Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature.

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell Ca2+ signals require an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial Ca2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+ activity and cortical capillary blood flow in vivo. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+ signaling and endothelium-dependent vasodilation.

Clinical efficacy analysis of butylphthalide combined with urinary kallidinogenase in treating chronic cerebral circulatory insufficiency.

OBJECTIVE: To investigate the clinical effect of butylphthalide combined with urinary kallidinogenase in the treatment of chronic cerebral circulatory insufficiency (CCCI). METHODS: A total of 102 CCCI patients admitted to our hospital from October 2020 to December 2021 were retrospectively enrolled in this study. According to the different therapeutic strategy, the patients were divided into combined group (treated with butylphthalide combined with urinary kallidinogenase, n = 51) and butylphthalide group (treated with butylphthalide, n = 51). Blood flow velocity and cerebral blood flow perfusion before and after treatment between the two groups were compared. The clinical efficacy and adverse events of the two groups were analyzed. RESULTS: After treatment, the effective rate of the combined group was significantly higher than the butylphthalide group (p = .015). Before treatment, the blood flow velocity of middle cerebral artery (MCA), vertebral artery (VA), basilar artery (BA) were comparable (p > .05, respectively), while after treatment, the blood flow velocity of MCA, VA, and BA in combined group were faster than those in butylphthalide group (p < .001, respectively). Before treatment, the relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), relative mean transmit time (rMTT) of the two groups were comparable (p > .05, respectively). After treatment, rCBF and rCBV in combined group were higher than those in butylphthalide group (p < .001, respectively), and rMTT in combined group was lower than that in butylphthalide group (p = .001). The rate of adverse events in the two groups were comparable (p = .558). CONCLUSION: Butylphthalide combined with urinary kallidinogenase can improve the clinical symptoms of CCCI patients, and the effect is promising, which is worthy of clinical application.

Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.

Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.

Effect of quercetin glycosides on cognitive functions and cerebral blood flow: a randomized, double-blind, and placebo-controlled study.

OBJECTIVE: This study aimed to examine the effects of quercetin glycoside-containing beverages on cognitive function and cerebral blood flow (CBF) in adult men and women aged between 60 and 75 years. PATIENTS AND METHODS: Eighty healthy men and women with no cognitive impairment and aware of ageing-related forgetfulness underwent a placebo-controlled, randomized, double-blind, and parallel-group trial. They regularly consumed 500 mL of beverage containing 110 mg of quercetin glycoside as isoquercitrin for 40 weeks. Cognitive function assessment by Cognitrax was the endpoint of the study. The participants were assessed for CBF, health-related quality of life, as well as physical, biological, and hematological parameters, and lateral index. RESULTS: Cognitrax demonstrated that the reaction time significantly improved in the quercetin glycoside intake group. The CBF measurement suggested that quercetin glycoside intake could likely suppress the decrease in cerebral blood volume, CBF, and cerebral activity owing to stress alleviation and inhibition of the accumulation of amyloid ß (Aß), a waste product in the brain, although there were no significant differences between the groups. CONCLUSIONS: Quercetin glycoside intake as a beverage could improve reaction time and may potentially inhibit the decrease in CBF and suppress Aß accumulation.

Peri-operative neurological monitoring with electroencephalography and cerebral oximetry: a narrative review.

Surgery and anaesthesia subject the brain to considerable stress in the peri-operative period. This may be caused by potentially neurotoxic anaesthetic drugs, impaired cerebral perfusion and reperfusion injury related to surgery or thromboembolic events. Patient monitoring using electroencephalogram and cerebral oximetry can assist in optimising depth of anaesthesia and assessment of cerebral metabolic activity. However, research findings have been contradictory as to whether these monitors can help ameliorate peri-operative neurocognitive complications. In this narrative review, we will discuss recent evidence in the use of electroencephalography and cerebral oximetry and the underlying scientific principles. It is important to appreciate the raw electroencephalographic changes under anaesthesia and those associated with ageing, in order to interpret depth of anaesthesia indices correctly. Cerebral oximetry is useful not only for the detection of cerebral desaturation but also to identify those patients who are particularly vulnerable to injury, for better risk stratification. An algorithm-based approach may be most effective in managing the episodes of cerebral desaturation.

