Ozone therapy mitigates parthanatos after ischemic stroke.

BACKGROUND: Stroke is a leading cause of death worldwide, with oxidative stress and calcium overload playing significant roles in the pathophysiology of the disease. Ozone, renowned for its potent antioxidant properties, is commonly employed as an adjuvant therapy in clinical settings. Nevertheless, it remains unclear whether ozone therapy on parthanatos in cerebral ischemia-reperfusion injury (CIRI). This study aims to investigate the impact of ozone therapy on reducing parthanatos during CIRI and to elucidate the underlying mechanism. METHODS: Hydrogen peroxide (H2O2) was utilized to mimic the generation of reactive oxygen species (ROS) in SH-SY5Y cell reperfusion injury in vitro, and an in vivo ischemic stroke model was established. Ozone saline was introduced for co-culture or intravenously administered to mice. Apoptosis and oxidative stress were assessed using flow cytometry and immunofluorescence. Western blotting was utilized to examine the expression of parthanatos signature proteins. The mechanism by which ozone inhibits parthanatos was elucidated through inhibiting PPARg or Nrf2 activity. RESULTS: The findings demonstrated that ozone mitigated H2O2-induced parthanatos by either upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) or activating peroxisome proliferator-activated receptorg (PPARg). Furthermore, through the use of calcium chelators and ROS inhibitors, it was discovered that ROS directly induced parthanatos and facilitated intracellular calcium elevation. Notably, a malignant feedback loop between ROS and calcium was identified, further amplifying the induction of parthanatos. Ozone therapy exhibited its efficacy by increasing PPARg activity or enhancing the Nrf2 translation, thereby inhibiting ROS production induced by H2O2. Concurrently, our study demonstrated that ozone treatment markedly inhibited parthanatos in stroke-afflicted mice. Additionally, ozone therapy demonstrated significant neuroprotective effects on cortical neurons, effectively suppressing parthanatos. CONCLUSIONS: These findings contribute valuable insights into the potential of ozone therapy as a therapeutic strategy for reducing parthanatos during CIRI, highlighting its impact on key molecular pathways associated with oxidative stress and calcium regulation.

Combining metabolomics and network pharmacology to investigate the protective effect of Jiawei Xinglou Chengqi Granules in ischemic stroke.

Jiawei Xinglou Chengqi Granule (JXCG) is an effective herbal medicine for the treatment of ischemic stroke (IS). JXCG has been shown to effectively ameliorate cerebral ischemic symptoms in clinical practice, but the underlying mechanisms are unclear. In this study, we investigated the mechanisms of action of JXCG in the treatment of IS by combining metabolomics with network pharmacology. The chemical composition of JXCG was analyzed using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Ultra-high performance liquid chromatography-tandem time-of-flight mass spectrometry (UHPLC-Q-TOF MS) untargeted metabolomics were used to identify differential metabolites within metabolic pathways. Network pharmacology was applied to mine potential targets of JXCG in the treatment of IS. The identified key targets were validated by constructing an integrated network of metabolomics and network pharmacology and by molecular docking using Cytoscape. The effect of JXCG on IS was evaluated in vivo, and the predicted targets and pathways of JXCG in IS therapy were assessed using immunoblotting. Combining metabolomics and network pharmacology, we identified the therapeutic targets of JXCG for IS. Notably, JXCG lessened neuronal damage and reduced cerebral infarct size in rats with IS. Western blot analysis showed that JXCG upregulated PRKCH and downregulated PRKCE and PRKCQ proteins. Our combined network pharmacology and metabolomics findings showed that JXCG may have therapeutic potential in the treatment of IS by targeting multiple factors and pathways.

Vascular vertigo and dizziness: managing and treating outpatients.

