Ketamine-induced prevention of SD-associated late infarct progression in experimental ischemia.

Spreading depolarizations (SDs) occur frequently in patients with malignant hemispheric stroke. In animal-based experiments, SDs have been shown to cause secondary neuronal damage and infarct expansion during the initial period of infarct progression. In contrast, the influence of SDs during the delayed period is not well characterized yet. Here, we analyzed the impact of SDs in the delayed phase after cerebral ischemia and the potential protective effect of ketamine. Focal ischemia was induced by distal occlusion of the left middle cerebral artery in C57BL6/J mice. 24 h after occlusion, SDs were measured using electrocorticography and laser-speckle imaging in three different study groups: control group without SD induction, SD induction with potassium chloride, and SD induction with potassium chloride and ketamine administration. Infarct progression was evaluated by sequential MRI scans. 24 h after occlusion, we observed spontaneous SDs with a rate of 0.33 SDs/hour which increased during potassium chloride application (3.37 SDs/hour). The analysis of the neurovascular coupling revealed prolonged hypoemic and hyperemic responses in this group. Stroke volume increased even 24 h after stroke onset in the SD-group. Ketamine treatment caused a lesser pronounced hypoemic response and prevented infarct growth in the delayed phase after experimental ischemia. Induction of SDs with potassium chloride was significantly associated with stroke progression even 24 h after stroke onset. Therefore, SD might be a significant contributor to delayed stroke progression. Ketamine might be a possible drug to prevent SD-induced delayed stroke progression.

Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice.

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

[Severe Carotid Artery Disease:Monitoring and Precautions for Prevention of Cerebral Ischemia].

Cerebrovascular complications in cardiovascular surgery have long been documented. It is very important to diagnose and evaluate the stenosis of carotid artery before cardiovascular surgery. When indicated, carotid endarterectomy( CEA) or carotid artery stenting( CAS) for severe carotid artery stenosis may be considered before cardiovascular surgery. However, it has not been necessary performed in the real-world. It seems to be appropriate to maintain a mean arterial pressure of 50-70 mmHg during cardiovascular surgery with extracorporeal circulation. In addition, perioperative cerebral metabolism and circulation monitoring using a near-infrared cerebral oxygen monitor such as rSO2 is very useful from the viewpoint of preventing exacerbation of cerebral ischemia.

Quantitative analysis of selected genetic markers of induced brain stroke ischemic tolerance detected in human blood.

A brain stroke is a serious disease and the second leading cause of death in the European Union. Carotid stenosis accounts for 15% of all ischemic cerebral strokes. However, there is currently no effective screening for carotid disease. Analysis of the DNA from peripheral blood is increasingly being used for several disease diagnoses. The potentially beneficial therapeutic method of inducing tissue tolerance to ischemia has so far been studied mainly in animal models. The aim of this study is to investigate changes in the gene expression of selected markers of brain ischemia during carotid endarterectomy, considered in this study as an activator of ischemic tolerance. During the carotid endarterectomy, there is a short-term occlusion of the internal carotid artery. Using the RT-qPCR method, we detected changes in the early identified gene markers of brain ischemia (ADM, CDKN1A, GADD45G, IL6, TM4SF1) in peripheral blood during sub lethal cerebral ischemia caused by carotid endarterectomy. Patients underwenting surgical procedure were divided into three groups: asymptomatic, symptomatic, and those who underwent carotid endarterectomy after an acute stroke. The results were compared to a negative/control group. Carotid endarterectomy had an impact on the expression of all monitored biomarkers. We observed statistically significant changes (p value 0.05-0.001) when comparing the groups among themselves, as well as the presence of ischemic tolerance of brain tissue to ischemic attacks. In conclusion, ADM, GADD45G, and TM4SF1 were affected in symptomatic patients, GADD45G and IL6 in acute patients, and CDKN1A and ADM in asymptomatic group after application of carotid endarterectomy.

Protective effects of anise in prevention of cerebral ischemia reperfusion injury in rats.

