Treatment Of Cerebral Ischemia Research Articles

Schisandrin B Protects against Ischemic Brain Damage by Regulating PI3K/AKT Signaling in Rats.

To explore the effect and mechanism of schisandrin B (Sch B) in the treatment of cerebral ischemia in rats. The cerebral ischemia models were induced by middle cerebral artery occlusion (MCAO) and reperfusion. Sprague-Dawley rats were divided into 6 groups using a random number table, including sham, MCAO, MCAO+Sch B (50 mg/kg), MCAO+Sch B (100 mg/kg), MCAO+Sch B (100 mg/kg)+LY294002, and MCAO+Sch B (100 mg/kg)+wortmannin groups. The effects of Sch B on pathological indicators, including neurological deficit scores, cerebral infarct volume, and brain edema, were subsequently studied. Tissue apoptosis was identified by terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining. The protein expressions involved in apoptosis, inflammation response and oxidative stress were examined by immunofluorescent staining, biochemical analysis and Western blot analysis, respectively. The effect of Sch B on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling was also explored. Sch B treatment decreased neurological deficit scores, cerebral water content, and infarct volume in MCAO rats (P<0.05 or P<0.01). Neuronal nuclei and TUNEL staining indicated that Sch B also reduced apoptosis in brain tissues, as well as the Bax/Bcl-2 ratio and caspase-3 expression (P<0.01). Sch B regulated the production of myeloperoxidase, malondialdehyde, nitric oxide and superoxide dismutase, as well as the release of cytokine interleukin (IL)-1 β and IL-18, in MCAO rats (P<0.05 or P<0.01). Sch B promoted the phosphorylation of PI3K and AKT. Blocking the PI3K/AKT signaling pathway with LY294002 or wortmannin reduced the protective effect of Sch B against cerebral ischemia (P<0.05 or P<0.01). Sch B reduced apoptosis, inflammatory response, and oxidative stress of MCAO rats by modulating the PI3K/AKT pathway. Sch B had a potential for treating cerebral ischemia.

Phenylboronic Ester-Bridged Chitosan/Myricetin Nanomicelle for Penetrating the Endothelial Barrier and Regulating Macrophage Polarization and Inflammation against Ischemic Diseases.

The brain and liver are more susceptible to ischemia and reperfusion (IR) injury (IRI), which triggers the reactive oxygen species (ROS) burst and inflammatory cascade and results in severe neuronal damage or hepatic injury. Moreover, the damaged endothelial barrier contributes to proinflammatory activity and limits the delivery of therapeutic agents such as some macromolecules and nanomedicine despite the integrity being disrupted after IRI. Herein, we constructed a phenylboronic-decorated chitosan-based nanoplatform to deliver myricetin, a multifunctional polyphenol molecule for the treatment of cerebral and hepatic ischemia. The chitosan-based nanostructures are widely studied cationic carriers for endothelium penetration such as the blood-brain barrier (BBB) and sinusoidal endothelial barrier (SEB). The phenylboronic ester was chosen as the ROS-responsive bridging segment for conjugation and selective release of myricetin molecules, which meanwhile scavenged the overexpressed ROS in the inflammatory environment. The released myricetin molecules fulfill a variety of roles including antioxidation through multiple phenolic hydroxyl groups, inhibition of the inflammatory cascade by regulation of the macrophage polarization from M1 to M2, and endothelial injury repairment. Taken together, our present study provides valuable insight into the development of efficient antioxidant and anti-inflammatory platforms for potential application against ischemic disease.

