has partially halted the search for new therapies in recent years, mainly because of the high investment risk required to develop a new treatment for a complex pathology, such as stroke, with a narrow intervention window and associated comorbidities. However, owing to recent progress in understanding the stroke pathophysiology, improvement in patient care in stroke units, development of new imaging techniques, search for new biomarkers for early diagnosis, and increasingly widespread use of mechanical recanalization therapies, new opportunities have opened for the study of neuroprotection. This review summarizes the main protective agents currently in use, some of which are already in the clinical evaluation phase. It also includes an analysis of how recanalization therapies, new imaging techniques, and biomarkers have improved their efficacy.

Mechanisms by Which Electroacupuncture Alleviates Neurovascular Unit Injury after Ischemic Stroke: A Potential Therapeutic Strategy for Ischemic Brain Injury after Stroke.

Stroke is the most common cerebrovascular disease and one of the leading causes of death and disability worldwide. The current conventional treatment for stroke involves increasing cerebral blood flow and reducing neuronal damage; however, there are no particularly effective therapeutic strategies for rehabilitation after neuronal damage. Therefore, there is an urgent need to identify a novel alternative therapy for stroke. Acupuncture has been applied in China for 3000 years and has been widely utilized in the treatment of cerebrovascular diseases. Accumulating evidence has revealed that acupuncture holds promise as a potential therapeutic strategy for stroke. In our present review, we focused on elucidating the possible mechanisms of acupuncture in the treatment of ischemic stroke, including nerve regeneration after brain injury, inhibition of inflammation, increased cerebral blood flow, and subsequent rehabilitation.

The correlation between CT perfusion deficits and immediate post-endovascular treatment contrast extravasation on dual energy CT in acute ischemic stroke patients

PurposeAfter endovascular therapy (EVT) for ischemic stroke, post-EVT CT imaging often shows areas of contrast extravasation (CE) caused by blood brain barrier disruption (BBBD). Before EVT, CT-perfusion (CTP) can be used to estimate salvageable tissue (penumbra) and irrevocably damaged infarction (core). In this study, we aimed to correlate CTP deficits to CE, as a surrogate marker for BBBD, after EVT for ischemic stroke. MethodsIn this single center study, EVT patients between 2010 and 2020 in whom both CTP at baseline and DECT post-EVT was performed were included. The presence of core and penumbra on CTP was assessed per ASPECTS region, resulting in a CTP-ASPECTScore and a CTP-ASPECTScore+penumbra. Likewise, CE on DECT was scored per ASPECTS region, resulting in a CE-ASPECTS. Correlation was assessed using Kendall’s tau correlation and positive predictive values (PPV) were calculated per ASPECTS region. Bland-Altman plots were created to visualize the agreement between the two scores. Results194 patients met our inclusion criteria. The median core and penumbra were 8 cc (IQR 1–25) and 103 cc (IQR 68–141), respectively. The median CTP-ASPECTScore, CTP-ASPECTScore+penumbra, and CE-ASPECTS were 7 (IQR 4–9), 3 (IQR 1–4), and 6 (IQR 4–9), respectively. The correlation between CTP-ASPECTScore and CE-ASPECTS was τ = 0.21, P <.001, and τ = 0.13, P =.02 between CTP-ASPECTScore+penumbra and CE-ASPECTS. Bland-Altman plots showed a mean difference (CTP-ASPECTS minus CE-ASPECTS) of 0.27 (95 %CI −6.7–7.2) for CTP-ASPECTScore and −3.2 (95 %CI −9.7–3.2) for CTP-ASPECTScore+penumbra. The PPVs of the CTP-ASPECTScore and CTP-ASPECTScore+penumbra were highest for the basal ganglia. ConclusionThere is a weak although significant correlation between pre-EVT CTP-ASPECTS and post-EVT CE-ASPECTS. The weak correlation may be attributed to various imaging limitations as well as patient related factors.

Type of anesthesia for endovascular therapy in acute ischemic stroke: A literature review and meta-analysis.

Endovascular thrombectomy (EVT) has been proven as the standard treatment for acute ischemic stroke (AIS) patients due to large vessel occlusion (LVO). However, the ideal anesthetic strategy during EVT still remains unclear. Therefore, this systematic review and meta-analysis aimed to determine the optimal anesthetic modality for patients with AIS undergoing EVT based on current randomized controlled trials (RCTs). The databases Medline (via PubMed), EMBASE, Web of Science, and the Cochrane Library were searched for RCTs comparing general anesthesia (GA) and conscious sedation (CS) in AIS patients undergoing EVT. The primary outcome was a favorable functional outcome at 90 days postintervention. Data analysis was conducted using the Review Manager software (RevMan V.5.3). Eight RCTs involving 1199 patients were included. There was no significant difference between GA and CS group in the rate of functional independence (risk ratio (RR) = 1.10, 95% confidence interval (CI) = 0.96 to 1.25; p = 0.17; I2 = 30%). Compared with the CS group, the GA group attained a higher successful recanalization rate (RR = 1.14, 95% CI = 1.08 to 1.20; p < 0.00001; I2 = 17%). In addition, patients in the GA were associated with a higher rate of hypotension (RR = 1.87, 95% CI = 1.44 to 2.41; p < 0.00001; I2 = 66%) and a higher incidence of pneumonia (RR = 1.38, 95% CI = 1.05 to 1.8; p = 0.02; I2 = 37%). For AIS patients receiving EVT, the choice of anesthetic modality did not influence the 3-month neurological outcome while GA is superior to CS in terms of successful reperfusion rate. Moreover, the patients in the GA group were at a higher risk of developing hypotension and pneumonia. Further studies are required to provide more sufficient evidence.