The aim of this study is to determine the protective efficacy of anise in cerebral ischemia and reperfusion injury in rats. In this study, 28 Wistar Albino rats, weighing 250-300 grams (g), were used. Four groups were formed with 7 rats in each group. Group 1 (n=7): Control group, Group 2 (n=7): Anise group, 5 mL/kg/day of anise aqueous extract prepared according to Gamberini's protocol was given orally by gavage for 30 days. Group 3 (n=7): Cerebral ischemia reperfusion (CIR) group, at the beginning of the experiment, 30 minutes of cerebral ischemia and 1 hour of reperfusion were induced and the animals were sacrificed by exanguination. Group 4 (n=7): Anise+ CIR group, After administering 30 days of anise's aqueous extract, CIR was induced and the study was terminated. TOS values of the Anise+ CIR group was significantly lower than that of the CIR group (p<0.05). Il-6 and TNF-α values of the CIR group were significantly higher than the Anise+ CIR group (p<0,05). Our study revealed that anise ameliorates oxidative damage and inflammation due to cerebral ischemia/reperfusion, by reducing the levels of inflammatory cytokines (TNF-α, Il-6).

Higher Habitual Dietary Intakes of Flavanols and Anthocyanins Differentially Associate with Lower Incidence of Ischemic Stroke Subtypes-A Follow-Up Analysis.

BACKGROUND: We previously reported that habitual consumption of dietary flavanol oligomers + polymers and anthocyanins is associated with a lower risk of ischemic stroke. However, no studies have investigated their relationship with ischemic stroke subtypes. OBJECTIVES: In this follow-up analysis, we aimed to examine the association of flavanol oligomers + polymers and anthocyanin intake with ischemic stroke subtypes, including the following: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) other determined etiology, and 5) undetermined etiology. METHODS: Participants (n = 55,094) from the Danish Diet, Cancer, and Health Study were followed up for <16 y for first-time ischemic stroke events, which were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Intakes of flavanol oligomers + polymers and anthocyanins were calculated from food frequency questionnaires using the Phenol-Explorer database, and their relationships with ischemic stroke subtypes were investigated using restricted cubic splines within Cox proportional hazards models. After multivariable adjustment, higher habitual intakes (quintile 5 compared with quintile 1) of flavanol oligomers + polymers and anthocyanins were associated with a lower risk of specific ischemic stroke subtypes, including large-artery atherosclerosis [flavanol oligomers + polymers, hazard ratio {HR} (95% confidence interval {CI}): 0.64 (0.47, 0.87)], cardioembolism [anthocyanins, HR (95% CI): 0.45 (0.25, 0.82)], and small-vessel occlusion [flavanol oligomers + polymers, HR (95% CI): 0.65 (0.54, 0.80); anthocyanins, HR (95% CI): 0.79 (0.64, 0.97)], but not stroke of other determined or undetermined etiology. CONCLUSIONS: Higher habitual intakes of flavanols and anthocyanins are differentially associated with a lower risk of ischemic stroke from atherosclerosis and/or cardioembolism but not with other subtypes.

The potential effect of salvianolic acid B against rat ischemic brain injury in combination with mesenchymal stem cells.

BACKGROUND: Mesenchymal stem cells (MSCs) and Salvianolic acid B (SAB) are known to exert potent anti-inflammatory and anti-oxidative properties. But the effect of SAB and MSCs combination treatment on the cerebral ischemia/reperfusion injury (CI/RI) is not clear. METHODS: After the CI/RI animal model established, rats were administered with MSCs and SAB individually or combination treatment. To evaluate the therapeutic potential, behavioral tests, TTC staining, Hematoxylin-eosin (HE) staining, and immunofluorescence assays were performed to evaluate the neuroprotection and endogenous neurogenesis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the anti-apoptosis and anti-inflammatory effect. Meanwhile, the expression of the TLR4/NF-ĸB/MYD88 signal pathway-related proteins was evaluated by Western blot. RESULTS: MSCs and SAB individually or combination treatment have protective effect in CI/RI rats. More importantly, the rats with the combination treatment showed a better behavioral recovery, neurogenesis and smaller infarct size compared with the rats administered with MSCs or SAB individually. Further research showed that the combination treatment decreased CI/RI induced inflammatory cytokines and oxidative stress, including inhibiting the production of IL-1ß, IL-6, TNF-α, decreasing the levels of malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD). In addition, the neuroprotection effect of SAB and MSCs combination was achieved through the regulation of TLR4/NF-κB/MyD88 signaling pathway related proteins, including inhibition the protein levels of TLR4, MYD88, p-NF-κB p65, TRAF6-and action of SIRT1 in brain tissues. CONCLUSION: The present study indicated that the MSCs and SAB combination treatment had better protective effect against rat ischemic brain injury. The combination of SAB and MSCs may provide a potent and promising strategy for the treatment of ischemic stroke and is worthy for further development.

