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Objective: Brain ischemia generally results in irreversible brain damage or death. One of the most important features of an ischemic stroke is disruption of the Blood-brain barrier (BBB). In this study, we examined the effect of cinnamon hydroalcoholic extract consumption on BBB permeability and expression of some genes regulating its function. Materials and Methods: Sixty male Wistar rats were divided into 5 groups; sham (high-fat diet+ sham surgery), Model (Middle Cerebral Artery Occlusion, MCAO+ high-fat diet), Lovastatin (high-fat diet + lovastatin + MCAO surgery), low and high dosage cinnamon (high-fat diet + cinnamon 130 or 260 mg, respectively+ MCAO surgery). The two doses of cinnamon (130 and 260 mg) were administered intraperitoneally. Twelve hours after ischemic stroke induction, brain right hemisphere tissues were collected and calpain I, calpainII, occludin and VEGF genes expression were quantified by Real-Time -PCR. Accordingly, p-selection protein levels were measured by ELISA method. Results: Cinnamon hydroalcoholic extract reduced the BBB permeability compared with the model group (p<0.05). Stroke increased calpain and VEGF genes while decreased occludin gene expression (p<0.001). Conversely, cinnamon administration increased occludin gene expression while calpain and VEGF genes were down-regulated (p<0.01). Pretreatment with cinnamon significantly diminished the P-Selectin protein levels as compared with the model group dose dependently (p<0.001). Conclusion: It seems that cinnamon restores BBB function by regulating the elements involved in its permeability. [ABSTRACT FROM AUTHOR]