The neuroprotective role of prolonged normobaric oxygenation applied during ischemia and in the early stage of reperfusion in cerebral ischemic rats

BackgroundRecanalization is the main treatment option for ischemic stroke. However, prognosis remains poor for about half of patients after recanalization, possibly due to the “no-reflow” phenomenon at the early phase of recanalization. Normobaric oxygenation (NBO) during ischemia can reportedly maintain the partial pressure of oxygen and exert a protective effect in ischemic brain tissue. Objectives and methodsThis study investigated whether prolonged NBO treatment during ischemia and the early phase of reperfusion (i/rNBO) has neuroprotective effects and to elucidate the underlying mechanisms in rats with middle cerebral artery occlusion plus reperfusion. ResultsNBO treatment significantly elevated the level of O2 in the atmosphere and arterial blood without altering the level of CO2. The infarcted cerebral volume was significantly reduced by application of i/rNBO as compared to iNBO (applied during ischemia) or rNBO (applied at the early phase of reperfusion), indicating better protective effects of i/rNBO. i/rNBO more effectively suppressed s-nitrosylation of MMP-2 (amplifying inflammation) as compared to iNBO and rNBO, dramatically downregulated the cleavage of poly(ADP-ribose)polymerase-1 (PARP-1, acting as the substrate of MMP-2), and suppressed neuronal apoptosis, as determined by the TUNEL assay and staining for NeuN. These results demonstrated that application of i/rNBO in the early stage of reperfusion significantly alleviated neuronal apoptosis via suppression of the MMP-2/PARP-1 pathway. ConclusionsThe mechanism underlying the neuroprotective role of i/rNBO involved prolonged NBO treatment for cerebral ischemia, suggesting that i/rNBO may allow expansion of the time window for NBO application in stroke patients following vascular recanalization.

Radiation Exposure in Interventional Stroke Treatment

PurposeTo evaluate patient-related radiation exposure in interventional stroke treatment by analyzing data from the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) and the German Society of Neuroradiology (DGNR) quality registry from 2019–2021.MethodsThe DeGIR/DGNR registry is the largest database of radiological interventions in Germany. Since the introduction of the registry in 2012, the participating hospitals have entered clinical and dose-related data on the procedures performed. To evaluate the current diagnostic reference level (DRL) for mechanical thrombectomy (MT) in stroke patients, we analyzed interventional data from 2019 to 2021 with respect to the reported dose area product (DAP) and factors that might contribute to the radiation dose, such as the localization of the occlusion, technical success using the modified treatment in cerebral ischemia (mTICI) score, number of passages, technical approach, additional intracranial/extracranial stenting, and case volume per center.ResultsA total of 41,538 performed MTs from 180 participating hospitals were analyzed. The median DAP for MT was 7337.5 cGy∙cm2 and the corresponding interquartile range (IQR) Q25 = 4064 cGy∙cm2 to Q75 = 12,263 cGy∙cm2. In addition, we discovered that the dose was significantly influenced by occlusion location, number of passages, case volume per center, recanalization score, and additional stenting.ConclusionWe conducted a retrospective study on radiation exposure during MT in Germany. Based on the results of more than 41,000 procedures, we observed that the DRL of 14,000 cGy·cm2 is currently appropriate but may be lowered over the next years. Furthermore, we identified several factors that contribute to high radiation exposure. This can aid in detecting the cause of an exceeded DRL and optimize the treatment workflow.

Optimal extra-anatomical reconstructions of the carotid and vertebrobasilar basins (case reports)

The paper considers a case of surgical treatment of a patient with a completed stroke in the brain stem in anamnesis and with a clinical picture of chronic vertebrobasilar insufficiency caused by combined occlusion of the right vertebral artery (VA), hypoplasia of the left VA, and pathological tortuosity of the right internal carotid artery (ICA). The patient underwent extra-anatomical reconstructive surgery: simultaneous lowering of the loop of the right ICA and its resection in the middle third with redressement and reimplantation in the proximal third of the ICA with the formation of the ICA-ICA end-to-side anastomosis and the subsequent creation of an end-to-side anastomosis between the free end of the resected ICA and the V3 segment of the right VA. In addition, a case of surgical treatment of isolated bifurcation of the common carotid artery (CCA) that occurs when the proximal CCA is occluded and the blood flow is maintained in the external carotid artery (ECA) and ICA is considered. These reconstructive surgical interventions for combined lesions of the main arteries of the head are safe and reliable methods for the treatment of chronic cerebral ischemia and effective prevention of recurrent ischemic strokes.