OBJECTIVE: Due the lack of data on the treatment of Vascular Vertigo and Dizziness, this study aimed to report how we managed and treated those outpatients according to the recently introduced American Heart Association and Stroke Association guidelines. METHODS: We conducted a longitudinal case series from May 2022 to February 2023. We included patients who met the Bárány Society's Vascular Vertigo and Dizziness classification and were eligible for therapy in accordance with the American Heart Association and Stroke Association guidelines, featuring aspects of the stroke group and transient attack group. RESULTS: Overall, 41 patients (51.2% female; median age 72 years) were enrolled; 10 (24.3%) had ischemic strokes, 30 (73.1%) had transient ischemic attack, and 1 (2.4%) had a probable isolated labyrinthine infarction. The patients received dual antiplatelet (48.7%), single antiplatelet therapy (48.7%), and anticoagulant therapy (2.4%). No new crises occurred in 95.2% of the patients, and the transient ischemic attack group showed a significant decrease in discomfort from imbalance on the visual analog scale. CONCLUSIONS: Antiplatelets and anticoagulants are safe and effective in treating Vascular Vertigo and Dizziness as they prevent new ischemic events and increase the flow of the posterior circulation, reducing vertigo/dizziness attacks and imbalance complaints.

Dual Antiplatelet Therapy vs Alteplase in Adult Patients with Acute Minor Ischemic Stroke: A Systematic Review and Meta-Analysis.

The efficacy and safety of dual antiplatelet therapy (DAPT) relative to intravenous (IV) alteplase in patients with acute minor ischemic stroke are insufficiently established. Therefore, we aimed to perform a meta-analysis to compare DAPT with IV alteplase in patients with acute minor stroke. MEDLINE, Embase, and Cochrane were searched for studies comparing DAPT with IV alteplase in patients with minor stroke. Functional and safety outcomes in 90 days were analyzed. Statistical analysis was performed using Rstudio 4.3.1. Subanalyses were performed restricted to non-disabling minor strokes and NIHSS score ≤ 3. PROSPERO (CRD42023440986). We included five studies with a total of 6,340 patients, of whom 4,050 (63.9%) received DAPT. The follow-up period for all included studies was 90 days. There was no significant difference for individual outcomes of mRS 0-1 (OR 1.26; 95% CI 0.85-1.89; p = 0.25), mRS 0-2 (OR 0.99; 95% CI 0.69-1.43; p = 0.97), or all-cause mortality (OR 0.80; 95% CI 0.20-3.13; p = 0.75) between groups. Symptomatic intracranial hemorrhage (sICH) was significantly lower (OR 0.11; 95% CI 0.003-0.36; p < 0.001) in patients treated with DAPT compared with IV alteplase. In terms of mRS 0-1 and mRS 0-2, we found no significant difference in both subgroup analyses. We found no statistically significant difference between DAPT and IV alteplase regarding functional outcome (mRS scores of 0-1 and 0-2) or all-cause mortality at 90 days in patients with minor ischemic stroke. Additionally, DAPT was associated with a significantly lower rate of sICH.

Ticagrelor versus clopidogrel in dual antiplatelet therapy after minor stroke or transient ischemic attack: an updated network meta-analysis.

BACKGROUND: Dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin is a well-established practice after a minor stroke or transient ischemic attack (TIA). However, ticagrelor plus aspirin may be an alternative. AIMS: We systematically searched PubMed, Embase, and Cochrane Central from inception to January 2024. We included randomized controlled trials (RCTs) enrolling adults with acute minor stroke or TIA within 72 hours of the onset of the symptoms. RESULTS: A total of 8 RCTs were included in our meta-analysis. Ticagrelor plus aspirin (RR, 0.70; 95% CrI 0.52, 0.91) and clopidogrel plus aspirin (RR, 0.79; 95% CrI 0.64, 0.98) were superior to aspirin in preventing stroke recurrence in overall analysis. Excluding studies with dual antiplatelet up to 90 days, ticagrelor plus aspirin was the only strategy that maintained superiority compared with aspirin regarding stroke recurrence (RR, 0.70; 95% CrI 0.51, 0.95) and ischemic stroke (RR, 0.68; 95% CrI 0.47, 0.94). There was no significant difference between treatment groups regarding hemorrhagic stroke, functional disability, and mortality. CONCLUSIONS: DAPTs were superior to aspirin in preventing recurrence or ischemic stroke. Although no significant difference was observed between DAPTs, ticagrelor plus aspirin may be related to worse major bleeding results, including intracranial bleeding. Ticagrelor plus aspirin is a considerable option for patients after a minor stroke or TIA.

