Effect of acupuncture on ischaemic stroke in patients with rheumatoid arthritis: a nationwide propensity score-matched study.

OBJECTIVE: To demonstrate that acupuncture is beneficial for decreasing the risk of ischaemic stroke in patients with rheumatoid arthritis (RA). DESIGN: A propensity score-matched cohort study. SETTING: A nationwide population-based study. PARTICIPANTS: Patients with RA diagnosed between 1 January 1997 and 31 December 2010, through the National Health Insurance Research Database in Taiwan. INTERVENTIONS: Patients who were administered acupuncture therapy from the initial date of RA diagnosis to 31 December 2010 were included in the acupuncture cohort. Patients who did not receive acupuncture treatment during the same time interval constituted the no-acupuncture cohort. PRIMARY OUTCOME MEASURES: A Cox regression model was used to adjust for age, sex, comorbidities, and types of drugs used. We compared the subhazard ratios (SHRs) of ischaemic stroke between these two cohorts through competing-risks regression models. RESULTS: After 1:1 propensity score matching, a total of 23 226 patients with newly diagnosed RA were equally subgrouped into acupuncture cohort or no-acupuncture cohort according to their use of acupuncture. The basic characteristics of these patients were similar. A lower cumulative incidence of ischaemic stroke was found in the acupuncture cohort (log-rank test, p<0.001; immortal time (period from initial diagnosis of RA to index date) 1065 days; mean number of acupuncture visits 9.83. In the end, 341 patients in the acupuncture cohort (5.95 per 1000 person-years) and 605 patients in the no-acupuncture cohort (12.4 per 1000 person-years) experienced ischaemic stroke (adjusted SHR 0.57, 95% CI 0.50 to 0.65). The advantage of lowering ischaemic stroke incidence through acupuncture therapy in RA patients was independent of sex, age, types of drugs used, and comorbidities. CONCLUSIONS: This study showed the beneficial effect of acupuncture in reducing the incidence of ischaemic stroke in patients with RA.

Effect of General Anesthesia Versus Conscious Sedation/Local Anesthesia on the Outcome of Patients with Minor Stroke and Isolated M2 Occlusion Undergoing Immediate Thrombectomy: A Retrospective Multicenter Matched Analysis.

BACKGROUND: This study investigates the impact of general anesthesia (GA) versus conscious sedation/local anesthesia (CS/LA) on the outcome of patients with minor stroke and isolated M2 occlusion undergoing immediate mechanical thrombectomy (iMT). METHODS: The databases of 16 comprehensive stroke centers were retrospectively screened for consecutive patients with isolated M2 occlusion and a baseline National Institutes of Health Stroke Scale score ≤5 who received iMT. Propensity score matching was used to estimate the effect of GA versus CS/LA on clinical outcomes and procedure-related adverse events. The primary outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-1. Secondary outcome measures were a 90-day mRS score of 0-2 and all-cause mortality, successful reperfusion, procedural-related symptomatic subarachnoid hemorrhage, intraprocedural dissections, and new territory embolism. RESULTS: Of the 172 patients who were selected, 55 received GA and 117 CS/LA. After propensity score matching, 47 pairs of patients were available for analysis. We found no significant differences in clinical outcome, rates of efficient reperfusion, and procedural-related complications between patients receiving GA or LA/CS (mRS score 0-1, P = 0.815; mRS score 0-2, P = 0.401; all-cause mortality, P = 0.408; modified Treatment in Cerebral Infarction score 2b-3, P = 0.374; symptomatic subarachnoid hemorrhage, P = 0.082; intraprocedural dissection, P = 0.408; new territory embolism, P = 0.462). CONCLUSIONS: In patients with minor stroke and isolated M2 occlusion undergoing iMT, the type of anesthesia does not affect clinical outcome or the rate of procedural-related complications. Our results agree with recent data showing no benefit of one specific anesthesiologic procedure over the other and confirm their generalizability also to patients with minor baseline symptoms.