Polysaccharide from Ganoderma lucidum alleviates cognitive impairment in a mouse model of chronic cerebral hypoperfusion by regulating CD4+CD25+Foxp3+ regulatory T cells.

Ganoderma lucidum (G. lucidum) is a kind of edible and medicinal mushroom. G. lucidum polysaccharide-1 (GLP-1) is one of the polysaccharides purified from crude GLP. Chronic cerebral hypoperfusion (CCH) as the common pathological basis of various forms of dementia is an important cause of cognitive impairment. In this study, a step-down test was used to evaluate the cognitive ability of CCH mice. Flow cytometry was used to detect the proportion of CD4+CD25+Foxp3+ regulatory T (Foxp3+Treg) cells. ELISA analysis and western blot analysis were used to detect the transforming growth factor-ß1 (TGF-ß1) and Interleukin-10 (IL-10) levels that Foxp3+Treg cells secreted. Metabolomic analysis based on gas chromatography-mass spectrometry (GC-MS) was used to evaluate the effect of GLP-1 on dysfunctional metabolism caused by inflammation. Results indicate that GLP-1 exhibited an alleviating cognitive impairment effect on CCH mice. The mechanism was related to GLP-1 by increasing Foxp3+Treg cell levels to increase levels of IL-10 and TGF-ß1 and regulate abnormal energy metabolism. These findings could provide preliminary results to exploit G. lucidum as a health care product or functional food for the adjuvant therapy of cognitive impairment of CCH.

Blood product resuscitation mitigates the effects of aeromedical evacuation after polytrauma.

BACKGROUND: The combined injury of traumatic brain injury and hemorrhagic shock has been shown to worsen coagulopathy and systemic inflammation, thereby increasing posttraumatic morbidity and mortality. Aeromedical evacuation to definitive care may exacerbate postinjury morbidity because of the inherent hypobaric hypoxic environment. We hypothesized that blood product resuscitation may mitigate the adverse physiologic effects of postinjury flight. METHODS: An established porcine model of controlled cortical injury was used to induce traumatic brain injury. Intracerebral monitors were placed to record intracranial pressure, brain tissue oxygenation, and cerebral perfusion. Each of the 42 pigs was hemorrhaged to a goal mean arterial pressure of 40 ± 5 mm Hg for 1 hour. Pigs were grouped according to resuscitation strategy used-Lactated Ringer's (LR) or shed whole blood (WB)-then placed in an altitude chamber for 2 hours at ground, 8,000 ft, or 22,000 ft, and then observed for 4 hours. Hourly blood samples were analyzed for proinflammatory cytokines and lactate. Internal jugular vein blood flow was monitored continuously for microbubble formation with altitude changes. RESULTS: Cerebral perfusion, tissue oxygenation, and intracranial pressure were unchanged among the six study groups. Venous microbubbles were not observed even with differing altitude or resuscitation strategy. Serum lactate levels from hour 2 of flight to the end of observation were significantly elevated in 22,000 + LR compared with 8,000 + LR and 22,000 + WB. Serum IL-6 levels were significantly elevated in 22,000 + LR compared with 22,000 + WB, 8,000 + LR and ground+LR at hour 1 of observation. Serum tumor necrosis factor-α was significantly elevated at hour 2 of flight in 8,000 + LR versus ground+LR, and in 22,000 + LR vs. 22,000 + WB at hour 1 of observation. Serum IL-1ß was significantly elevated hour 1 of flight between 8,000 + LR and ground+LR. CONCLUSION: Crystalloid resuscitation during aeromedical transport may cause a prolonged lactic acidosis and proinflammatory response that can predispose multiple-injury patients to secondary cellular injury. This physiologic insult may be prevented by using blood product resuscitation strategies.

Effect of drug interventions on cerebral hemodynamics in ischemic stroke patients.