Intravenous Thrombolysis in Patients 90 Years or Older with Moderate to Severe Acute Ischemic Stroke Increases Ambulation at Discharge and Is Safe: A Prospective Cohort Study from a Single Center in Santiago, Chile.

INTRODUCTION: The World Health Organization predicts that the global population aged 60 years and older will double by 2050, leading to a significant rise in the public health impact of acute ischemic stroke (AIS). Existing stroke guidelines do not specify an upper age limit for the administration of intravenous thrombolysis (IVT), although some suggest a relative exclusion criterion in patients aged ≥80 in the 3-4.5-h window. Many physicians avoid treating these patients with IVT, argumenting high risk and little benefit. Our aim was to investigate the efficacy and safety of IVT treatment in patients with non-minor AIS aged ≥90, admitted to our institution. The primary efficacy endpoint was the ability to walk at discharge (mRS 0-3), and the primary safety endpoints were death and symptomatic intracranial hemorrhagic transformation (sIHT) at discharge. METHODS: Patients with AIS aged ≥90 admitted to our center from January 2003 to December 2022 were included. They were selected if had an NIHSS ≥5, were previously ambulatory (prestroke mRS score 3 or less), and arrived within 6 h from symptom onset. Those treated or not with IVT were compared with univariate analysis. RESULTS: The mean age was 93.2 (2.4) years, and 51 (73.9%) were female. The admission mRS and NIHSS were 1 (IQR 0-2) and 14 (IQR 7-22), respectively. Thrombolyzed patients had a shorter time from symptom onset to door and lower glycemia on admission. IVT was associated with a higher proportion of patients achieving mRS 0-3 at discharge (p = 0.03) and at 90 days (p = 0.04). There were no differences between groups in the risk of death (p = 0.55) or sIHT (p = 0.38). CONCLUSION: In this small sample, ambulatory patients aged ≥90 with moderate or severe AIS treated with IVT had increased odds of being able to walk independently at discharge than those not treated, without safety concerns.

Morbimortality and determinants of reperfusion in ischemic stroke.

BACKGROUND: Cerebrovascular accident (or stroke) and ischemic heart disease are the the major causes of death in the world. It is estimated that about 85% of strokes are ischemic in origin. Reperfusion therapy in the acute phase of ischemic stroke with a recombinant human tissue plasminogen activator is effective, but some factors influence the success of this treatment. OBJECTIVE: The aim of this study was to evaluate clinical aspects and possible determinants for reperfusion after venous thrombolysis. METHODS: This is a retrospective, cross-sectional, observational study based on a review of hospital records of inpatients diagnosed with ischemic stroke treated with intravenous thrombolysis, the main outcome being reperfusion or not. RESULTS: Data from this study revealed a predominance of females in the group of reperfused patients and males in the non-reperfused group, both maintaining moderate severity on the National Institutes of Health Stroke Scale and admission without statistical significance (p>0.18). In addition, the mean admission severity score was 13.2 for the group of reperfused patients and 14.2 for those not reperfused, and the mean ejection fraction of both groups was within normal functionality, with a mean of 0.50 for reperfused patients and 0.62 for non-reperfused patients. CONCLUSION: We found an association between successful venous chemical thrombolysis reperfusion and lower mortality in patients with acute stroke.

The GPER1 agonist G1 reduces brain injury and improves the qEEG and behavioral outcome of experimental ischemic stroke.