Background: Accurate longitudinal risk prediction for DCI (delayed cerebral ischemia) occurrence after subarachnoid hemorrhage (SAH) is essential for clinicians to administer appropriate and timely diagnostics, thereby improving treatment planning and outcome. This study aimed to develop an improved longitudinal DCI prediction model and evaluate its performance in predicting DCI between day 4 and 14 after aneurysm rupture. Methods: Two DCI classification models were trained: (1) a static model based on routinely collected demographics and SAH grading scores and (2) a dynamic model based on results from laboratory and blood gas analysis anchored at the time of DCI. A combined model was derived from these two using a voting approach. Multiple classifiers, including Logistic Regression, Support Vector Machines, Random Forests, Histogram-based Gradient Boosting, and Extremely Randomized Trees, were evaluated through cross-validation using anchored data. A leave-one-out simulation was then performed on the best-performing models to evaluate their longitudinal performance using time-dependent Receiver Operating Characteristic (ROC) analysis. Results: The training dataset included 218 patients, with 89 of them developing DCI (41%). In the anchored ROC analysis, the combined model achieved a ROC AUC of 0.73 ± 0.05 in predicting DCI onset, the static and the dynamic model achieved a ROC AUC of 0.69 ± 0.08 and 0.66 ± 0.08, respectively. In the leave-one-out simulation experiments, the dynamic and voting model showed a highly dynamic risk score (intra-patient score range was 0.25 [0.24, 0.49] and 0.17 [0.12, 0.25] for the dynamic and the voting model, respectively, for DCI occurrence over the course of disease. In the time-dependent ROC analysis, the dynamic model performed best until day 5.4, and afterwards the voting model showed the best performance. Conclusions: A machine learning model for longitudinal DCI risk assessment was developed comprising a static and a dynamic sub-model. The longitudinal performance evaluation highlighted substantial time dependence in model performance, underscoring the need for a longitudinal assessment of prediction models in intensive care settings. Moreover, clinicians need to be aware of these performance variations when performing a risk assessment and weight the different model outputs correspondingly. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a significant global health issue, ranking fifth among all causes of death and a leading cause of serious long‐term disability. Ischemic stroke leads to severe outcomes, including permanent brain damage and neuronal dysfunction. Therefore, decreasing and preventing neuronal injuries caused by stroke has been the focus of therapeutic research. In recent years, many studies have shown that fluctuations in hormonal levels influence the prognosis of ischemic stroke. Thus, it is relevant to understand the role of hormones in the pathophysiological mechanisms of ischemic stroke for preventing and treating this health issue. Here, we investigate the contribution of the prolactin/vasoinhibin axis, an endocrine system regulating blood vessel growth, immune processes, and neuronal survival, to the pathophysiology of ischemic stroke. Male mice with brain overexpression of prolactin or vasoinhibin by adeno‐associated virus (AAV) intracerebroventricular injection or lacking the prolactin receptor (Prlr−/−) were exposed to transient middle cerebral artery occlusion (tMCAO) for 45 min followed by 48 h of reperfusion. Overexpression of vasoinhibin or the absence of the prolactin receptor led to an increased lesion volume and decreased survival rates in mice following tMCAO, whereas overexpression of prolactin had no effect. In addition, astrocytic distribution in the penumbra was altered, glial fibrillary acidic protein and S100b mRNA expressions were reduced, and interleukin‐6 mRNA expression increased in the ischemic hemisphere of mice overexpressing vasoinhibin. Of note, prolactin receptor‐null mice (Prlr−/−) showed a marked increase in serum vasoinhibin levels. Furthermore, vasoinhibin decreased astrocyte numbers in mixed hippocampal neuron–glia cultures. These observations suggest that increased vasoinhibin levels may hinder astrocytes' protective reactivity. Overall, this study suggests the involvement of the prolactin/vasoinhibin axis in the pathophysiology of ischemic stroke‐induced brain injury and provides insights into the impact of its dysregulation on astrocyte reactivity and lesion size. Understanding these mechanisms could help develop therapeutic interventions in ischemic stroke and other related neurological disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hypoperfusion due to blood pressure (BP) reduction is a potential mechanism of cerebral ischemia after intracerebral hemorrhage. However, prior evaluations of the relationship between BP reduction and ischemia have been conflicting. Untreated chronic hypertension is common in intracerebral hemorrhage and alters cerebral autoregulation. We hypothesized that the risk of diffusion-weighted imaging (DWI) hyperintensities from acute BP reduction is modified by premorbid BP control. METHODS: Individuals enrolled in the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage) from 2010 to 2015 were categorized as untreated, treated, or nonhypertensive based on preintracerebral hemorrhage diagnosis and antihypertensive medication use. The percent reduction of systolic BP (SBP) was calculated between presentation and 24 hours from admission. The primary outcome was the presence of DWI lesions. Using logistic regression, we tested the association between chronic hypertension status, SBP reduction, and their interaction with DWI lesion presence. RESULTS: From 3000 participants, 877 with available magnetic resonance imaging met inclusion (mean age, 60.5±13.3 years; 42.5% women). DWI lesions were detected in 25.9%. Untreated, treated, and no hypertension accounted for 32.6%, 47.9%, and 19.5% of cases, respectively. SBP reduction was not directly associated with DWI lesions; however, an interaction effect was observed between SBP reduction and chronic hypertension status (P=0.036). Nonhypertensive subjects demonstrated a linear risk of DWI lesion presence with greater SBP reduction, whereas untreated hypertension demonstrated a stable risk across a wide range of SBP reduction (P=0.023). CONCLUSIONS: Premorbid BP control, especially untreated hypertension, may influence the relationship between DWI lesions and acute BP reduction after intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

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Background and Objective: The alteration of mitochondrial functions, especially the opening of the mitochondrial permeability transition pore (mPTP), has been proposed as a key mechanism in the development of lesions in cerebral ischemia, wherefore it is considered as an important target for drugs against ischemic injury. In this study, we aimed to investigate the effects of mitochondrial complex I inhibitors as possible regulators of mPTP using an in vitro brain ischemia model of the pentobarbital/ketamine (PBK)-anesthetized rats. Results: We found that PBK anesthesia itself delayed Ca2+-induced mPTP opening and partially recovered the respiratory functions of mitochondria, isolated from rat brain cortex and cerebellum. In addition, PBK reduced cell death in rat brain slices of cerebral cortex and cerebellum. PBK inhibited the adenosine diphosphate (ADP)-stimulated respiration of isolated cortical and cerebellar mitochondria respiring with complex I-dependent substrates pyruvate and malate. Moreover, pentobarbital alone directly increased the resistance of isolated cortex mitochondria to Ca2+-induced activation of mPTP and inhibited complex I-dependent respiration and mitochondrial complex I activity. In contrast, ketamine had no direct effect on functions of isolated normal cortex and cerebellum mitochondria. Conclusions: Altogether, this suggests that modulation of mitochondrial complex I activity by pentobarbital during PBK anesthesia may increase the resistance of mitochondria to mPTP opening, which is considered the key event in brain cell necrosis during ischemia. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months. Methods: CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders. Results: 125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07–8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%). Conclusion: Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization. [ABSTRACT FROM AUTHOR]

Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1–20 mg/kg (in vivo) and 0.5–5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments. [ABSTRACT FROM AUTHOR]

Objective(s): This study assessed the effects of electroacupuncture (EA) stimulation at different frequencies at the Dazhui and Baihui acupoints in the subacute phase after transient global cerebral ischemia (GCI). Materials and Methods: Rats were subjected to GCI for 25 min, followed by reperfusion for 7 days. EA at acupoints was performed at 10, 30, or 50 Hz, 1 day after reperfusion and then once daily for 6 consecutive days. Results: EA at acupoints at 10 and 50 Hz effectively down-regulated apoptosis in the hippocampal cornu ammonis 1(CA1) area and ameliorated memory deficits. Moreover, EA treatment at 10 and 50 Hz markedly increased phospho (p)-extracellular signal-regulated protein kinase 1/2 (ERK1/2), p-ERK1/2/neuronal nuclei (NeuN), p-cAMP response element-binding protein (CREB)/p-ERK1/2, B-cell lymphoma-2 (Bcl-2)/p-CREB, and X-linked inhibitor of apoptosis protein/NeuN expression levels and decreased Bcl-2 homologous antagonist/killer, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI, cytochrome c, cleaved caspase-3, and apoptosis-inducing factor expression levels. Furthermore, 10-Hz EA treatment effectively increased p-p38 mitogen-activated protein kinase (MAPK), p-p38 MAPK/NeuN, and p-CREB/p-p38 MAPK expression levels. Pretreatment with U0126 (ERK1/2 inhibitor) completely abrogated the effects of 10- and 50-Hz EA treatments on the aforementioned protein expression levels. Similarly, pretreatment with SB203580 (p38 MAPK inhibitor) completely abrogated the effects of 10-Hz treatment on the aforementioned protein expression levels. Conclusion: The effects of 10- and 50-Hz EA treatments on mitochondria-related apoptosis can be attributed to the activation of ERK1/2/p38 MAPK/CREB/Bcl-2- and ERK1/2/CREB/Bcl-2-mediated signaling, respectively, in the hippocampal CA1 area at 7 days after transient GCI.