Blood Pressure Changes in Association with Nimodipine Therapy in Patients with Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Nimodipine is recommended to prevent delayed cerebral ischemia in patients with spontaneous subarachnoid hemorrhage (SAH). Here, we studied hemodynamic side effects of different nimodipine formulations (per os [PO] and intravenous [IV]) in patients with SAH undergoing continuous blood pressure monitoring. METHODS: This observational cohort study includes consecutive patients with SAH (271 included in the IV group, 49 in the PO group) admitted to a tertiary care center between 2010 and 2021. All patients received prophylactic IV or PO nimodipine. Hemodynamic responses were evaluated based on median values within the first hour after continuous IV nimodipine initiation or PO nimodipine application (601 intakes within 15 days). Significant changes were defined as > 10% drop in systolic blood pressure (SBP) or diastolic blood pressure from baseline (median values 30 min before nimodipine application). With the use of multivariable logistic regression, risk factors associated with SBP drops were identified. RESULTS: Patients were admitted with a median Hunt & Hess score of 3 (2-5; IV 3 [2-5], PO 1 [1-2], p < 0.001) and were 58 (49-69) years of age. Initiation of IV nimodipine was associated with a > 10% SBP drop in 30% (81/271) of patients, with a maximum effect after 15 min. A start or increase in noradrenaline was necessary in 136/271 (50%) patients, and colloids were administered in 25/271 (9%) patients within 1 h after IV nimodipine initiation. SBP drops > 10% occurred after 53/601 (9%) PO nimodipine intakes, with a maximum effect after 30-45 min in 28/49 (57%) patients. Noradrenaline application was uncommon (3% before and 4% after nimodipine PO intake). Hypotensive episodes to an SBP < 90 mm Hg were not observed after IV or PO nimodipine application. In multivariable analysis, only a higher SBP at baseline was associated with a > 10% drop in SBP after IV (p < 0.001) or PO (p = 0.001) nimodipine application, after adjusting for the Hunt & Hess score on admission, age, sex, mechanical ventilation, days after intensive care unit admission, and delayed cerebral ischemia. CONCLUSIONS: Significant drops in SBP occur in one third of patients after the start of IV nimodipine and after every tenth PO intake. Early recognition and counteracting with vasopressors or fluids seems necessary to prevent hypotensive episodes.

[Association of nutritional status with clinical outcomes of stroke patients with acute anterior circulation large vessel occlusion after emergency endovascular treatment].

OBJECTIVE: To explore the influence of nutritional status on 90-day functional outcomes of stroke patients with acute large vessel occlusion in the anterior circulation after endovascular treatment (EVT). METHODS: We retrospectively analyzed the baseline, laboratory, surgical and 90-day follow-up data of patients with stroke resulting from acute large vessel occlusion in the anterior circulation, who underwent emergency endovascular treatment in our hospital from July, 2015 to December, 2020. A favorable outcome was defined as a modified Rankin scale score ≤2 at 90 days. Univariate and multivariate regression analyses were performed to explore the relationship between nutritional status and 90-day functional outcomes of the patients. RESULTS: A total of 459 patients (mean age of 68.29±11.21 years, including 260 males) were enrolled in this study. According to their prognostic nutritional index (PNI), the patients were divided into normal nutrition group (392 cases, 85.4%), moderate malnutrition group (44 cases, 9.6%), and severe malnutrition group (23 cases, 5.0%). Univariate analysis showed that the patients with good clinical outcomes had a lower proportion of malnutrition with a younger age, a lower rate of diabetes, lower baseline blood pressure, lower baseline NIHSS score, higher baseline ASPECT score, and higher rates of good collateral circulation and complete vascular recanalization. Multivariate analysis showed that in addition to age, diabetes, baseline systolic blood pressure, successful recanalization, baseline ASPECT score, baseline NIHSS score and collateral circulation, a greater PNI was a protective factor for a good 90-day outcome of patients after EVT (moderate vs severe: OR=0.245, 95% CI: 0.066-0.908, P=0.035; normal vs severe: OR=0.185, 95% CI: 0.059-0.581, P=0.004). CONCLUSION: Nutritional status an important factor affecting the 90-day outcomes after EVT of stroke patients with acute large vessel occlusion in the anterior circulation.