Astrocytic TRPV4 Channels and Their Role in Brain Ischemia

Transient receptor potential cation channels subfamily V member 4 (TRPV4) are non-selective cation channels expressed in different cell types of the central nervous system. These channels can be activated by diverse physical and chemical stimuli, including heat and mechanical stress. In astrocytes, they are involved in the modulation of neuronal excitability, control of blood flow, and brain edema formation. All these processes are significantly impaired in cerebral ischemia due to insufficient blood supply to the tissue, resulting in energy depletion, ionic disbalance, and excitotoxicity. The polymodal cation channel TRPV4, which mediates Ca2+ influx into the cell because of activation by various stimuli, is one of the potential therapeutic targets in the treatment of cerebral ischemia. However, its expression and function vary significantly between brain cell types, and therefore, the effect of its modulation in healthy tissue and pathology needs to be carefully studied and evaluated. In this review, we provide a summary of available information on TRPV4 channels and their expression in healthy and injured neural cells, with a particular focus on their role in ischemic brain injury.

Microbiota-derived short-chain fatty acids mediate the effects of dengzhan shengmai in ameliorating cerebral ischemia via the gut-brain axis.

Dengzhan shengmai (DZSM) formula, composed of four herbal medicines (Erigeron breviscapus, Panax ginseng, Schisandra chinensis, and Ophiopogon japonicus), is widely used in the recovery period of ischemic cerebrovascular diseases; however, the associated molecular mechanism remains unclear. The purpose of this study was to uncover the links between the microbiota-gut-brain axis and the efficacy of DZSM in ameliorating cerebral ischemic diseases. The effects of DZSM on the gut microbiota community and bacteria-derived short-chain fatty acid (SCFA) production were evaluated in vivo using a rat model of cerebral ischemia and in vitro through the anaerobic incubation with fresh feces derived from model animals. Subsequently, the mechanism underlying the role of SCFAs in the DZSM-mediated treatment of cerebral ischemia was explored. We found that DZSM treatment significantly altered the composition of the gut microbiota and markedly enhanced SCFA production. The consequent increase in SCFA levels led to the upregulation of the expression of monocarboxylate transporters and facilitated the transportation of intestinal SCFAs into the brain, thereby inhibiting the apoptosis of neurocytes via the regulation of the PI3K/AKT/caspase-3 pathway. The increased intestinal SCFA levels also contributed to the repair of the 2VO-induced disruption of gut barrier integrity and inhibited the translocation of lipopolysaccharide from the intestine to the brain, thus attenuating neuroinflammation. Consequently, cerebral neuropathy and oxidative stress were significantly improved in 2VO model rats, leading to the amelioration of cerebral ischemia-induced cognitive dysfunction. Finally, fecal microbiota transplantation could reproduce the beneficial effects of DZSM on SCFA production and cerebral ischemia. Our findings suggested that SCFAs mediate the effects of DZSM in ameliorating cerebral ischemia via the gut microbiota-gut-brain axis.

Rescue thrombolysis for medium vessel occlusion (RESCUE-TNK): Rationale and design of a phase 2 randomized trial.