Stroke is one of the principal cerebrovascular diseases in human populations and contributes to a majority of the functional impairments in the elderly. Recent discoveries have led to the inclusion of electroencephalography (EEG) in the complementary prognostic evaluation of patients. The present study describes the EEG, behavioral, and histological changes that occur following cerebral ischemia associated with treatment by G1, a potent and selective G protein-coupled estrogen receptor 1 (GPER1) agonist in a rat model. Treatment with G1 attenuated the neurological deficits induced by ischemic stroke from the second day onward, and reduced areas of infarction. Treatment with G1 also improved the total brainwave power, as well as the theta and alpha wave activity, specifically, and restored the delta band power to levels similar to those observed in the controls. Treatment with G1 also attenuated the peaks of harmful activity observed in the EEG indices. These improvements in brainwave activity indicate that GPER1 plays a fundamental role in the mediation of cerebral injury and in the behavioral outcome of ischemic brain injuries, which points to treatment with G1 as a potential pharmacological strategy for the therapy of stroke.

Anti-Inflammatory Effects of Flavonoids in Common Neurological Disorders Associated with Aging.

Aging reduces homeostasis and contributes to increasing the risk of brain diseases and death. Some of the principal characteristics are chronic and low-grade inflammation, a general increase in the secretion of proinflammatory cytokines, and inflammatory markers. Aging-related diseases include focal ischemic stroke and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Flavonoids are the most common class of polyphenols and are abundantly found in plant-based foods and beverages. A small group of individual flavonoid molecules (e.g., quercetin, epigallocatechin-3-gallate, and myricetin) has been used to explore the anti-inflammatory effect in vitro studies and in animal models of focal ischemic stroke and AD and PD, and the results show that these molecules reduce the activated neuroglia and several proinflammatory cytokines, and also, inactivate inflammation and inflammasome-related transcription factors. However, the evidence from human studies has been limited. In this review article, we highlight the evidence that individual natural molecules can modulate neuroinflammation in diverse studies from in vitro to animal models to clinical studies of focal ischemic stroke and AD and PD, and we discuss future areas of research that can help researchers to develop new therapeutic agents.

Short-Term Efficacy Outcomes of Tenecteplase versus Alteplase for Acute Ischemic Stroke: A Meta-Analysis of 5 Randomized Trials.

Tenecteplase (TNK) has been shown to be noninferior to Alteplase (ALT) for long term efficacy and safety outcomes. Whether this also applies to short term efficacy outcomes such as early clinical improvement and recanalization is unknown. To compare TNK and ALT regarding the short term efficacy outcomes: early neurological improvement and recanalization. The PRISMA was used to conduct a meta analysis, adapted to noninferiority analysis. The primary outcome was early (24-72 h) neurological improvement, defined as either NIHSS score 0 or reduction of at least 8 points compared to baseline. Recanalization was a secondary outcome. The noninferiority margin was set at 6.5%. Search strategy yielded 5 randomized clinical trials (1585 patients: 828 TNK, 757 ALT). Mean age was 70.8, 58.8% were men, mean baseline NIHSS was 7, and mean onset to treatment time was 148 min. Patients in intervention group received TNK at doses of 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), and 0.4 mg/kg (68.6%), while all ALT patients received 0.9 mg/kg. In random effects meta analysis, TNK was noninferior to ALT for the primary outcome, early major neurological improvement (risk difference 8% in favor of TNK, 95% CI 1%-15%). Recanalization was also noninferior for the TNK compared to the ALT group (risk difference 9% in favor of TNK, 95% CI 6% to 23%). Fixed effects models yielded similarly noninferior results and signaled for a possible TNK superiority for both early neurological improvement and recanalization. TNK is noninferior to ALT at the short term efficacy outcomes: early neurological improvement and recanalization.