The ischemic penumbra is sensitive to alterations in cerebral perfusion. A myriad of drugs are used in acute ischemic stroke (AIS) management, yet their impact on cerebral hemodynamics is poorly understood. As part of the Cerebral Autoregulation Network led INFOMATAS project (Identifying New Targets for Management and Therapy in Acute Stroke), this paper reviews some of the most common drugs a patient with AIS will come across and their potential influence on cerebral hemodynamics with a particular focus being on cerebral autoregulation (CA). We first discuss how compounds that promote clot lysis and prevent clot formation could potentially impact cerebral hemodynamics, before focusing on how the different classes of antihypertensive drugs can influence cerebral hemodynamics. We discuss the different properties of each drug and their potential impact on cerebral perfusion and CA. With emerging interest in CA status of AIS patients, either during or soon after treatment when timely reperfusion and salvageable tissue is at its most critical, the properties of these pharmacological agents may be relevant for modelling cerebral perfusion accuracy and for setting individualised treatment strategies.

Mechanisms of Flow-Mediated Dilation of Pial Collaterals and the Effect of Hypertension.

Leptomeningeal anastomoses are small distal anastomotic vessels also known as pial collaterals in the brain. These vessels redirect blood flow during an occlusion and are important for stroke treatment and outcome. Pial collaterals have unique hemodynamic forces and experience significantly increased luminal flow and shear stress after the onset of ischemic stroke. However, there is limited knowledge of how pial collaterals respond to flow and shear stress, and whether this response is altered in chronic hypertension. Using an in vitro system, pial collaterals from normotensive and hypertensive rats (n=6-8/group) were isolated and luminal flow was induced with intravascular pressure maintained at 40 mm Hg. Collateral lumen diameter was measured following each flow rate in the absence or presence of pharmacological inhibitors and activators. Collaterals from male and female Wistar rats dilated similarly to increased flow (2 µL/minute: 58.4±18.7% versus 67.9±7.4%; P=0.275), and this response was prevented by inhibition of the transient receptor potential vanilloid type 4 channel, as well as inhibitors of nitric oxide and intermediate-conductance calcium-activated potassium channels, suggesting shear stress-induced activation of this pathway was involved. However, the vasodilation was significantly impaired in hypertensive rats (2 µL/minute: 17.7±7.7%), which was restored by inhibitors of reactive oxygen species and mimicked by angiotensin II. Thus, flow- and shear stress-induced vasodilation of pial collaterals appears to be an important stimulus for increasing collateral flow during large vessel occlusion. Impairment of this response during chronic hypertension may be related to poorly engaged pial collaterals during ischemic stroke in hypertensive subjects.

Xi-Xian-Tong-Shuan capsule alleviates vascular cognitive impairment in chronic cerebral hypoperfusion rats by promoting white matter repair, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors.

BACKGROUND: While the number of cases of vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has been increasing every year, there are currently no clinically effective treatment methods. At present, Xi-Xian-Tong-Shuan capsule is predominantly used in patients with acute cerebral ischemia; however, its protective effect on CCH has rarely been reported. OBJECTIVE: To explore the underlying mechanisms by which Xi-Xian-Tong-Shuan capsule alleviates cognitive impairment caused by CCH. METHODS: A model of CCH was established in specific-pathogen-free (SPF)-grade male Sprague-Dawley (SD) rats using bilateral common carotid artery occlusion (BCCAO). Xi-Xian-Tong-Shuan capsules were intragastrically administered for 42 days after the BCCAO surgery. We then assessed for changes in cognitive function, expression levels of pro-inflammatory factors, and coagulation function as well as for the presence of white matter lesions and neuronal loss. One-way ANOVA and Tukey's test were used to analyze the experimental data. RESULTS: The rats showed significant cognitive dysfunction after the BCCAO surgery along with white matter lesions, a loss of neurons, and elevated levels of inflammatory factors, all of which were significantly reversed after intervention with Xi-Xian-Tong-Shuan capsules. CONCLUSION: Xi-Xian-Tong-Shuan capsules can ameliorate vascular cognitive impairment in CCH rats by preventing damage of white matter, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors. Our study provides a new reference for the clinical treatment of chronic cerebral ischemia with Xi-Xian-Tong-Shuan capsules.

Clots in unusual places: lots of stress, limited data, critical decisions.