Porcine cardiac blood - Salvia miltiorrhiza root alleviates cerebral ischemia reperfusion injury by inhibiting oxidative stress induced apoptosis through PI3K/AKT/Bcl-2/Bax signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bge. mixed with porcine cardiac blood (PCB-DS) is mainly employed for the treatment of brain ischemia-induced mental disturbances, palpitations and phlegm confusion based on the traditional principle of Menghe medical sect. PCB is the guide to DS and enhances the effect of DS. However, the potential mechanism of PCB-DS preventing cerebral ischemia/reperfusion injury (CIRI) from the perspective of oxidative stress induced cell apoptosis remains unknown. AIM OF THE STUDY: To investigate the pharmacological activity and molecular mechanism of PCB-DS against CIRI. MATERIALS AND METHODS: DS samples processed with different methods were prepared and UPLC-Q-TOF-MS/MS was employed for qualitative analysis of the respective processing product. The middle cerebral artery occlusion reperfusion model was then established to investigate the pharmacological activities of PCB-DS. Pathological changes in the rat brain were observed by triphenyl tetrazolium chloride (TTC), hematoxylin-eosin, and TUNEL staining. The levels of IL-6, IL-1ß, and TNF-α were detected by ELISA to evaluate the inflammatory damage. Metabolomics of cerebrospinal fluid was further used to explore the potential mechanism of PCB-DS in preventing CIRI. Based on this, the levels of oxidative stress-related lactate dehydrogenase (LDH), reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were determined. The protein levels of PI3K, AKT, Bcl-2, Bax, cleaved-caspase-3, and cleaved-caspase-9 proteins of the cerebral infarct zone were finally measured by western blotting. RESULTS: Forty-seven components were identified in four processing products. Compared to DS, the content of total aqueous components in PCB-DS was significantly increased including salvianolic acid B isomer, salvianolic acid D, salvianolic acid F, and salvianolic acid H/I/J. Among the DS, DS processed with wine, DS processed with pig blood, and DS processed with porcine cardiac blood, PCB-DS best alleviated the CIRI through the neurological score, brain infarct volume, brain histopathology and the levels of inflammatory factors in the brain. Twenty-five significant metabolites in the cerebrospinal fluid were screened out between the sham and I/R groups. They were mainly involved in the beta-alanine metabolism, histidine metabolism, and lysine degradation, which indicated that PCB-DS may inhibit oxidative stress-induced apoptosis to achieve treating ischemic stroke. The results of biomedical examination showed that PCB-DS could alleviate oxidative damage, significantly downregulate the expression of Bax, cleaved caspase-3 and cleaved caspase-9, and upregulate the expression of p-PI3K, p-AKT, and Bcl-2. CONCLUSION: In summary, this study demonstrated that PCB-DS alleviated CIRI and the molecular mechanism may be related to inhibiting the oxidative stress induced apoptosis through PI3K/AKT/Bcl-2/Bax signaling pathway.

circ-Gucy1a2 Protects Mice from Cerebral Ischemia-Reperfusion Injury by Attenuating Neuronal Apoptosis and Mitochondrial Membrane Potential Loss.

Cerebral ischemia-reperfusion (I/R) injury (CI/RI) is a severe problem in patients with cerebral ischemia. The current study explored the influences of circular (circ)-Gucy1a2 on neuronal apoptosis and mitochondrial membrane potential (MMP) in the brain tissue of CI/RI mice. Forty-eight mice were randomized into the sham group, transient middle cerebral artery occlusion (tMCAO) group, lentivirus negative control (LV-NC) group, and LV-Gucy1a2 group. Mice were first injected with lentivirus loaded with LV-Gucy1a2 or LV-NC via lateral ventricle, followed by the establishment of CI/RI models 2 weeks later. Twenty-four hours after CI/RI, the neurological impairment of mice was assessed using a 6-point scoring system. The cerebral infarct volume and brain histopathological changes were determined in CI/RI mice through histological staining. In vitro, pcDNA3.1-NC and pcDNA3.1-Gucy1a2 were transfected into mouse primary cortical neurons for 48 hours, followed by the establishment of oxygen-glucose deprivation/reoxygenation (OGD/R) models. The levels of circ-Gucy1a2 in mouse brain tissues and neurons were examined using RT-qPCR. Neuronal proliferation and apoptosis, MMP loss, and oxidative stress (OS)-related indexes in neurons were detected using CCK-8 assay, flow cytometry, JC-1 staining, and H2DFFDA staining. CI/RI mouse models and OGD/R cell models were successfully established. After CI/RI, neurons in mice were impaired and the cerebral infarction volume was increased. circ-Gucy1a2 was poorly expressed in CI/RI mouse brain tissues. Overexpression of circ-Gucy1a2 increased OGD/R-induced neuronal proliferation and mitigated apoptosis, MMP loss, and OS. Overall, circ-Gucy1a2 was down-regulated in brain tissues of CI/RI mice, and overexpression of circ-Gucy1a2 can protect mice from CI/RI.