Experiencia en el manejo del ataque cerebrovascular isquémico en dos centros de tercer nivel de la ciudad de Ibagué (Colombia) entre junio del 2019 y junio del 2020 / Ischemic stroke management - Experience in two third-level hospitals in Ibague (Colombia) from June 2019 to June 2020

RESUMEN INTRODUCCION: El ataque cerebrovascular (ACV) de etiología isquémica es una patología cuya incidencia y mortalidad aumentaron en la última década. Cuando se maneja oportunamente, mediante trombólisis como terapia inicial, mejora su desenlace y funcionalidad. En el departamento del Tolima (Colombia) no hay registros de esta patología y en el país la bibliografía al respecto es limitada. El objetivo de este estudio es evaluar los desenlaces clínicos del manejo agudo con r-tPA en los pacientes que presentaron ACV isquémico en dos instituciones de la ciudad de Ibagué, capital de dicho departamento, entre junio del 2019 y junio del 2020, e identificar los tiempos de atención hospitalaria y las principales variables asociadas con el grupo de pacientes que fallecieron. MATERIALES Y METODOS: Estudio descriptivo de corte transversal del manejo del ACV isquémico con r-tPA, en el que se describen las variables sociodemográficas, la escala NIHSS como evaluación neurológica inicial, los tiempos de atención (inicio-aguja, puerta-tac y puerta-aguja), los desenlaces postoperatorios y el Rankin modificado al egreso. RESULTADOS: Se incluyeron 38 pacientes con una media de 67,37 años, el 60,53 % fueron mujeres. La escala NIHSS al ingreso fue 13,47 puntos (DE 5,24). Los tiempos de atención fueron 183 minutos (DE 72,63) inicio-aguja, 41 minutos (RIQ 17-72) puerta-TAC y 101,50 minutos (RIQ 77 - 137,25) puerta-aguja. La mortalidad fue del 23,68 %. CONCLUSION: La mortalidad y el desenlace funcional del ACV en nuestra población fueron similares a los reportados en la literatura nacional e internacional, sin embargo, es preciso implementar protocolos de atención del infarto cerebral para incrementar el número de pacientes con desenlace favorable, acortando los tiempos de atención en toda la cadena del tratamiento adecuado del infarto cerebral.

ABSTRACT INTRODUCTION: Ischemic stroke is a growing disease in the last decade, increasing both its incidence and its mortality. However, timely thrombolysis management as initial therapy can improve both disease progression as well as an individual's functionality. In Tolima, there are no registries of this disease and in Colombia in general, the literature is limited. The objective of this study is to investigate the clinical outcomes of the acute management of ischemic stroke using r-tPA as well as identifying in-hospital treatment times, at two institutions in Ibague between 2019 and 2020. METHODS AND MATERIALS: Using a cross-sectional descriptive study, we describe the management of ischemic stroke using r-tPA, describing sociodemographic variables, NIHSS scale as the initial neurological evaluation, in-hospital treatment times (symptoms-to-needle, door-to-TAC, door-to-needle), the clinical outcomes, and lastly the modified Rankin score upon discharge. RESULTS: We included 38 patients with median age of 67,37 years, 60,53 % were females. The initial average NIHSS scale upon admission was 13,47 (DE 5,24). In-hospital attention time averages were: symptoms-to-needle 183 minutes (DE 72,63), door-to-CAT 41 minutes (RIQ 17-72), and door-to-needle 101,50 minutes (RIQ 77-137,25). Overall the rate of mortality was 23,68 %. CONCLUSIONS: Mortality and functionality outcomes of the stroke population observed was similar to previously reported, both nationally and internationally. However, protocols should be implemented for the timely ischemic stroke management to improve the number of patients with favorable outcomes, by reducing the in-hospital attention times in all areas of the management chain.

Comparative effects of dexmedetomidine and propofol on brain and lung damage in experimental acute ischemic stroke.