Photothrombotic Mouse Models for the Study of Melatonin as a Therapeutic Tool After Ischemic Stroke.

Melatonin is a potent neuroprotective agent which has shown therapeutic effects in animal models of brain injury such as stroke. Currently, there are few effective treatments for the therapeutics of stroke, the second leading cause of death and a major cause of disability worldwide. As demonstrated by the high number of publications during the last two decades, there is growing interest in understanding how and if melatonin could be a possible drug for stroke in humans, given also its very low and limited toxicity. Here, we describe the detailed protocol for performing the photothrombotic model of stroke which involves the occlusion of small cerebral vessels caused by the photoactivation of the previously injected light-sensitive dye Rose Bengal. Importantly, this model allows for the study of cellular and molecular mechanisms underlying the pathophysiology of stroke and thus can be used for investigating the neuropharmacological role of melatonin and the melatonin system in stroke. In particular, future research is warranted to demonstrate how and if melatonin impacts neurodegeneration, neuroprotection, and neuro-regeneration occurring after the brain injury caused by the occlusion of cerebral vessels.

Analysis of Angiographic Treatment Response to Intra-Arterial Nimodipine Bolus Injection in Patients with Medically Refractory Cerebral Vasospasm After Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Intra-arterial nimodipine (IAN) injections are performed in refractory delayed cerebral ischemia (DCI) related to cerebral vasospasm (CVS) after spontaneous subarachnoid hemorrhage (sSAH), but the clinical benefits are inconclusive and angiographic treatment failure is observed. We analyzed angiographic IAN response in a detailed vessel-specific manner and examined the impact of poor angiographic response on the further clinical course. METHODS: Clinical data were retrospectively assessed in patients with spontaneous subarachnoid hemorrhage with symptomatic CVS receiving IAN bolus treatment. Clinical and angiographic predictors for poor angiographic response, DCI-related infarction, and unfavorable outcome were analyzed. RESULTS: Eighty-nine patients were included and 356 treated vessel segments, mainly located in the anterior circulation (93%), were analyzed. Angiographic response was good in 77% of the treated segments. Older age, poor World Federation of Neurosurgical Societies (WFNS) grade 4-5 and early onset of CVS were independently associated with poor angiographic response. The factors short-segment, distal, and bilateral CVS as well as treatment of multiple vessel segments, WFNS grade 4-5, and early onset of CVS were significantly associated with an increased risk of DCI-related infarction. Clinical outcome was significantly influenced by poor WFNS grade and early onset of CVS, whereas poor angiographic response was not related to DCI-related infarction or unfavorable outcome. CONCLUSIONS: The risk of angiographic treatment failure is significantly increased in older patients and those with poor WFNS grade as in cases of early-onset CVS. Although the extent of angiographic CVS significantly affected the development of DCI-related infarction, poor angiographic response had no impact on cerebral infarction and clinical outcome.

Therapeutic Approaches for Cerebrovascular Dysfunction After Aneurysmal Subarachnoid Hemorrhage: An Update and Future Perspectives.