Haplotype-phased genome unveils the butylphthalide biosynthesis and homoploid hybrid origin of Ligusticum chuanxiong.

Butylphthalide is one of the first-line drugs for ischemic stroke therapy, while no biosynthetic enzyme for butylphthalide has been reported. Here, we present a haplotype-resolved genome of Ligusticum chuanxiong, a long-cultivated and phthalide-rich medicinal plant in Apiaceae. On the basis of comprehensive screening, four Fe(II)- and 2-oxoglutarate-dependent dioxygenases and two CYPs were mined and further biochemically verified as phthalide C-4/C-5 desaturases (P4,5Ds) that effectively promoted the forming of (S)-3-n-butylphthalide and butylidenephthalide. The substrate promiscuity and functional redundancy featured for P4,5Ds may contribute to the high phthalide diversity in L. chuanxiong. Notably, comparative genomic evidence supported L. chuanxiong as a homoploid hybrid with Ligusticum sinense as a potential parent. The two haplotypes demonstrated exceptional structure variance and diverged around 3.42 million years ago. Our study is an icebreaker for the dissection of phthalide biosynthetic pathway and reveals the hybrid origin of L. chuanxiong, which will facilitate the metabolic engineering for (S)-3-n-butylphthalide production and breeding for L. chuanxiong.

Lipid-Lowering Therapy and Risk of Hemorrhagic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

There is debate over whether statins increase risk of hemorrhagic stroke, so we assessed current evidence, including data from new statin trials and trials of nonstatin low-density lipoprotein-cholesterol (LDL-C)-and triglyceride-lowering therapies. We performed a systematic review of large randomized clinical trials (≥1000 patients with ≥2 years follow-up) of LDL-C-lowering therapy (statin, ezetimibe, and PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitor) and triglyceride-lowering therapy (omega-3 supplements and fibrate) that reported hemorrhagic stroke as an outcome. We searched MEDLINE, Embase, and Cochrane Library up to July 2, 2021 and updated a meta-analysis of cardiovascular statin trials published in 2012. Among our several subgroup analyses, we looked at difference depending on stroke status and also depending on age. We identified 37 trials for LDL-C lowering (284 301 participants) and 11 for triglyceride lowering (120 984 participants). Overall, we found a higher risk of hemorrhagic stroke for LDL-C lowering, risk ratio (RR) 1.16 (95% CI, 1.01-1.32, P=0.03). For statins (33 trials, 216 258 participants), RR=1.17 (95% CI, 1.01-1.36); for PCSK-9 inhibitors (2 trials, 46 488 participants), RR=0.86 (95% CI, 0.43-1.74); and for ezetimibe (2 trials, 21 555 participants), RR=1.14 (95% CI, 0.64-2.03). In statin trials of patients with previous stroke/transient ischemic attack, RR was 1.46 (95% CI, 1.05-2.04), and in trials with mean age ≥65 years old, RR=1.34 (95% CI, 1.04-1.73) (Pint=0.14 and Pint=0.23 respectively); for triglyceride lowering (11 trials, 120 984 participants), RR=1.05 (95% CI, 0.86-1.30). We found evidence for a small increased risk of hemorrhagic stroke events with LDL-C-lowering therapies but no clear evidence for triglyceride-lowering therapies. URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021275363.

Efficacy and safety of hyperbaric oxygen therapy in acute ischaemic stroke: a systematic review and meta-analysis