Hemodynamic Management in the Prevention and Treatment of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

One of the most serious complications after subarachnoid hemorrhage (SAH) is delayed cerebral ischemia, the cause of which is multifactorial. Delayed cerebral ischemia considerably worsens neurological outcome and increases the risk of death. The targets of hemodynamic management of SAH have widely changed over the past 30 years. Hypovolemia and hypotension were favored prior to the era of early aneurysmal surgery but were subsequently replaced by the use of hypervolemia and hypertension. More recently, the concept of goal-directed therapy targeting euvolemia, with or without hypertension, is gaining preference. Despite the evolving concepts and the vast literature, fundamental questions related to hemodynamic optimization and its effects on cerebral perfusion and patient outcomes remain unanswered. In this review, we explain the rationale underlying the approaches to hemodynamic management and provide guidance on contemporary strategies related to fluid administration and blood pressure and cardiac output manipulation in the management of SAH.

Naringenin attenuates cerebral ischemia/reperfusion injury by inhibiting oxidative stress and inflammatory response via the activation of SIRT1/FOXO1 signaling pathway in vitro.

PURPOSE: To explore the protection of naringenin against oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell injury, a cell model of cerebral ischemia/reperfusion (I/R) injury in vitro, focusing on SIRT1/FOXO1 signaling pathway. METHODS: Cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, malondialdehyde (MDA) content, 4-hydroxynonenoic acid (4-HNE) level, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured by commercial kits. Inflammatory cytokines levels were determined by enzyme-linked immunosorbent assay (ELISA). The protein expressions were monitored by Western blot analysis. RESULTS: Naringenin significantly ameliorated OGD/R-induced cytotoxicity and apoptosis in HT22 cells. Meanwhile, naringenin promoted SIRT1 and FOXO1 protein expressions in OGD/R-subjected HT22 cells. In addition, naringenin attenuated OGD/R-induced cytotoxicity, apoptosis, oxidative stress (the increased ROS, MDA and 4-HNE levels, and the decreased SOD, GSH-Px and CAT activities) and inflammatory response (the increased tumor necrosis factor-α, interleukin [IL]-1ß, and IL-6 levels and the decreased IL-10 level), which were blocked by the inhibition of the SIRT1/FOXO1 signaling pathway induced by SIRT1-siRNA transfection. CONCLUSIONS: Naringenin protected HT22 cells against OGD/R injury depending on its antioxidant and anti-inflammatory activities via promoting the SIRT1/FOXO1 signaling pathway.

Perioperative cerebral perfusion in aortic arch surgery: a potential link with neurological outcome.

OBJECTIVES: The aim of this study was to examine whether perioperative changes in cerebral blood flow (CBF) relate to postoperative neurological deficits in patients undergoing aortic arch surgery involving antegrade selective cerebral perfusion (ASCP). METHODS: We retrospectively analysed data from patients who underwent aortic arch surgery involving ASCP and perioperative transcranial Doppler assessments. Linear mixed-model analyses were performed to examine perioperative changes in mean bilateral blood velocity in the middle cerebral arteries, reflecting changes in CBF, and their relation with neurological deficits, i.e. ischaemic stroke and/or delirium. Logistic regression analyses were performed to explore possible risk factors for postoperative neurological deficits. RESULTS: In our study population (N = 102), intraoperative blood velocities were lower compared to preoperative levels, and lowest during ASCP. Thirty-six (35%) patients with postoperative neurological deficits (ischaemic stroke, n = 9; delirium, n = 25; both, n = 2) had lower blood velocity during ASCP compared to patients without (25.4 vs 37.0 cm/s; P = 0.002). Logistic regression analyses revealed lower blood velocity during ASCP as an independent risk factor for postoperative neurological deficits (odds ratio = 0.959; 95% confidence interval: 0.923, 0.997; P = 0.037). CONCLUSIONS: Lower intraoperative CBF during ASCP seems independently related to postoperative neurological deficits in patients undergoing aortic arch surgery. Because CBF is a modifiable factor during ASCP, our observation has significant potential to improve clinical management and prevent neurological deficits.