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe subtype of stroke occurring at a relatively young age with a significant socioeconomic impact. Treatment of aSAH includes early aneurysm exclusion, intensive care management, and prevention of complications. Once the aneurysm rupture occurs, blood spreading within the subarachnoid space triggers several molecular pathways causing early brain injury and delayed cerebral ischemia. Pathophysiologic mechanisms underlying brain injury after aSAH are not entirely characterized, reflecting the difficulties in identifying effective therapeutic targets for patients with aSAH. Although the improvements of the last decades in perioperative management, early diagnosis, aneurysm exclusion techniques, and medical treatments have increased survival, vasospasm and delayed cerebral infarction are associated with high mortality and morbidity. Clinical practice can rely on a few specific therapeutic agents, such as nimodipine, a calcium-channel blocker proved to reduce severe neurologic deficits in these patients. Therefore, new pharmacologic approaches are needed to improve the outcome of this life-threatening condition, as well as a tailored rehabilitation plan to maintain the quality of life in aSAH survivors. Several clinical trials are investigating the efficacy and safety of emerging drugs, such as magnesium, clazosentan, cilostazol, interleukin 1 receptor antagonists, deferoxamine, erythropoietin, and nicardipine, and continuous lumbar drainage in the setting of aSAH. This narrative review focuses on the most promising therapeutic interventions after aSAH.

Large practice variations in diagnosis and treatment of delayed cerebral ischemia after subarachnoid hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) contributes to poor outcomes after subarachnoid hemorrhage (SAH). The pathophysiology of DCI is not fully understood, which has hindered the adoption of a uniform definition. Furthermore, a reliable diagnostic test and an effective evidence-based treatment are lacking. This could lead to variations in care. METHODS: A web-based survey on the variations in the definition, diagnosis, and treatment of DCI was designed and sent to 314 intensivists, neurologists, and neurosurgeons of all 9 hospitals in the Netherlands who care for patients with SAH. The responders were categorized into physicians responsible for the coordination of SAH care and those who were not. For questions on the definition and diagnosis, only the responses from the coordinating physicians were evaluated. For the treatment questions, all the responses were evaluated. RESULTS: The response rate was 34% (106 of 314). All 9 hospitals were represented. Of the responses, 27 did not provide answers for the definition, diagnosis, or treatment questions; 79 responses were used for analysis. Signs of vasospasm were required by 21 of the 47 coordinating physicians (44%) when considering DCI. Of the 47 coordinating physicians, 24 (51%) did not use a diagnostic test results for a positive diagnosis of DCI. When patients were discharged within 21 days, 33 of the 73 responders (45%) did not provide a prescription for nimodipine continuation. Finally, all but one hospital had treated DCI with hypertension induction. CONCLUSIONS: We found large variations in the definition, diagnosis, and treatment of DCI in the Netherlands. In the absence of evidence-based treatment, standardization of management seems warranted in an effort to optimize DCI care.

Establishing a high throughput drug screening system for cerebral ischemia using zebrafish larvae.

We previously generated an ischemic stroke in a zebrafish model using N2 gas perfusion; however, this model was an unsuitable drug screening system due to low throughput. In this study, we examined a zebrafish ischemic stroke model using an oxygen absorber to assess drug effects. Hypoxic exposure more than 2 h using the oxygen absorber significantly induced cell death in the brain and damage to the neuronal cells. To confirm the utility of the ischemic model induced by the oxygen absorber, we treated zebrafish with neuroprotective agents. MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, significantly suppressed cell death in the brain, and edaravone, a free radical scavenger, significantly reduced the number of dead cells. These results suggest that the activation of NMDA receptors and the production of reactive oxygen species induce neuronal cell damage in accordance with previous mammalian reports. We demonstrate the suitability of an ischemic stroke model in zebrafish larvae using the oxygen absorber, enabling a high throughput drug screening.

Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model.

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism.

Smurf2 exerts neuroprotective effects on cerebral ischemic injury.