Although much less common than deep vein thrombosis of the lower extremities or lungs, clots in unusual locations, including the splanchnic, cerebral, retinal, upper-extremity, and renal locations, present with significant morbidity and mortality. In the last 2 decades, treatment of clots in these unusual locations is primarily managed medically, with interventional and surgical approaches reserved for more severe or refractory cases. The hematologist is well positioned to provide consultation to organ-specific specialties (ie, neurosurgery, hepatology, ophthalmology), especially because acquired and congenital hypercoagulability plays a major role, and anticoagulation is often the primary treatment. Historically, treatment has been based on expert opinion, but systematic reviews and meta-analyses have recently been published. Various societies have produced guidelines for the treatment of clots in unusual locations; however, randomized clinical trial data remain scarce. In the last few years, increasing data have emerged concerning the efficacy of the direct oral anticoagulants in treating clots in unusual locations. Cases have recently been described highlighting atypical thrombosis associated with COVID-19 infection as well as with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine and Johnson and Johnson's Janssen Ad26.COV2.S vaccine. This article reviews clots in unusual locations with an emphasis on the splanchnic (mesenteric, portal, splenic, hepatic) and cerebral circulation. Through a case-based approach, key questions are posed, and data are presented to help guide diagnosis and treatment.

Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion.

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations.

Factors affecting brain structure in smoking-related diseases: Chronic Obstructive Pulmonary Disease (COPD) and coronary artery disease.

BACKGROUND: Changes in brain structure and cognitive decline occur in Chronic Obstructive Pulmonary Disease (COPD). They also occur with smoking and coronary artery disease (CAD), but it is unclear whether a common mechanism is responsible. METHODS: Brain MRI markers of brain structure were tested for association with disease markers in other organs. Where possible, principal component analysis (PCA) was used to group markers within organ systems into composite markers. Univariate relationships between brain structure and the disease markers were explored using hierarchical regression and then entered into multivariable regression models. RESULTS: 100 participants were studied (53 COPD, 47 CAD). PCA identified two brain components: brain tissue volumes and white matter microstructure, and six components from other organ systems: respiratory function, plasma lipids, blood pressure, glucose dysregulation, retinal vessel calibre and retinal vessel tortuosity. Several markers could not be grouped into components and were analysed as single variables, these included brain white matter hyperintense lesion (WMH) volume. Multivariable regression models showed that less well organised white matter microstructure was associated with lower respiratory function (p = 0.028); WMH volume was associated with higher blood pressure (p = 0.036) and higher C-Reactive Protein (p = 0.011) and lower brain tissue volume was associated with lower cerebral blood flow (p<0.001) and higher blood pressure (p = 0.001). Smoking history was not an independent correlate of any brain marker. CONCLUSIONS: Measures of brain structure were associated with a range of markers of disease, some of which appeared to be common to both COPD and CAD. No single common pathway was identified, but the findings suggest that brain changes associated with smoking-related diseases may be due to vascular, respiratory, and inflammatory changes.

Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor ß (TGF-ß) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-ß binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Neuroprotective strategies of cerebrolysin for the treatment of infants with neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Perinatal asphyxia (PA) is a devastating neonatal condition characterized by a lack of oxygen supporting the organ systems. PA can lead to hypoxic-ischemic encephalopathy (HIE), a brain dysfunction due to oxygen deprivation with a complex neurological sequela. The pathophysiology of HIE and PA is not entirely understood, with therapeutic hypothermia being the standard treatment with only limited value. However, alternative neuroprotective therapies can be a potential treatment modality. METHODS: In this review, we will characterize the biochemical mechanisms of PA and HIE, while also giving insight into cerebrolysin, a neuroprotective treatment used for HIE and PA. RESULTS: We found that cerebrolysin has up to 6-month treatment window post-ischemic insult. Cerebrolysin injections of 0.1 ml/kg of body weight twice per week were found to provide gross motor and speech deficit improvement. CONCLUSION: Our literature search emphasizes the positive effects of cerebrolysin for general improvement outcomes. Nevertheless, biomarker establishment is warranted to improve patient outcomes.

Mizagliflozin, a selective SGLT1 inhibitor, improves vascular cognitive impairment in a mouse model of small vessel disease.