Acute ischemic stroke is associated with pulmonary complications, and often dexmedetomidine and propofol are used to decrease cerebral metabolic rate. However, it is unknown the immunomodulatory actions of dexmedetomidine and propofol on brain and lungs during acute ischemic stroke. The effects of dexmedetomidine and propofol were compared on perilesional brain tissue and lung damage after acute ischemic stroke in rats. Further, the mean amount of both sedatives was directly evaluated on alveolar macrophages and lung endothelial cells primarily extracted 24-h after acute ischemic stroke. In twenty-five Wistar rats, ischemic stroke was induced and after 24-h treated with sodium thiopental (STROKE), dexmedetomidine and propofol. Dexmedetomidine, compared to STROKE, reduced diffuse alveolar damage score [median(interquartile range); 12(7.8-15.3) vs. 19.5(18-24), p = 0.007)], bronchoconstriction index [2.28(2.08-2.36) vs. 2.64(2.53-2.77), p = 0.006], and TNF-α expression (p = 0.0003), while propofol increased VCAM-1 expression compared to STROKE (p = 0.0004). In perilesional brain tissue, dexmedetomidine, compared to STROKE, decreased TNF-α (p = 0.010), while propofol increased VCAM-1 compared to STROKE (p = 0.024). In alveolar macrophages and endothelial cells, dexmedetomidine decreased IL-6 and IL-1ß compared to STROKE (p = 0.002, and p = 0.040, respectively), and reduced IL-1ß compared to propofol (p = 0.014). Dexmedetomidine, but not propofol, induced brain and lung protection in experimental acute ischemic stroke.

The Nrf2 Pathway in Ischemic Stroke: A Review.

Ischemic stroke, characterized by the sudden loss of blood flow in specific area(s) of the brain, is the leading cause of permanent disability and is among the leading causes of death worldwide. The only approved pharmacological treatment for acute ischemic stroke (intravenous thrombolysis with recombinant tissue plasminogen activator) has significant clinical limitations and does not consider the complex set of events taking place after the onset of ischemic stroke (ischemic cascade), which is characterized by significant pro-oxidative events. The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of a great number of antioxidant and/or defense proteins, has been pointed as a potential pharmacological target involved in the mitigation of deleterious oxidative events taking place at the ischemic cascade. This review summarizes studies concerning the protective role of Nrf2 in experimental models of ischemic stroke, emphasizing molecular events resulting from ischemic stroke that are, in parallel, modulated by Nrf2. Considering the acute nature of ischemic stroke, we discuss the challenges in using a putative pharmacological strategy (Nrf2 activator) that relies upon transcription, translation and metabolically active cells in treating ischemic stroke patients.

Disparities between Asian and Non-Asian Thrombolyzed Acute Ischemic Stroke Patients in the Enhanced Control of Hypertension and Thrombolysis Stroke Trial.

BACKGROUND AND PURPOSE: As outcomes for acute ischemic stroke (AIS) vary according to clinical profile and management approaches, we aimed to determine disparities in clinical outcomes between Asian and non-Asian participants of the international, Enhanced Control of Hypertension and Thrombolysis Stroke study (ENCHANTED). METHODS: ENCHANTED was a multicenter, prospective, partial-factorial, randomized, open trial of low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) alteplase, and intensive (target systolic blood pressure [SBP] 130-140 mm Hg) or guideline-recommended (<180 mm Hg) BP management, in thrombolysis-eligible AIS patients. Logistic regression models were used to examine the associations with outcomes of death or disability (modified Rankin scale [mRS] scores 2-6), major disability (mRS 3-5), death, and intracranial hemorrhage (ICH), with adjustment prognostic factors, alteplase dose, and mean SBP over 1-24 h. RESULTS: Among 4,551 thrombolyzed AIS patients (mean age 66.7 years, 37.8% female), there were 65.4% Asians who were younger, fewer female, and with less atrial fibrillation, hypercholesterolemia, premorbid symptoms, and concomitant antihypertensive, antithrombotic and statin treatment, and more prior stroke, compared to non-Asians. Frequencies of hypertension, coronary artery disease, and diabetes mellitus were comparable between groups. Asian patients were less likely to be admitted to an acute stroke unit and receive early mobilization by a therapist or rehabilitation but more likely to receive intensive care. There were no significant differences between Asians and non-Asians in functional outcome (defined by mRS scores 2-6 or 3-5; adjusted odds ratio [OR] 1.00, 95% confidence interval [CI] 0.85-1.19 [p = 0.958] and OR 0.95, 95% CI 0.80-1.13 [p = 0.572], respectively), or death (OR 1.25, 95% CI 0.95-1.65; p = 0.116), despite Asians having greater odds of ICH (OR 1.51, 95% CI 1.23-1.86; p = 0.0001) and neurological deterioration within 24 h (OR 1.58, 95% CI 1.18-2.12; p = 0.002). CONCLUSIONS: Within the context of an international clinical trial of thrombolyzed AIS patients, demography, risk factors, management, and odds of early neurological deterioration and ICH, all differ between Asian and non-Asian participants. However, patterns of functional recovery are similar between these major regional groups.