The present study aimed to explore specific mechanisms involved in mediating the neuroprotective effects of Smad ubiquitination regulatory factor 2 (Smurf2) in cerebral ischemic injury. A middle cerebral artery occlusion (MCAO) mouse model and an oxygen-glucose deprivation (OGD)-treated neuron model were developed. The expression of Smurf2, Yin Yang 1 (YY1), hypoxia-inducible factor-1 alpha (HIF1α), and DNA damage-inducible transcript 4 gene (DDIT4) was analyzed. Thereafter, the expression of Smurf2, YY1, HIF1α, and DDIT4 was altered in the MCAO mice and OGD-treated neurons. Apoptosis in tissues and cerebral infarction were assessed. In neurons, the expression of apoptosis-related proteins, viability, and apoptosis were assessed, followed by evaluation of lactate dehydrogenase leakage rate. The interaction between Smurf2 and YY1 was analyzed by coimmunoprecipitation assay and that between YY1 ubiquitination by in vivo ubiquitination experiment. The results showed downregulation of Smurf2 and upregulation of YY1, HIF1α, and DDIT4 in both MCAO mice and OGD-treated neurons. Smurf2 elevated YY1 ubiquitination and degradation, and YY1 increased HIF1α expression to promote DDIT4 in neurons. Overexpressed Smurf2 or downregulated YY1, HIF1α, or DDIT4 reduced the volume of cerebral infarction and apoptosis in MCAO mice, while enhancing cell viability and reducing apoptosis and lactate dehydrogenase leakage in OGD-treated neurons. In summary, our findings elucidated a neuroprotective role of Smurf2 in cerebral ischemic injury via inactivation of the YY1/HIF1α/DDIT4 axis.

Ischemic stroke secondary to self-inflicted carotid sinus massage: a case report.

BACKGROUND: The risk of stroke after carotid sinus massage is greater if there is preexisting carotid stenosis or carotid plaques. We present the case of a patient with underlying 40% carotid stenosis, who developed a watershed stroke after a self-neck massage in our stroke unit. We show a well-documented case with magnetic resonance images before and after the neck massage. We report a case of a watershed brain infarct after a self-massage of the carotid sinus, with preexisting carotid artery stenosis. Neck massage continues to be a significant cause of stroke and should therefore not be performed by patients. Clinicians must be aware of the implications of a carotid sinus massage in both the outpatient and inpatient settings. CASE PRESENTATION: We admitted a 58-year-old white male patient, with no relevant medical history, to our department with a brain stem infarct. During his stay at our stroke unit, the patient performed a self-neck massage with consecutive bradycardia and asystole, resulting in left-side hemiparesis. The underlying cause of the hemodynamic stroke is believed to be secondary to this intensive neck massage performed by the patient. The patient also suffered from unknown right internal carotid artery stenosis. CONCLUSION: Clinicians and patients must be aware that neck massage can lead to ischemic stroke. We postulate that repetitive impaired cardiac output can lead to a hemodynamic (watershed-type) stroke.

Non-steroidal anti-inflammatory drugs in the pathophysiology of vasospasms and delayed cerebral ischemia following subarachnoid hemorrhage: a critical review.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition associated with the development of early brain injury (EBI) and delayed cerebral ischemia (DCI). Pharmacological treatment of vasospasm following aSAH currently mainly comprises nimodipine administration. In the past few years, many drugs that can potentially benefit cases of subarachnoid hemorrhage have become available. The objective of this review is to critically assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) following aSAH. A systematic literature review was conducted following PRISMA guidelines. The search was aimed at studies addressing aSAH and NSAIDs during the 2010 to 2019 period, and it yielded 13 articles. Following the application of search criteria, they were divided into two groups, one containing 6 clinical articles and the other containing 7 experimental articles on animal models of aSAH. Inflammatory cerebral changes after aneurysm rupture contribute to the development of EBI, DCI and cerebral vasospasm. It appears that NSAIDs (especially coxibs) are even more effective in reducing vasospasm than nimodipine. Other beneficial effects of NSAIDs include reduction in mortality, improved functional outcome and increased hypoaggregability. However, despite these positive effects, there is only one randomized, double-blind, placebo-controlled trial showing a tendency towards a better outcome with lower incidence of vasospasm or mortality in patients following aSAH.