Previously, we showed that sodium/glucose cotransporter 1 (SGLT1) participates in vascular cognitive impairment in small vessel disease. We hypothesized that SGLT1 inhibitors can improve the small vessel disease induced-vascular cognitive impairment. We examined the effects of mizagliflozin, a selective SGLT1 inhibitor, and phlorizin, a non-selective SGLT inhibitor, on vascular cognitive impairment in a mouse model of small vessel disease. Small vessel disease was created using a mouse model of asymmetric common carotid artery surgery (ACAS). Two and/or 4 weeks after ACAS, all experiments were performed. Cerebral blood flow (CBF) was decreased in ACAS compared with sham-operated mice. Phlorizin but not mizagliflozin reversed the decreased CBF of ACAS mice. Both mizagliflozin and phlorizin reversed the ACAS-induced decrease in the latency to fall in a wire hang test of ACAS mice. Moreover, they reversed the ACAS-induced longer escape latencies in the Morris water maze test of ACAS mice. ACAS increased SGLT1 and proinflammatory cytokine gene expressions in mouse brains and phlorizin but not mizagliflozin normalized all gene expressions in ACAS mice. Hematoxylin/eosin staining demonstrated that they inhibited pyknotic cell death in the ACAS mouse hippocampus. In PC12HS cells, IL-1ß increased SGLT1 expression and decreased survival rates of cells. Both mizagliflozin and phlorizin increased the survival rates of IL-1ß-treated PC12HS cells. These results suggest that mizagliflozin and phlorizin can improve vascular cognitive impairment through the inhibition of neural SGLT1 and phlorizin also does so through the improvement of CBF in a mouse model of small vessel disease.

Effects of NLRP3 inflammasome blockade on postresuscitation cerebral function in a rat model of cardiopulmonary resuscitation.

Cardiac arrest (CA) remains a major public health issue. Inflammatory responses with overproduction of interleukin-1ß regulated by NLRP3 inflammasome activation play a crucial role in cerebral ischemia/reperfusion injury. We investigated the effects of the selective NLRP3-inflammasome inhibitor MCC950 on post-resuscitation cerebral function and neurologic outcome in a rat model of cardiac arrest. Thirty-six male rats were randomized into the MCC950 group, the control group, or the sham group (N = 12 of each group). Each group was divided into a 6 h non-survival subgroup (N = 6) and a 24 h survival subgroup (N = 6). Ventricular fibrillation (VF) was electrically induced and untreated for 6 min, followed by 8 min of precordial compressions and mechanical ventilation. Resuscitation was attempted with a 4J defibrillation. Either MCC950 (10 mg/kg) or vehicle was injected intraperitoneally immediately after the return of spontaneous circulation (ROSC). Rats in the sham group underwent the same surgical procedures without VF and CPR. Brain edema, cerebral microcirculation, plasma interleukin Iß (IL-1ß), and neuron-specific enolase (NSE) concentration were measured at 6 h post-ROSC of non-survival subgroups, while 24 h survival rate, neurological deficits were measured at 24 h post-ROSC of survival subgroups. Post-resuscitation brain edema was significantly reduced in animals treated with MCC950 (p < 0.05). Cerebral perfused vessel density (PVD) and microcirculatory flow index (MFI) values were significantly higher in the MCC950 group compared with the control group (p < 0.05). The plasma concentrations of IL-1ß and NSE were significantly decreased in animals treated with MCC950 compared with the control group (p < 0.05). 24 h-survival rate and neurological deficits score (NDS) was also significantly improved in the MCC950 group compared with the control group (p < 0.05). NLRP3 inflammasome blockade with MCC950 at ROSC reduces the circulatory level of IL-1ß, preserves cerebral microcirculation, mitigates cerebral edema, improves the 24 h-survival rate, and neurological deficits.

Local Application of Magnesium Sulfate Solution Suppressed Cortical Spreading Ischemia and Reduced Brain Damage in a Rat Subarachnoid Hemorrhage-Mimicking Model.