The best reperfusion strategy for medium-sized vessel occlusion (MeVO) is not well established. Given the proven treatment effect of intra-arterial thrombolysis in patients with large vessel occlusion (LVO), we hypothesized that intra-arterial tenecteplase (TNK) could increase the recanalization rate of MeVO and thus improve clinical outcome. To explore the safety and efficacy of intra-arterial TNK in patients with MeVO. A maximum of 80 patients are required to test the superiority hypothesis, using power = 80% and α = 0.025 to conduct the one-sided test. Rescue treatment for mEdium veSsel oCclUsion by intra-artErial TNK (RESCUE-TNK) is a pilot, randomized, open-label, blinded end point, and multicenter trial. Eligible patients including primary MeVO as detected by the first DSA examination or secondary MeVO after endovascular treatment (EVT) for LVO will be assigned into the experimental group and control group as a ratio of 1:1. The experimental group will be treated with intra-arterial TNK (0.2-0.3 mg/min, for 20-30 min) via a microcatheter placed proximal to the site of occlusion, and the control group will be treated with routine therapy. Both groups of patients will be given standard stroke care based on the guidelines. The primary efficacy end point is successful recanalization of MeVO, defined as the expanded treatment in cerebral ischemia (eTICI) score 2b67-3 after the procedure, while the primary safety end point is symptomatic intracranial hemorrhage (sICH), defined as National Institutes of Health Stroke Scale score increase ≥4 caused by intracranial hemorrhage within 24 (-6/+24) hours after randomization. The results of RESCUE-TNK will provide evidence for the efficacy and safety of intra-arterial TNK in the recanalization of patients with MeVO.

The Frequency of CYP2C19 Loss-of-Function Variants in Patients with Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack in the Dutch Population

Introduction: The CYP2C19 enzyme converts clopidogrel into an active metabolite. Carriers of CYP2C19 loss-of-function (LOF) variants with a history of ischemic stroke or transient ischemic attack (TIA) using clopidogrel may have a higher risk of recurrent stroke. To study the implications of genetic CYP2C19 heterogeneity in treatment of cerebral ischemia, knowledge about the prevalence of CYP2C19 LOF variants within the population is important. We investigated the frequency of CYP2C19 LOF variants in patients with non-cardioembolic ischemic stroke or TIA in the Dutch population. Methods: We performed a single-center observational study with a cross-sectional design in a Dutch thrombectomy-capable stroke center. We included all patients presenting with non-cardioembolic ischemic stroke or TIA. We determined the frequency of CYP2C19 LOF variants in the full cohort. Additionally, we compared the frequency of CYP2C19 LOF variants in two subgroups: patients with first-ever non-cardioembolic ischemic stroke or TIA versus patients with recurrent ischemic stroke or TIA using clopidogrel because of a history of ischemic stroke or TIA. Results: We enrolled 410 patients between January 1, 2021, and July 1, 2021. 109 (26.6%) patients were carriers of CYP2C19 LOF variants. We found no difference in the frequency of CYP2C19 LOF variants between patients with first-ever ischemic stroke or TIA versus patients with recurrent ischemic stroke or TIA using clopidogrel (25.9 vs. 31.9%, respectively, p = 0.31). Discussion and Conclusion: About a quarter of patients with non-cardioembolic ischemic stroke or TIA in the Dutch population carry a CYP2C19 LOF variant. This is lower than estimates found in studies with Asian populations but similar to estimates found among Caucasian patients in other parts of the world.

Anti-apoptosis effect of traditional Chinese medicine in the treatment of cerebral ischemia-reperfusion injury.

Cerebral ischemia, one of the leading causes of neurological dysfunction of brain cells, muscle dysfunction, and death, brings great harm and challenges to individual health, families, and society. Blood flow disruption causes decreased glucose and oxygen, insufficient to maintain normal brain tissue metabolism, resulting in intracellular calcium overload, oxidative stress, neurotoxicity of excitatory amino acids, and inflammation, ultimately leading to neuronal cell necrosis, apoptosis, or neurological abnormalities. This paper summarizes the specific mechanism of cell injury that apoptosis triggered by reperfusion after cerebral ischemia, the related proteins involved in apoptosis, and the experimental progress of herbal medicine treatment through searching, analyzing, and summarizing the PubMed and Web Of Science databases, which includes active ingredients of herbal medicine, prescriptions, Chinese patent medicines, and herbal extracts, providing a new target or new strategy for drug treatment, and providing a reference for future experimental directions and using them to develop suitable small molecule drugs for clinical application. With the research of anti-apoptosis as the core, it is important to find highly effective, low toxicity, safe and cheap compounds from natural plants and animals with abundant resources to prevent and treat Cerebral ischemia/reperfusion (I/R) injury (CIR) and solve human suffering. In addition, understanding and summarizing the apoptotic mechanism of cerebral ischemia-reperfusion injury, the microscopic mechanism of CIR treatment, and the cellular pathways involved will help to develop new drugs.