Glutamate (Glu) is a major excitatory neurotransmitter in the brain, essential for synaptic plasticity, neuronal activity, and memory formation. However, its dysregulation leads to excitotoxicity, implicated in neurodegenerative diseases and brain ischemia. Vesicular glutamate transporters (VGLUTs) regulate Glu loading into synaptic vesicles, crucial for maintaining optimal extracellular Glu levels. This study investigates the neuroprotective effects of VGLUT1 inhibition in HT22 cells overexpressing VGLUT1 under oxygen glucose deprivation (OGD) conditions. HT22 cells, a hippocampal neuron model, were transduced with lentiviral vectors to overexpress VGLUT1. Cells were subjected to OGD, with pre-incubation of Chicago Sky Blue 6B (CSB6B), an unspecific VGLUT inhibitor. Cell viability, lactate dehydrogenase (LDH) release, mitochondrial membrane potential, and hypoxia-related protein markers (PARP1, AIF, NLRP3) were assessed. Results indicated that VGLUT1 overexpression increased vulnerability to OGD, evidenced by higher LDH release and reduced cell viability. CSB6B treatment improved cell viability and reduced LDH release in OGD conditions, particularly at 0.1 μM and 1.0 μM concentrations. Moreover, CSB6B preserved mitochondrial membrane potential and decreased levels of PARP1, AIF, and NLRP3 proteins, suggesting neuroprotective effects through mitigating excitotoxicity. This study demonstrates that VGLUT1 inhibition could be a promising therapeutic strategy for ischemic brain injury, warranting further investigation into selective VGLUT1 inhibitors. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to monitor blood-brain barrier permeability within 24 h and during the delayed cerebral ischemia (DCI) time window (DCITW) spanning 4–14 days after aneurysmal subarachnoid hemorrhage (aSAH) and to investigate its correlation with both DCI occurrence and outcomes at three months. Methods: A total of 128 patients were stratified based on the DCI occurrence and three-month modified Rankin scale scores. Comparison of Ktrans at admission (admission Ktrans) and during DCITW (DCITW Ktrans) was conducted between DCI and non-DCI groups, as well as between groups with good and poor outcomes. Changes in Ktrans were also analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of DCI and poor outcomes. Results: Admission Ktrans (0.58 ± 0.18 vs 0.47 ± 0.12, p = 0.002) and DCITW Ktrans (0.54 ± 0.19 vs 0.41 ± 0.14, p < 0.001) were significantly higher in the DCI group compared with the non-DCI group. Although both were higher in the poor outcome group than the good outcome group, the difference was not statistically significant at admission (0.53 ± 0.18 vs 0.49 ± 0.14, p = 0.198). Ktrans in the non-DCI group (0.47 ± 0.12 vs 0.41 ± 0.14, p = 0.004) and good outcome group (0.49 ± 0.14 vs 0.41 ± 0.14, p < 0.001) decreased significantly from the admission to DCITW. Multivariate analysis identified DCITW Ktrans and admission Ktrans as independent predictors of poor outcomes (OR = 1.73, 95%CI: 1.24–2.43, p = 0.001) and DCI (OR = 1.75, 95%CI: 1.25–2.44, p = 0.001), respectively. Conclusion: Elevated Ktrans at admission is associated with the occurrence of DCI. Continuous monitoring of Ktrans from admission to DCITW can accurately identify reversible and irreversible changes and can predict outcomes at 3 months. Clinical relevance statement: Ktrans measured with CT perfusion is a valuable tool for predicting both delayed cerebral ischemia and three-month outcomes following aneurysmal subarachnoid hemorrhage. Monitoring changes in Ktrans from admission to time window of delayed cerebral ischemia can guide treatment and management decisions for aneurysmal subarachnoid hemorrhage patients. Key Points: • Ktrans measured at admission and during the delayed cerebral ischemia time window (4–14 days) holds distinct clinical significance following aneurysmal subarachnoid hemorrhage. • Admission Ktrans serves as a predictor for delayed cerebral ischemia, while continuous assessment of Ktrans from admission to the delayed cerebral ischemia time window can predict three-month outcomes. • Monitoring Ktrans at different stages improves instrumental in enhancing decision-making and treatment planning for patients with aneurysmal subarachnoid hemorrhage. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and brain ischemia/reperfusion cause neurodegenerative processes that can continue after the acute stage with the development of severe brain atrophy with dementia. In this case, the long-term neurodegeneration of the brain is similar to the neurodegeneration characteristic of Alzheimer's disease (AD) and is associated with the accumulation of beta amyloid and tau protein. In the pathogenesis of AD as well as in the pathogenesis of cerebral ischemia and TBI oxidative stress, progressive inflammation, glial activation, blood–brain barrier dysfunction, and excessive activation of autophagy are involved, which implies the presence of many targets that can be affected by neuroprotectors. That is, multivariate cascades of nerve tissue damage represent many potential targets for therapeutic interventions. One of such substances that can be used in multi-purpose therapeutic strategies is methylene blue (MB). This drug can have an antiapoptotic and anti-inflammatory effect, activate autophagy, inhibit the aggregation of proteins with an irregular shape, inhibit NO synthase, and bypass impaired electron transfer in the respiratory chain of mitochondria. MB is a well-described treatment for methemoglobinemia, malaria, and encephalopathy caused by ifosfamide. In recent years, this drug has attracted great interest as a potential treatment for a number of neurodegenerative disorders, including the effects of TBI, ischemia, and AD. [ABSTRACT FROM AUTHOR]

Background: Currently, no evidence exists on the expression of apoptosis (CASP3), autophagy (BECN1), and mitophagy (BNIP3) genes in the CA3 area after ischemia with long-term survival. Objective: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6–24 months. Methods: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer's disease. Results: First time, we demonstrated overexpression of the CASP3 gene in CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. Conclusions: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3. This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect and potential mechanism of early exercise intervention on cerebral myelin in cerebral ischemia rats. Methods A total of 18 SD rats were randomly divided into the sham group, the middle cerebral artery occlusion resting group (MCAO-SED) and the middle cerebral artery occlusion exercise group (MCAO-EX), with 6 rats in each group. Except the sham group, the middle cerebral artery occlusion model was prepared by modified Longa line embolization method in other groups. After modeling, rats in the MCAO-EX group were placed on a treadmill for exercise intervention for 28 days. Neurological function was assessed by modified neural function deficit score (mNSS). Infarct volume was detected by MRI scanning (T2), myelin basic protein (MBP) expression was detected by immunofluorescence. Myelin sheath structure was detected by transmission electron microscopy. Western blot assay was used to detect endoplasmic reticulum stress-related protein expression. Apoptosis was detected by TUNEL staining. Results After 28 days of intervention, compared with the MCAO-SED group, the nerve function recovered well in the MCAO-EX group, infarct volume decreased, myelin integrity increased, MBP fluorescence intensity expression increased and MBP expression level increased. The expression levels of ATF6, p-IRE1, p-PERK and cleaved caspase 3 were significantly decreased, and apoptosis was reduced. Conclusion Early exercise can inhibit endoplasmic reticulum stress-induced apoptosis, promote cerebral myelin repair, reduce infarct size and improve nerve function. [ABSTRACT FROM AUTHOR]