Attenuation of Heat-Induced Hypothalamic Ischemia, Inflammation, and Damage by Hyperbaric Oxygen in Rats.

The present study was attempted to assess the mechanisms underlying the beneficial effects of hyperbaric oxygen (HBO2; 100% O2 at 253 kpa) in treating experimental heatstroke. Anesthetized rats were divided into five major groups: normothermic control (NC) rats treated with normobaric air (NBA; 21% O2 at 101 kpa; NC + NBA); NC rats treated with HBO2 (NC + HBO2); heatstroke (HS) rats treated with NBA (HS + NBA); HS rats treated with hyperbaric air (HBA; 21% at 253 kpa; HS + HBA); and HS rats treated with HBO2 (HS + HBO2). HS groups were exposed to heat (43°C) for exactly 68 min and then allowed to recover at 26°C. HBA or HBO2 was adopted 68 or 78 min after the start of heat exposure. Survival time values for (HS + NBA) rats, (HS + HBA) rats at 68 min, (HS + HBA) rats at 78 min, (HS + HBO2) rats at 68 min, and (HS + HBO2) rats at 78 min were found to be 90 ± 3, 133 ± 12, 109 ± 9, 240 ± 18, and 170 ± 15 min, respectively. Resuscitation with HBA or HBO2 at 68 min was superior to those treated at 78 min in prolonging the survival time values. All (HS + NBA) animals displayed hyperthermia, hypotension, and increased cellular levels of ischemia, oxidative stress and damage markers, pro-inflammatory cytokines, and an indicator of polymorphonuclear cell accumulation in their hypothalamus as compared to those of NCs. Heat-induced hyperthermia was not affected by HBA or HBO2 treatment. However, heat-induced hypotension and hypothalamic ischemia, oxidative stress, neuronal damage, and inflammation were all significantly reduced by HBA or HBO2 therapy. Compared to those of HBA therapy, HBO2 therapy had a significantly higher beneficial effect in treating heatstroke. Our results suggested that HBO2 improved heatstroke outcomes, in part, by restoring normal hypothalamic function. Delaying the onset of HBO2 therapy reduced the therapeutic efficiency.

Kellerin from Ferula sinkiangensis exerts neuroprotective effects after focal cerebral ischemia in rats by inhibiting microglia-mediated inflammatory responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula sinkiangensis K. M. Shen is a traditional Chinese medicine that has a variety of pharmacological properties relevant to neurological disorders and inflammations. Kellerin, a novel compound extracted from Ferula sinkiangensis, exerts a strong anti-neuroinflammatory effect by inhibiting microglial activation. Microglial activation plays a vital role in ischemia-induced brain injury. However, the potential therapeutic effect of kellerin on focal cerebral ischemia is still unknown. AIM OF THE STUDY: To explore the effect of kellerin on cerebral ischemia and clarify its possible mechanisms, we applied the middle cerebral artery occlusion (MCAO) model and the LPS-activated microglia model in our study. MATERIALS AND METHODS: Neurological outcome was examined according to a 4-tiered grading system. Brain infarct size was measured using TTC staining. Brain edema was calculated using the wet weight minus dry weight method. Neuron damage and microglial activation were observed by immunofluorescence in MCAO model in rats. In in vitro studies, microglial activation was examined by flow cytometry and the viability of neuronal cells cultured in microglia-conditioned medium was measured using MTT assay. The levels of pro-inflammatory cytokines were measured by qRT-PCR and ELISA. The proteins involved in NF-κB signaling pathway were determined by western blot. Intracellular ROS was examined using DCFH-DA method and NADPH oxidase activity was measured using the NBT assay. RESULTS: We found that kellerin improved neurological outcome, reduced brain infarct size and decreased brain edema in MCAO model in rats. Under the pathologic conditions of focal cerebral ischemia, kellerin alleviated neuron damage and inhibited microglial activation. Moreover, in in vitro studies of LPS-stimulated BV2 cells kellerin protected neuronal cells from being damaged by inhibiting microglial activation. Kellerin also reduced the levels of pro-inflammatory cytokines, suppressed the NF-κB signaling pathway, and decreased ROS generation and NADPH oxidase activity. CONCLUSIONS: Our discoveries reveal that the neuroprotective effects of kellerin may largely depend on its inhibitory effect on microglial activation. This suggests that kellerin could serve as a novel anti-inflammatory agent which may have therapeutic effects in ischemic stroke.