Effects of intranasal guanosine administration on brain function in a rat model of ischemic stroke.

Ischemic stroke is a major cause of morbidity and mortality worldwide and only few affected patients are able to receive treatment, especially in developing countries. Detailed pathophysiology of brain ischemia has been extensively studied in order to discover new treatments with a broad therapeutic window and that are accessible to patients worldwide. The nucleoside guanosine (Guo) has been shown to have neuroprotective effects in animal models of brain diseases, including ischemic stroke. In a rat model of focal permanent ischemia, systemic administration of Guo was effective only when administered immediately after stroke induction. In contrast, intranasal administration of Guo (In-Guo) was effective even when the first administration was 3 h after stroke induction. In order to validate the neuroprotective effect in this larger time window and to investigate In-Guo neuroprotection under global brain dysfunction induced by ischemia, we used the model of thermocoagulation of pial vessels in Wistar rats. In our study, we have found that In-Guo administered 3 h after stroke was capable of preventing ischemia-induced dysfunction, such as bilateral suppression and synchronicity of brain oscillations and ipsilateral cell death signaling, and increased permeability of the blood-brain barrier. In addition, In-Guo had a long-lasting effect on preventing ischemia-induced motor impairment. Our data reinforce In-Guo administration as a potential new treatment for brain ischemia with a more suitable therapeutic window.

Improvement of a Novel Proposal for Antioxidant Treatment Against Brain Damage Occurring in Ischemic Stroke Patients.

The underlying mechanism of cerebral injury occurring in patients with acute ischemic stroke involves a key pathophysiological role of oxidative stress. Thus, reactive oxygen species are related to the development of brain edema, calcium overload, mitochondrial dysfunction, excitotoxicity, iron release and inflammation. Nevertheless, although experimental studies have tested the use of antioxidants as an adjuvant therapy in this setting, clinical data and randomized trials are still lacking. Current approved pharmacological therapy is aimed at reperfusion strategies; however, the therapeutic window is limited and also challenged by the injury known to result from the reperfusion. We have recently defined a time-course occurrence of pathological events triggered by reperfusion-dependent increased reactive oxygen species, thus suggesting the beneficial role of the pertinent use of antioxidants. The present study was aimed to support the hypothesis that an enhanced antioxidant neuroprotection could be achieved by the use of two or more antioxidants opportunely provided to ischemic stroke patients focused against the specific mechanism occurring throughout the pathophysiological process. From this paradigm, using an underexplored therapeutic principle, it could be suggested that antioxidant-based therapy is a novel, promising, safe, available and cost-effective strategy against the deleterious effects of ischemic stroke that needs to be further studied in clinical protocols.

Cerebral autoregulation and response to intravenous thrombolysis for acute ischemic stroke.