Umbelliferone protects against cerebral ischemic injury through selective autophagy of mitochondria.

Effective therapeutic treatments for ischemic stroke are limited. Previous studies suggest selective activation of mitophagy alleviates cerebral ischemic injury while excessive autophagy is detrimental. However, few compounds are available to selectively activate mitophagy without affecting autophagy flux. Here, we found that acute administration of Umbelliferone (UMB) upon reperfusion exerted neuroprotective effects against ischemic injury in mice subjected to transient middle cerebral artery occlusion (tMCAO) and suppressed oxygen-glucose deprivation reperfusion (OGD-R)-induced apoptosis in SH-SY5Y cells. Interestingly, UMB promoted the translocation of mitophagy adaptor SQSTM1 to mitochondria and further reduced the mitochondrial content as well as the expression of SQSTM1 in SHSY5Y cells after OGD-R. Importantly, both the mitochondrial loss and reduction of SQSTM1 expression after UMB incubation can be reversed by autophagy inhibitor chloroquine and wortmannin, proving the mitophagy activation by UMB. Nevertheless, UMB failed to further affect neither LC3 lipidation nor the number of autophagosomes after cerebral ischemia in vivo and in vitro. Furthermore, UMB facilitated OGD-R-induced mitophagy in a Parkin-dependent manner. Inhibition of autophagy/mitophagy either pharmaceutically or genetically abolished the neuroprotective effects of UMB. Taken all, these results suggest that UMB protects against cerebral ischemic injury, both in vivo and in vitro, via promoting mitophagy without increasing the autophagic flux. UMB might serve as a potential leading compound for selectively activating mitophagy and the treatment of ischemic stroke.

A Review on Polyphenols in Salicornia ramosissima with Special Emphasis on Their Beneficial Effects on Brain Ischemia.

There has been an increasing interest in the consumption of halophytes as a healthy food in the last few years. Salicornia ramosissima is a seasonal Mediterranean halophyte with an interesting profile of bioactive compounds, including more than 60 identified polyphenols with a broad range of biological activities. Accumulating evidence supports the role of dietary polyphenols in the prevention of cardiovascular diseases, such as stroke. Stroke is the second cause of death worldwide and it is estimated that a substantial proportion of stroke incidence and recurrence may be prevented by healthier dietary patterns. Here, we have grouped the phenolic acids and flavonoids identified in S. ramosissima and reviewed their potential protective effect on brain ischemia, which are mostly related to the reduction of oxidative stress and inflammation, the inhibition of cell death pathways and their role in the preservation of the vascular function. Despite the fact that most of these compounds have been reported to be neuroprotective through multiple mechanisms, human studies are still scarce. Given the safe profile of polyphenols identified in S. ramosissima, this halophyte plant could be considered as a source of bioactive compounds for the nutraceutical industry.

Diet Supplementation with Polyphenol-Rich Salicornia ramosissima Extracts Protects against Tissue Damage in Experimental Models of Cerebral Ischemia.

Strokes are the second most common cause of death worldwide and a leading cause of disability. Regular consumption of polyphenols has been shown to reduce the risk of suffering a cardiovascular event. For this reason, we have investigated the protective effect of Salicornia ramosissima, a seasonal halophyte that synthetizes high amounts of bioactive compounds, including polyphenols, in response to environmental stress. Aqueous, hydroalcoholic, and ethanolic extracts were prepared to investigate if dietary supplementation prior to ischemic challenge can prevent subsequent damage using two animal models. First, we screened the protective effect against hypoxia-reoxygenation in Drosophila melanogaster and observed that both ethanolic and hydroalcoholic extracts protected flies from the deleterious effects of hypoxia. Second, we confirmed the protective effect of S. ramosissima ethanolic extract against brain ischemia using the transient middle cerebral artery occlusion mice model. Four weeks of oral supplementation with the ethanolic extract before artery occlusion reduced infarct volume and lowered the plasma levels of the DNA peroxidant product 8-hydroxydeoxyguanosine. Phytochemical profiling of S. ramosissima ethanolic extract revealed 50 compounds. Thus, it represents a valuable source of bioactive compounds that show promising disease-modifying activities and could be further developed as an effective food supplement for the prevention or treatment of neurovascular disorders.