Hypobaric hypoxia preconditioning protects against hypothalamic neuron apoptosis in heat-exposed rats by reversing hypothalamic overexpression of matrix metalloproteinase-9 and ischemia.

Background: Hypoxia-inducible factor-1α (HIF-1α), heat shock protein-72 (HSP-72), hemeoxygenase-1 (HO-1), and matrix metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets in the brain for cerebral ischemia. To elucidate their underlying mechanisms, we first aimed to ascertain whether these proteins participate in the pathogenesis of heat-induced ischemic damage to the hypothalamus of rats. Second, we investigated whether hypobaric hypoxia preconditioning (HHP) attenuates heat-induced hypothalamic ischemic/hypoxic injury by modulating these proteins in situ. Methods: Anesthetized rats treated with or without HHP were subjected to heat stress. Hypothalamic ischemic/hypoxic damage was evaluated by measuring hypothalamic levels of cerebral blood flow (CBF), partial oxygen pressure (PO2), and hypothalamic temperature via an implanted probe. Hypothalamic apoptotic neurons were counted by measuring the number of NeuN/caspase-3/DAPI triple-stained cells. Hypothalamic protein expression of HIF-1α, HSP-72, HO-1, and MMP-9 was determined biochemically. Results: Before the start of the thermal experiments, rats were subjected to 5 hours of HHP (0.66 ATA or 18.3% O2) daily for 5 consecutive days per week for 2 weeks, which led to significant loss of body weight, reduced brown adipose tissue (BAT) wet weight and decreased body temperature. The animals were then subjected to thermal studies. Twenty minutes after heat stress, heat-exposed rats not treated with HHP displayed significantly higher core and hypothalamic temperatures, hypothalamic MMP-9 levels, and numbers of hypothalamic apoptotic neurons but significantly lower mean blood pressure, hypothalamic blood flow, and PO2 values than control rats not exposed to heat. In heat-exposed rats, HHP significantly increased the hypothalamic levels of HIF-1α, HSP-72, and HO-1 but significantly alleviated body and hypothalamic hyperthermia, hypotension, hypothalamic ischemia, hypoxia, neuronal apoptosis and degeneration. Conclusions: HHP may protect against hypothalamic ischemic/hypoxic injury and overexpression of MMP-9 by upregulating the hypothalamic expression of HIF-1α, HSP-72, and HO-1 in rats subjected to heatstroke.

Neuroprotection of benzoinum in cerebral ischemia model rats via the ACE-AngI-VEGF pathway.

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.

Panax notoginseng for Cerebral Ischemia: A Systematic Review.

Panax notoginseng is the most widely used Chinese medicinal herb for the prevention and treatment of ischemic diseases. Its main active ingredients are saponins, including ginsenoside Rb1, ginsenoside Rg1, and notoginsenoside R1, among others. This review provides an up-to-date overview on the pharmacological roles of P. notoginseng constituents in cerebral ischemia. The saponins of P. notoginseng induce a variety of pharmacological effects in the multiscale mechanisms of cerebral ischemic pathophysiology, including anti-inflammatory activity, reduction of oxidative stress, anti-apoptosis, inhibition of amino acid excitotoxicity, reduction of intracellular calcium overload, protection of mitochondria, repairing the blood-brain barrier, and facilitation of cell regeneration. Regarding cell regeneration, P. notoginseng not only promotes the proliferation and differentiation of neural stem cells, but also protects neurons, endothelial cells and astrocytes in cerebral ischemia. In conclusion, P. notoginseng may treat cerebrovascular diseases through multiple pharmacological effects, and the most critical ones need further investigation.