Abstract Number ‐ 25: Acute Ischemic Stroke Intervention With Penumbra RED Reperfusion Catheters: Updated Subset Analysis From INSIGHT Registry

Introduction The prospective INSIGHT Registry is a multicenter ‘multi‐omic’ analysis of thrombi associated with acute hemorrhagic or ischemic stroke. This updated interim analysis evaluated the performance of Penumbra RED catheters used during aspiration thrombectomy for acute ischemic stroke (AIS). Methods All AIS cases in which Penumbra RED aspiration catheters (RED 62, 68, or 72) were utilized as a frontline treatment were included in the analysis. Retrieved clot fragments were classified based on their gross appearance. Key time metrics and procedural data were also collected, including first‐pass / post‐procedure modified Treatment in Cerebral Ischemia (mTICI) score. Results Of 400 patients enrolled across 25 US centers, 161 underwent thrombectomy with Penumbra RED catheters over ten months (Jul 2021 through Apr 2022). The mean patient age was 70.7 years, and 50.9% were female. The middle cerebral artery first segment (M1) was the most common primary occlusion site (60.4%; 96/159). IV t‐PA was administered before the procedure in 13.7% (22/161) of patients. The median time from stroke onset / last known well to mTICI≥ 2b was 5.0 hrs. [IQR 3‐11], and the median time from a puncture to mTICI≥ 2b was 23.0 mins [IQR 15‐31]. Firm‐red clots represented 45.3% (67/148), while soft‐red clots were found in 37.8% (56/148) of retrieved clots. In turn, firm‐white and soft‐white clots were seen in 11.5% (17/148) and 5.4% (8/148) of cases, respectively. Rates of the first pass and final mTICI≥ 2b scores by clot type are shown in Table 1. Conclusions Aspiration thrombectomy with Penumbra RED catheters resulted in good revascularization rates for all clot types.

Modified treatment in cerebral ischemia 1 versus modified treatment in cerebral ischemia 0 before endovascular stroke treatment in middle cerebral artery’s M1-occlusion: Predictor for revascularization success and outcome?

Background Little is known about the implications for revascularization success of target vessel occlusions (TVOs) with persisting antegrade perfusion before initiation of endovascular stroke treatment (EST) (modified treatment in cerebral ischemia (mTICI 1)) compared to a complete occlusion (mTICI 0). Here, we compared these two states of TVO. Methods Retrospective, single-center analysis of patients treated for M1-segment middle cerebral artery (MCA) occlusion with EST from January 2015 until May 2020 in a tertiary stroke center. Primary study endpoint was successful recanalization (mTICI 2c-3) after one thrombectomy attempt. Secondary endpoints were clinical outcome (modified Rankin Scale (mRS) 90 days after stroke onset), complication rate, and rate of underlying atherosclerotic disease. The two study groups were compared in univariate analysis including patient characteristics and procedural details. Results In this study, 422/581 patients (72.6%) presented with complete M1-occlusion compared to 159/581 (27.4%) with incomplete M1-occlusion. Neither did the recanalization success rate differ between the study groups nor the rate of complications (mTICI 0: 2.4%, mTICI 1: 0.6%, p = 0.304) or underlying atherosclerotic disease. Patients with incomplete initial occlusion showed a lower mRS at discharge (median interquartile range (IQR) mTICI 0: 4 (3–5) vs. mTICI 1: 3 (2–6), p = 0.014), but a comparable mRS 90 days after stroke onset (mTICI 0: 3 (2–6) vs. mTICI 1: 4 (2–6), p = 0.479). Conclusion Complete M1-occlusions (mTICI 0) and incomplete occlusions (mTICI 1) show the same recanalization success, comparable complication rate, and clinical outcome as well as the same rate of underlying atherosclerotic disease. Thus, incomplete M1-occlusions do not allow for an individualized interventional approach.