Effect of early stellate ganglion block in cerebral vasospasm after aneurysmal subarachnoid hemorrhage (BLOCK-CVS): study protocol for a randomized controlled trial.

INTRODUCTION: Stellate ganglion block has been reported to expand cerebral vessels and alleviate vasospasm after aneurysmal subarachnoid hemorrhage. However, the causal relationship between early stellate ganglion block and cerebral vasospasm prevention has not yet been established. The purpose of this study was to explore the effectiveness and safety of early stellate ganglion block as a preventive treatment for cerebral vasospasm and delayed cerebral ischemia. METHODS/DESIGN: This is a single-center, prospective, randomized, controlled, blinded endpoint assessment superiority trial. A total of 228 patients will be randomized within 48 h of aneurysmal subarachnoid hemorrhage onset in a 1:1 ratio into two groups, one group receiving an additional e-SGB and the other group receiving only a camouflaging action before anesthesia induction in the operating room. The primary outcome is the incidence of symptomatic vasospasm within 14 days after aSAH. Further safety and efficacy parameters include the incidence of radiographic vasospasm, new cerebral infarction, postoperative delirium, and complications up to 90 days after surgery; postoperative cerebral hemodynamics; Mini-Mental State Examination score; modified Rankin scale score; and all-cause mortality up to 90 days after surgery. DISCUSSION: This is a randomized controlled trial to explore the effectiveness and safety of early stellate ganglion block as a preventive treatment to reduce cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. If the results are positive, it may provide a new direction for the prevention and treatment of cerebral vasospasm and delayed cerebral ischemia. TRIAL REGISTRATION: The study was registered on Clincaltrials.gov on December 13, 2020 (NCT04691271).

Cornin protects against cerebral ischemia/reperfusion injury by preventing autophagy via the PI3K/Akt/mTOR pathway.

BACKGROUND: Ischemia stroke is the leading cause of disability, which is a consequence of vascular occlusion. The purpose of this study is to investigate the effect of cornin which is isolated from the fruit of Verbena officinalis L, against astrocytes autophagy induced by cerebral ischemia/reperfusion (CI/R) injury in vitro and in vivo and its potential mechanism. METHODS: Cornin at dose of 2.5, 5 and 10 mg/kg were intravenously injected to MCAO rats at 15 min after reperfusion. The infarction volume, blood-brain barrier (BBB), neurological severity score (mNSS), and autophagy related protein were used to evaluated the protective effects and potential mechanism of cornin in autophagy with or without phosphoinositide-3 kinase (PI3K)inhibitor LY294002 and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) at 24 h after CI/R injury. The potential protective effects and mechanism of cornin at concention of 10 ~ 1000 nM were also evaluated in oxygen glucose deprivation/reperfusion (OGD/R) in U87 cells. RESULTS: The results suggest that cornin at dose of 5 or 10 mg/kg significantly reduce the cerebral infarction volume and blood-brain barrier (BBB) leakage, and improve neurological recovery in MCAO rats. Cleaved caspase-3 and Bax levels were significantly decreased, while B-cell lymphoma-2 (Bcl-2) and the apoptosis regulator ratio (Bcl-2/Bax) were markedly increased when treated with 2.5-10 mg/kg cornin. The obvious decreased expressions of glial fibrillary acidic protein (GFAP), myosin-like BCL2 interacting protein (Beclin-1) and microtubule-associated protein light chain 3 II (LC3-II) and increased of neuronal nuclei (NeuN), sequestosome-1 (p62), phosphorylated mTOR (p-mTOR), and phosphorylated Akt (p-Akt) were observed in MCAO rats treated with 10 mg/kg cornin, which was counteracted by LY294002. The expression of autophagy-related proteins with or without LY294002 and mTOR siRNA presented the similar results as in vitro in OGD/R in U87 cells. CONCLUSIONS: These results indicate that cornin improved neurological recovery after cerebral ischemia injury by preventing astrocytes autophagy induced by CI/R via the PI3K/Akt/mTOR signaling pathway.

Kaempferol Mediated AMPK/mTOR Signal Pathway Has a Protective Effect on Cerebral Ischemic-Reperfusion Injury in Rats by Inducing Autophagy.

Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury and its pathological mechanism is related to autophagy. The underlying mechanism of kaempferol on cerebral I/R injury needs to be explored. To establish I/R injury, we used a middle cerebral artery occlusion-reperfusion (MCAO) model in rats. MCAO rats were treated with the same amount of saline (I/R group); Treatment group rats were treated orally with kaempferol (50, 100, 200 mg/kg) for 7 days before surgery. After reperfusion for 24 h, the scores of neurological deficits and infarct volume in each group were evaluated. LC3, Beclin-1 p62, AMPK and mTOR protein expression levels were examined by TTC staining, immunofluorescence staining, qRT-PCR and western blotting assay. H&E and TTC staining showed that compared with model group, the infarction size of rats in kaempferol group was markedly reduced. Meanwhile, the results showed that kaempferol had a dose-dependent nerve function repairability. Nissl and TUNEL staining showed that kaempferol could reduce neuronal apoptosis and ameliorate neuronal impairment after I/R. Western blotting and qRT-PCR results showed that kaempferol could protect the brain from ischemia reperfusion by activating autophagy. In addition, add AMPK inhibitor, western blotting and immumohistochemical staining showed that kaempferol mediated AMPK/mTOR signal pathway in MCAO rats. Kaempferol could mediate the AMPK signal pathway to regulate autophagy and inhibit apoptosis to protect brain against I/R injury.

Analgecine protects against cerebral ischemia-reperfusion through apoptosis inhibition and anti-neuroinflammation in rats.

Stroke influence the quality of life of patients and leave big public health issues as acute cerebrovascular disease all over the world. Analgecine (AGC) relieves pain and accelerates repair of nerve injury. This current study aims to observe the pharmacological effects and related mechanisms of AGC in cerebral ischemic stroke among middle cerebral artery ischemia-reperfusion (MCAO) rats. After seven days of AGC administration, motor function was enhanced as evidenced by the prehensile traction test. Morphological ameliorations were observed by immunohistochemistry analysis. The protein expression levels of HSP70, Bcl-2, Bax, TRAF-6, MyD88, BDNF, NGF, pCREB, CREB, pTrkB, TrkB, pAKT and AKT were estimated by western blot. Meanwhile, AGC alleviated MCAO-induced inflammation chiefly by decreasing inflammatory cytokines in rat brain tissues. These results above suggested that MCAO-caused brain infarction was obviously alleviated by AGC. The immunohistochemistry data showed that AGC reduced neuronal injury and apoptosis, and inhibited microglia and astrocytes activation. The protein results suggested the expression of apoptosis-relevant proteins decreased among AGC treated groups and the neurotrophin related proteins were obviously enhanced by CREB/BDNF/TrkB/AKT and HSP70/Bcl-2/Bax pathways. Collectively, the results demonstrated that AGC primarily promoted neuro-nutrition, reduced the injury of nerve apoptosis and ameliorated neuroinflammation. In summary, AGC played a neuroprotective role, which had provided reliable evidence for AGC to be a potential drug in treating stroke.

Intraoperative neurophysiological monitoring during urgent surgical extracranial internal carotid artery recanalization.

OBJECTIVE: The clinical outcome of surgical extracranial internal carotid artery (eICA) recanalization may be adversely affected by intraoperative ischemia. Median nerve somatosensory evoked potential (SEP) amplitude correlates well with cerebral blood flow. Our study presents the value of intraoperative SEP and selective shunting in the prevention of intraoperative ischemia development during urgent eICA recanalization. METHODS: Prospective recruitment of patients with acute unilateral eICA occlusion. All underwent surgical recanalization with intraoperative monitoring of scalp median SEPs. Preoperative clinical findings, cerebral collaterals, and 3 month functional outcome were evaluated. RESULTS: The cohort consisted of 33 patients. Intraoperative SEP amplitude decreased significantly in 6 (18.2%). An intraluminal shunt was inserted twice (6.1%), surgical complications occurred in 6 (18.2%), intracerebral hemorrhage was not found. Favorable outcome 3 months after surgery according to the modified Rankin scale (mRS 0-2) was achieved in 28 (84.8%), 3 patients died (9.1%). CONCLUSIONS: Intraoperative SEP during urgent eICA recanalization seems to be beneficial. Thanks to the effective measure based on the intraoperative SEP changes, the clinical outcome in four(12.1%) could be positively affected. SIGNIFICANCE: The results suggest that selective shunting based on intraoperative median SEPs may prevent intraoperative ischemia and may improve overall outcome of urgent eICA recanalization.