Protopanaxadiol ginsenoside Rd protects against NMDA receptor-mediated excitotoxicity by attenuating calcineurin-regulated DAPK1 activity.

Neuroprotective strategies in the treatment of stroke have been attracting a great deal of attentions. Our previous clinical and basic studies have demonstrated that protopanaxadiol ginsenoside-Rd (Rd), a monomer compound extracted from Panax ginseng or Panax notoginseng, has neuroprotective effects against ischemic stroke, probably due to its ability to block Ca2+ overload, an usual consequence of the overactivation of NMDA receptor (NMDAR). As an extending study, we explored here whether Rd exerted its neuroprotection as a novel NMDAR blocker. Our whole-cell patch-clamp results showed that Rd reduced NMDAR currents of cultured rat cortical neurons (EC50 = 7.7 µM) dose-dependently by acting on extrasynaptic NMDAR NR2b subunit. However, unexpectedly, cell transfection and radioligand binding assays revealed that Rd did not bind to the NMDAR channel directly. Alternatively, it inhibited the phosphorylation of NR2b at Ser-1303, a target of death associated protein kinase 1 (DAPK1). Moreover, cell-based and cell-free enzymatic assays showed that Rd did not inhibit the activity of DAPK1 directly, but blocked the activity of calcineurin, a key phosphatase for activating DAPK1. Importantly, other protopanaxadiol ginsenosides were also found to have potential inhibitory effects on calcineurin activity. Furthermore, as expected, calcineurin inhibition by cyclosporin A could mimic Rd's effects and protect against NMDA-, oxygen glucose deprivation- or transient ischemic stroke-induced neuronal injury. Therefore, our present study provided the first evidence that Rd could exert an inhibitive effect on NMDAR-triggered currents and sequential excitotoxicity through mitigation of DAPK1-mediated NR2b phosphorylation by attenuating calcineurin activity.

Biologic therapy in supra-aortic Takayasu arteritis can improve symptoms of cerebral ischaemia without surgical intervention.

OBJECTIVES: Takayasu arteritis commonly results in severe arterial injury with stenoses, occlusions and occasionally aneurysms. Arterial disease may compromise organ blood flow and result in significant cardiovascular morbidity and premature mortality. Involvement of the supra-aortic arteries is common, and in its most severe form may compromise cerebral blood supply, resulting in signs of cerebral ischaemia including visual impairment, dysphasia, transient hemiparesis, loss of consciousness and stroke. In addition to combination immunosuppression, the management paradigm for symptomatic cerebral ischaemia includes revascularization. The invasive nature of this surgery, the risk of complications and the relatively high rate of re-stenosis is of concern to patients and their physicians alike. The aim of this study was to determine whether combined immunosuppression with early escalation to biologic therapy improved outcomes and reduced the need for high risk surgical intervention. METHODS: A retrospective review of 145 Takayasu arteritis patients attending Imperial College Healthcare between 2010-2018 was conducted to identify those with cerebral ischaemia secondary to supra-aortic disease and to analyse their treatment and outcomes. RESULTS: Eight patients (5.5%) were identified. Seven patients received long-term combined immunosuppressive therapy and six were prescribed biologics. The data revealed a higher than expected comprehensive response to therapy, with significant falls in disease activity, the cerebral ischaemia score and the prednisolone dose required, over a median follow-up of 37 months. Serial imaging analysis detected no arterial disease progression after the initiation of optimal therapy. Only one patient required surgical intervention for persistent neurological symptoms. CONCLUSION: Early use of biologic therapy in those with supra-aortic Takayasu arteritis presenting with cerebral ischaemia may reduce the numbers of patients requiring surgical intervention and improve outcomes.