We hypothesized that knowledge of cerebral autoregulation (CA) status during recanalization therapies could guide further studies aimed at neuroprotection targeting penumbral tissue, especially in patients that do not respond to therapy. Thus, we assessed CA status of patients with acute ischemic stroke (AIS) during intravenous r-tPA therapy and associated CA with response to therapy. AIS patients eligible for intravenous r-tPA therapy were recruited. Cerebral blood flow velocities (transcranial Doppler) from middle cerebral artery and blood pressure (Finometer) were recorded to calculate the autoregulation index (ARI, as surrogate for CA). National Institute of Health Stroke Score was assessed and used to define responders to therapy (improvement of ≥ 4 points on NIHSS measured 24-48 h after therapy). CA was considered impaired if ARI < 4. In 38 patients studied, compared to responders, non-responders had significantly lower ARI values (affected hemisphere: 5.0 vs. 3.6; unaffected hemisphere: 5.4 vs. 4.4, p = 0.03) and more likely to have impaired CA (32% vs. 62%, p = 0.02) during thrombolysis. In conclusion, CA during thrombolysis was impaired in patients who did not respond to therapy. This variable should be investigated as a predictor of the response to therapy and to subsequent neurological outcome.

Intranasal Dexamethasone Reduces Mortality and Brain Damage in a Mouse Experimental Ischemic Stroke Model.

Neuroinflammation triggered by the expression of damaged-associated molecular patterns released from dying cells plays a critical role in the pathogenesis of ischemic stroke. However, the benefits from the control of neuroinflammation in the clinical outcome have not been established. In this study, the effectiveness of intranasal, a highly efficient route to reach the central nervous system, and intraperitoneal dexamethasone administration in the treatment of neuroinflammation was evaluated in a 60-min middle cerebral artery occlusion (MCAO) model in C57BL/6 male mice. We performed a side-by-side comparison using intranasal versus intraperitoneal dexamethasone, a timecourse including immediate (0 h) or 4 or 12 h poststroke intranasal administration, as well as 4 intranasal doses of dexamethasone beginning 12 h after the MCAO versus a single dose at 12 h to identify the most effective conditions to treat neuroinflammation in MCAO mice. The best results were obtained 12 h after MCAO and when mice received a single dose of dexamethasone (0.25 mg/kg) intranasally. This treatment significantly reduced mortality, neurological deficits, infarct volume size, blood-brain barrier permeability in the somatosensory cortex, inflammatory cell infiltration, and glial activation. Our results demonstrate that a single low dose of intranasal dexamethasone has neuroprotective therapeutic effects in the MCAO model, showing a better clinical outcome than the intraperitoneal administration. Based on these results, we propose a new therapeutic approach for the treatment of the damage process that accompanies ischemic stroke.

Ischemic Stroke and Disseminated Tuberculosis in Intensive Care: A Case Report.

BACKGROUND Tuberculosis (TB) continues to be a major public health problem worldwide. Extrapulmonary tuberculosis at the level of the central nervous system is the most devastating and deadly form of tuberculosis. CASE REPORT We present the case of a 73-year-old male Ecuadorian patient with no history of contact with tuberculosis and with a clinical picture of 4 days of evolution characterized by aphasia, deviation of the labial commissure, and deterioration of the level of consciousness with a Glasgow coma score of 7/15. A brain tomography showed evidence of indirect signs of cerebral ischemia; the patient was therefore diagnosed with non-specific cerebrovascular disease. Due to the critical nature of his clinical picture, the patient entered the Intensive Care Unit (ICU), where a chest x-ray was performed and bilateral perihilar alveolar opacities with a reticular and nodular pattern were visualized. These results, combined with the bronchoalveolar brushing, evidenced the presence of Mycobacterium tuberculosis. Adenosine of deaminase (ADA) was also detected in the cerebrospinal fluid with 30.7 µ/L and a molecular biology technique was used with high-multiplex real-time polymerase matrix MALDI-TOF mass spectrometry (Brucker Daltonics) for rapid identification of the causative agent. DNA/polymerase chain reaction (PCR) analyses were used for detection of M. tuberculosis, subsequently confirming the presence of cerebral tuberculosis. CONCLUSIONS This case illustrated an infrequent form of disseminated tuberculosis in a critically ill patient. Timely diagnosis and appropriate management are essential to reducing mortality.