Background: Neuromonitoring during carotid endarterectomy (CEA) under general anesthesia is desirable and may be useful for preventing brain ischemia, but the selection of the most appropriate method remains controversial. Purpose: To determine the effectiveness of near infrared spectroscopy (NIRS) compared to multimodality intraoperative neuromonitoring (IONM) in indicating elective shunts and predicting postoperative neurological status. Methods: This is a retrospective observational study including 86 consecutive patients with CEA under general anesthesia. NIRS and multimodality IONM were performed during the procedure. IONM included electroencephalography (EEG), somatosensory evoked potentials (SSEPs) and transcranial motor-evoked potentials (TcMEPs). Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were calculated for each neuromonitoring modality. Results: NIRS presented a sensitivity and a specificity for detecting brain ischemia of 77.7% and 89.6%, respectively (PPV = 46.6% and NPV = 97.2%). In contrast, a 100% sensitivity and specificity for multimodality IONM was determined (PPV and NPV = 100%). No significant difference (in demographical or clinical data) between "true positive" and "false-positive" patients was identified. Among the methods included in multimodality IONM, EEG showed the best results for predicting postoperative outcome after CEA (PPV and NPV=100%). Conclusion: NIRS is inferior to multimodality IONM in detecting brain ischemia and predicting postoperative neurological status during CEA under general anesthesia. [ABSTRACT FROM AUTHOR]

How brain functions in the distorted ischemic state before and after reperfusion is unclear. It is also uncertain whether there are any indicators within ischemic brain that could predict surgical outcomes. To alleviate these issues, we applied individual brain connectome in chronic steno‐occlusive vasculopathy (CSOV) to map both ischemic symptoms and their postbypass changes. A total of 499 bypasses in 455 CSOV patients were collected and followed up for 47.8 ± 20.5 months. Using multimodal parcellation with connectivity‐based and pathological distortion‐independent approach, areal MR features of brain connectome were generated with three measurements of functional connectivity (FC), structural connectivity, and PageRank centrality at the single‐subject level. Thirty‐three machine‐learning models were then trained with clinical and areal MR features to obtain acceptable classifiers for both ischemic symptoms and their postbypass changes, among which, 11 were deemed acceptable (AUC > 0.7). Notably, the FC feature‐based model for long‐term neurological outcomes performed very well (AUC > 0.8). Finally, a Shapley additive explanations plot was adopted to extract important individual features in acceptable models to generate "fingerprints" of brain connectome. This study not only establishes brain connectomic fingerprint databases for brain ischemia with distortion, but also provides informative insights for how brain functions before and after reperfusion. [ABSTRACT FROM AUTHOR]