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium.

A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI). Currently, INI is being considered as a promising drug to treat Alzheimer's disease and mild cognitive impairment. The clinical application of INI is being developed for the treatment of other neurodegenerative diseases and improve cognitive abilities in stress, overwork, and depression. At the same time, much attention has recently been paid to the prospects of using INI for the treatment of cerebral ischemia, traumatic brain injuries, and postoperative delirium (after anesthesia), as well as diabetes mellitus and its complications, including dysfunctions in the gonadal and thyroid axes. This review is devoted to the prospects and current trends in the use of INI for the treatment of these diseases, which, although differing in etiology and pathogenesis, are characterized by impaired insulin signaling in the brain.

The Benefit of a Complete over a Successful Reperfusion Decreases with Time.

Time from stroke onset to reperfusion (TSOR) is strongly associated with outcomes after endovascular treatment. A near-to-complete or complete reperfusion (modified Treatment in Cerebral Ischemia [mTICI] 2c-3) is associated with improved outcomes compared with a successful reperfusion (mTICI 2b). However, it is unknown whether this association remains stable as TSOR increases. Therefore, we sought to investigate the association between TSOR and outcomes according to the reperfusion status. We analyzed data from the Endovascular Treatment in Ischemic Stroke registry, a prospective, observational, multicentric study of acute ischemic stroke patients treated with endovascular treatment in 21 centers in France. We included patients with anterior occlusions (M1, internal carotid artery, tandem), with a known time of symptom onset. Outcomes were early neurological improvement at 24hours and favorable outcome (modified Rankin Scale between 0 and 2) at 90 days. Overall, 4,444 patients were analyzed. Compared with a mTICI 2b, a mTICI 2c-3 at 1 hour was associated with higher mean marginal probabilities of early neurological improvement (25.6%, 95% CI 11.7-39.5, p=0.0003) and favorable outcome (15.2%, 95% CI 3.0-27.4, p=0.0143), and progressively declined with TSOR. The benefit of a mTICI 2c-3 over a mTICI 2b was no longer significant regarding the rates of early neurological improvement and favorable outcome after a TSOR of 414 and 344minutes, respectively. The prognostic value of a complete over a successful reperfusion progressively declined with time, and no difference regarding the rates of favorable outcome was observed between a complete and successful reperfusion beyond 5.7 hours. ANN NEUROL 2023;93:934-941.

Futile reperfusion of endovascular treatment for acute anterior circulation large vessel occlusion in the ANGEL-ACT registry

BackgroundSome patients with large vessel occlusion (LVO) still cannot achieve functional independence despite successful reperfusion after endovascular treatment (EVT), named futile reperfusion. We aimed to explore the incidence and predictors...

Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-Level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort.

Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR=0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR=1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (β = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p< 0.001) and midline shift (adjusted odds ratio=0.36, 95% CI=0.23-0.57, p< 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI=1.86-3.88, p< 0.001) became insignificant (acOR=1.39, 95% CI=0.95-2.04, p= 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804.

Psychoactive Isoxazoles, Muscimol, and Isoxazole Derivatives from the Amanita (Agaricomycetes) Species: Review of New Trends in Synthesis, Dosage, and Biological Properties.