ObjectiveThis study aims to evaluate the efficacy and safety of adjunctive hyperbaric oxygen therapy (HBOT) in acute ischaemic stroke (AIS) based on existing evidence.MethodsWe conducted a comprehensive search through April 15, 2023, of seven major databases for randomized controlled trials (RCTs) comparing adjunctive hyperbaric HBOT with non-HBOT (no HBOT or sham HBOT) treatments for AIS. Data extraction and assessment were independently performed by two researchers. The quality of included studies was evaluated using the tool provided by the Cochrane Collaboration. Meta-analysis was conducted using Rev Man 5.3.ResultsA total of 8 studies involving 493 patients were included. The meta-analysis showed no statistically significant differences between HBOT and the control group in terms of NIHSS score (MD = -1.41, 95%CI = -7.41 to 4.58), Barthel index (MD = 8.85, 95%CI = -5.84 to 23.54), TNF-α (MD = -5.78, 95%CI = -19.93 to 8.36), sICAM (MD = -308.47, 95%CI = -844.13 to 13227.19), sVCAM (MD = -122.84, 95%CI = -728.26 to 482.58), sE-selectin (MD = 0.11, 95%CI = -21.86 to 22.08), CRP (MD = -5.76, 95%CI = -15.02 to 3.51), adverse event incidence within ≤ 6 months of follow-up (OR = 0.98, 95%CI = 0.25 to 3.79). However, HBOT showed significant improvement in modified Rankin score (MD = 0.10, 95%CI = 0.03 to 0.17), and adverse event incidence at the end of treatment (OR = 0.42, 95%CI = 0.19 to 0.94) compared to the control group.ConclusionWhile our findings do not support the routine use of HBOT for improving clinical outcomes in AIS, further research is needed to explore its potential efficacy within specific therapeutic windows and for different cerebral occlusion scenarios. Therefore, the possibility of HBOT offering clinical benefits for AIS cannot be entirely ruled out.

METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke

BackgroundStroke is a major medical problem, and novel therapeutic targets are urgently needed. This study investigates the protective role and potential mechanisms of the N6-methyladenosine (m6A) RNA methyltransferase METTL3 against cerebral injury resulting from insufficient cerebral blood flow.MethodsIn this study, we constructed mouse MCAO models and HT-22 cell OGD/R models to mimic ischemic stroke-induced brain injury and neuronal damage. We generated NEDD4L knockout and METTL3 overexpression models and validated therapeutic effects using infarct volume, brain edema, and neurologic scoring. We performed qRT-PCR, western blotting, and co-immunoprecipitation to assess the influence of NEDD4L on ferroptosis markers and TFRC expression. We verified the effect of NEDD4L on TFRC ubiquitination by detecting half-life and ubiquitination. Finally, we validated the impact of METTL3 on NEDD4L mRNA stability and MCAO outcomes in both in vitro and in vivo experimental models.ResultWe find NEDD4L expression is downregulated in MCAO models. Overexpressing METTL3 inhibits the iron carrier protein TFRC by upregulating the E3 ubiquitin ligase NEDD4L, thereby alleviating oxidative damage and ferroptosis to protect the brain from ischemic injury. Mechanistic studies show METTL3 can methylate and stabilize NEDD4L mRNA, enhancing NEDD4L expression. As a downstream effector, NEDD4L ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis.ConclusionIn summary, we uncover the METTL3-NEDD4L-TFRC axis is critical for inhibiting post-ischemic brain injury. Enhancing this pathway may serve as an effective strategy for stroke therapy. This study lays the theoretical foundation for developing m6A-related therapies against ischemic brain damage.

Abstract 84: Efficacy of Endovascular Therapy in Acute Ischemic Stroke by Alberta Stroke Program Early Computed Tomography Score and National Institutes of Health Stroke Scale-A Secondary Analysis of a Randomized Controlled Trial

Introduction and Aims: The ANGEL-ASPECT trial demonstrated the effectiveness of endovascular therapy (EVT) in acute ischemic stroke (AIS) patients with large infarct. We did a secondary analysis to explore the efficacy of EVT according to Alberta Stroke Program Early Computed Tomography Score (ASPECT) and National Institutes of Health Stroke Scale (NIHSS). Methods: ANGEL-ASPECT trial was a randomized clinical trial involving patients with acute anterior-circulation large-vessel occlusion and an ASPECT score of 3-5 or an infarct-core volume of 70-100ml. Patients were randomly assigned to EVT or standard medical treatment (SMT) alone. We categorized patients based on the combination of ASPECT (≤3 or 4-5) and NIHSS (&lt;20 or ≥20) into four groups: low ASPECT &amp; low NIHSS; low ASPECT &amp; high NIHSS; high ASPECT &amp; low NIHSS and high ASPECT &amp; high NIHSS. We assessed the efficacy of EVT using ordinal shift analysis of 90-day modified Rankin Scale (mRS). Results: Among 455 patients, the prevalence of the four groups were 190 (41.8%), 70 (15.4%), 157 (34.5%) and 38 (8.4%), respectively. A significant shift in the distribution of 90-days mRS toward better outcomes in favor of EVT was observed in patients with low ASPECT &amp; low NIHSS (common OR [cOR], 2.25; 95% CI, 1.34-3.76; P=0.002), and high ASPECT &amp; low NIHSS (cOR, 2.30; 95% CI, 1.31-4.05; P=0.004), but not in other two groups with high NIHSS (all P &gt;0.05). Conclusions: EVT was associated with better outcomes in AIS patients with large infarct and mild-to-moderate stroke severity (NIHSS &lt;20), but not in those with severe stroke severity (NIHSS ≥20). Stroke severity should be considered when planning EVT for AIS patients with large infarcts.