OBJECTIVE: Cortical spreading depolarization (CSD), cortical spreading ischemia (CSI), and early brain injury are involved in the occurrence of delayed brain ischemia after subarachnoid hemorrhage (SAH). We tested whether local application of magnesium (Mg) sulfate solution suppressed CSD and CSI, and decreased brain damage in a rat SAH-mimicking model. METHODS: Nitric oxide synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and high concentration potassium solution were topically applied to simulate the environment after SAH. We irrigated the parietal cortex with artificial cerebrospinal fluid (ACSF), containing L-NAME (1 mM), K+ (35 mM), and Mg2+ (5 mM). Forty-five rats were divided into 3 groups: sham surgery (sham group), L-NAME + [K+]ACSF (control group), and L-NAME + [K+]ACSF + [Mg2+] (Mg group). CSD was induced by topical application with 1 M KCl solution in 3 groups. The effects of Mg administration on CSD and cerebral blood flow were evaluated. Histological brain tissue damage, body weight, and neurological score were assessed at 2 days after insult. RESULTS: Mg solution significantly shortened the total depolarization time, and reduced CSI, histological brain damage, and brain edema compared with those of the control group (P < 0.05). Body weight loss was significantly suppressed in the Mg group (P < 0.05), but neurological score did not improve. CONCLUSIONS: Local application of Mg suppressed CSI and reduced brain damage in a rat SAH-mimicking model. Mg irrigation therapy may be beneficial to suppress brain damage due to CSI after SAH.

Xenon Nanobubbles for the Image-Guided Preemptive Treatment of Acute Ischemic Stroke via Neuroprotection and Microcirculatory Restoration.

Early lesion site diagnosis and neuroprotection are crucial to the theranostics of acute ischemic stroke. Xenon (Xe), as a nontoxic gaseous neuroprotectant, holds great promise for ischemic stroke therapy. In this study, Xe-encapsulated lipid nanobubbles (Xe-NBs) have been prepared for the real-time ultrasound image-guided preemptive treatment of the early stroke. The lipids are self-assembled at the interface of free Xe bubbles, and the mean diameter of Xe-NBs is 225 ± 11 nm with a Xe content of 73 ± 2 µL/mL. The in vitro results show that Xe-NBs can protect oxygen/glucose-deprived PC12 cells against apoptosis and oxidative stress. Based on the ischemic stroke mice model, the biodistribution, timely ultrasound imaging, and the therapeutic effects of Xe-NBs for stroke lesions were investigated in vivo. The accumulation of Xe-NBs to the ischemic lesion endows ultrasound contrast imaging with the lesion area. The cerebral blood flow measurement indicates that the administration of Xe-NBs can improve microcirculatory restoration, resulting in reduced acute microvascular injury in the lesion area. Furthermore, local delivery of therapeutic Xe can significantly reduce the volume of cerebral infarction and restore the neurological function with reduced neuron injury against apoptosis. Therefore, Xe-NBs provide a novel nanosystem for the safe and rapid theranostics of acute ischemic stroke, which is promising to translate into the clinical management of stroke.

Tannic acid protects aged brain against cerebral hypoperfusion via modulation of Nrf2 and inflammatory pathways.

Current study purposed to investigate the neuroprotective effects of Tannic Acid (TA) on mild chronic cerebral hypoperfusion model in rats. Male Wistar rats were subjected to permanent Unilateral Common Carotid Artery Occlusion (UCCAO), followed by TA treatment (0.05% w/v) in drinking water for one month. Nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, blood triglyceride, blood glucose, and liver enzymes' activity were detected after the experimental period. Also, behavioral tests, hematoxylin and eosin (H&E) staining, and PET scan were performed after treatment. Post-treatment of TA improved locomotion and memory function (P < 0.001), and reduced neural cell death (P < 0.001) in the treatment group compared to UCCAO rats. Furthermore, long-term TA treatment significantly increased the levels of Nrf2 (P < 0.001), NQO-1 (P < 0.001), and HO-1 (P < 0.001) in the hippocampus of the treatment group compared to the UCCAO group. TA consumption in the treatment group applied its anti-inflammatory effects via reducing the activity of NF-κB and TNF-α in comparison with the UCCAO group (P < 0.001 for both). Blood triglyceride, blood glucose, and liver enzymes did not change considerably in the groups (P > 0.05). The current results indicate that long-term post-treatment of TA exhibits protective effects against memory deficit and motor dysfunction. The cellular mechanism of TA in hypoperfused rats might be associated with the activation of antioxidant pathways, especially the Nrf2 pathway, and suppressing inflammatory factors like NF-κB and TNF-α.