Herbal products found in nature can serve as great systems of study for drug design. The Amanita muscaria mushroom is native to many parts of the Northern Hemisphere and has a very distinctive appearance with its red cap and white spotted warts. The mushroom comprises several pharmacologically active alkaloids, including muscazone, muscarine, ibotenic acid, and muscimol, the latter two compounds being potent GABA agonists. Muscimol has served as a backbone in the design of GABA agonists devoid of effects on the GABA-metabolizing enzyme, GABA transaminase, and GABA uptake systems. In this sense, several analogs of muscimol have been synthesized and studied including THIP, THPO, iso-THIP, iso-THAZ and 4-PIOL which all interact with the GABA receptors much differently. The growing pharmacological and toxicological interest based on many conflicting opinions on the use of the neuroprotective role of muscimol analogs against some neurodegenerative diseases, its potent role in the treatment of cerebral ischemia and other socially significant health conditions provided the basis for this review.

Integrated transcriptomics, proteomics and metabolomics to identify biomarkers of astragaloside IV against cerebral ischemic injury in rats.

The herb Astragali Radix is a food-medicine herb. A major component of Astragali Radix, astragaloside IV (AS-IV), has neuroprotective effects in IS, but its mechanisms are not well understood. Our research used a transient middle cerebral artery occlusion (MCAO) rat model for longitudinal multi-omics analyses of the side of the brain affected by ischemia. Based on transcriptomic and proteomic analysis, we found that 396 differential expression targets were up-regulated and 114 differential expression targets were down-regulated. A total of 117 differential metabolites were identified based on metabonomics. Finally, we found 8 hub genes corresponding to the compound-reaction-enzyme-gene network using the Metscape plug-in for Cytoscape 3.7.1. We found that the related key metabolites were 3,4-dihydroxy-L-phenylalanine, 2-aminomuconate semialdehyde, (R)-3-hydroxybutanoate, etc., and the affected pathways were tyrosine metabolism, tryptophan metabolism, butanoate metabolism, purine metabolism, etc. We further validated these targets using 4D-PRM proteomics and found that seven targets were significantly different, including Aprt, Atic, Gaa, Galk1, Glb1, Me2, and Hexa. We aimed to uncover the mechanism of AS-IV in the treatment of ischemic brain injury through a comprehensive strategy combining transcriptomics, proteomics, and metabolomics.

Network pharmacology-based and pharmacological evaluation of the effects of Curcumae Radix on cerebral ischemia–Reperfusion injury

Objective: This study aimed to investigate the network pharmacology of curcumae radix (CR, Yujin) and explore the mechanism of CR in the treatment of cerebral ischemia–reperfusion injury (CIRI). Materials and Methods: Network analysis and pharmacological evaluation were performed to explore the protective role of CR to treat CIRI. The potential target genes of the active components and CIRI were identified using SwissTarget Prediction, Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine, GeneCards, and Online Mendelian Inheritance in Man. Furthermore, network analysis was performed using Cytoscape software. Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the R software. In vivo experiments were performed using the water extract of CR (WECR) on PC12 cells induced by hypoxia/reoxygenation (H/R) to simulate ischemia/reperfusion injury. Results: The results exhibited that 21 active compounds identified in CR were associated with 73 targets of CIRI. Functional analysis showed that multiple pathways, including response to stress, regulation of apoptotic process, and hypoxia-inducible factor 1 signaling pathway, were significantly enriched. In addition, STAT3, IL4, HIFIA, and CTNNB1 were predicted to be the most important genes among the 36 hub genes. Furthermore, WECR treatment significantly improved PC12 cell injury and decreased apoptosis levels in cells induced by H/R, with malondialdehyde contents reduced and superoxide dismutase or glutathione peroxidase levels increased. Conclusions: Network analysis and pharmacological evaluation of CR could provide valuable directions for further research on CR and improve comprehension of CIRI.

Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling.

Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia. However, whether there is a synergistic effect between the two remains unclear. In this study, we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes (MSC-exos) via the tail vein and underwent 14 successive days of treadmill exercise. Neurological assessment, histopathology, and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume, evident synaptic formation and axonal regeneration, and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment. These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone. Mechanistically, further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling. These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment, which may be related to activation of the JNK1/c-Jun signaling pathway. This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.