Objective To investigate the protective effect of sevoflurane postconditioning against cerebral ischemia/reperfusion (I/R) injury in rats and its mechanism of action. Methods A total of 80 specific pathogen-free healthy adult male Sprague-Dawley rats were selected and randomly divided into sham-operation group (S group), cerebral I/R group (I/R group), cerebral I/R+sevoflurane postconditioning group (ISP group), and cerebral I/R+sevoflurane postconditioning+nuclear factor ery-throid 2-related factor 2 (Nrf2) inhibitor group (ISPB group), with 20 rats in each group. All rats except those in the S group were used to establish a rat model of cerebral I/R injury using the suture method for occlusion of the middle cerebral artery for 2 h, followed by reperfusion for 24 h, and for the rats in the S group, threading was performed below the middle cerebral artery without ligation. The rats in the ISP group were given inhalation of 3% sevoflurane immediately after reperfusion for 30 min, and those in the ISPB group were given intraperitoneal injection of the Nrf2 inhibitor brusatol (2 mg/kg) at 30 min before ischemia in addition to the treatment in the ISP group. After successful modeling, neurological deficit score was used to eval-uate the degree of neurological impairment. Left ventricular blood samples and pathological sections of brain tissue were obtained, and 2,3,5-triphenyltetrazolium chloride staining was used to determine the percentage of cerebral infarct volume; enzyme-linked immunosorbent assay was used to measure the serum levels of inflammatory factors (interleukin-1β [IL-1β] and tumor necrosis factor-α [TNF-α]) and oxidative stress-related factors (malondialdehyde [MDA] and superoxide dismutase [SOD]); Western blotting was used to mea-sure the expression of apoptosis-related proteins (B-cell lymphoma-2 [Bcl-2], Bcl-2 related x [Bax], and Caspase-3) and Nrf2 signaling pathway-related proteins (Nrf2 and heme oxygenase-1 [HO-1]) in brain tissue; immunofluorescence assay was used to measure the expression of Nrf2 inside and outside the nucleus of brain tissue cells. Results Compared with the I/R group, the ISP group had significant reductions in neurological deficit score, the percentage of cerebral infarct volume, the serum levels of IL-1β, TNF-α, and MDA, and the levels of Bax and Caspase-3 in brain tissue (t=5.76-18.39,P

The search for natural biologically active substances having a neuroprotective effect against cerebral ischemia-reperfusion injury is one of the major priorities of modern neuroscience and medicine. Intranasal insulin (INI) exerts a pronounced restorative effect on various neurodegenerative diseases, but the mechanisms of its action and its therapeutic effects in cerebral ischemia have not been well studied, including in type 2 diabetes mellitus (DM2) which increases the risk of cerebrovascular dysfunction. The aim of the work was to study the effect of INI on metabolic parameters and inflammatory factors in male Wistar rats with DM2, exposed to cerebral ischemia, as compared to nondiabetic animals. DM2 was induced by a combination of high-fat diet and low-dose (25 mg/kg) streptozotocin administration. Cerebral ischemia was studied in a rat model of global forebrain ischemia-reperfusion (IR) injury induced by occlusion of both common carotid arteries, followed by a 7-day reperfusion. Two h after the end of ischemic exposure, the rats were treated with INI at a dose of 0.5 or 2.0 IU/rat, after which the drug was administered at the same dose, once a day, for the following 7 days. INI was found to prevent body weight loss in both nondiabetic and DM2 IR-exposed rats, while elevating plasma total cholesterol levels and epididymal fat fraction in IR-exposed nondiabetic animals only. In IR-exposed DM2 rats, INI (at both doses used) reduced postprandial plasma levels of glucose and insulin, indicative of improved glucose tolerance, as well as plasma levels of inflammatory factors, C-reactive protein (at a dose of 0.5 IU/rat/day), and tumor necrosis factor-α (at a dose of 2 IU/rat/day), indicative of its anti-inflammatory potential. Thus, a post-IR course treatment with INI improves metabolic parameters and abates inflammatory responses in DM2 rats, which may be in high demand when correcting ischemic stroke in patients with DM2. [ABSTRACT FROM AUTHOR]

Background: Brain ischemia–reperfusion injury is a complex process, and neuroinflammation is an important secondary contributing pathological event. Neutrophils play major roles in ischemic neuroinflammation. Once activated, neutrophils express formyl peptide receptors (FPRs), which are special receptors of a class of chemoattractants and may be potential targets to regulate the activity of neutrophils and control cerebral ischemic injury. This study was aimed to explore the ameliorating effect of Cyclosporin H (CsH), a potent FPR antagonist, on brain ischemic injury by inhibiting the activation and migration of neutrophils, and improving cerebral blood flow. Methods: We employed a middle cerebral artery occlusion (MCAO) Model on rats and performed behavioral, morphological, and microPET imaging assays to investigate the potential restoring efficacy of CsH on cerebral ischemic damages. Peptide N-cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF), an antagonist to the neutrophil FPR with a high binding affinity, was used for imaging neutrophil distribution. Results: We found that CsH had similar effect with edaravone on improving the neurobehavioral deficient symptoms after cerebral ischemia–reperfusion, and treatment with CsH also alleviated ischemic cerebral infarction. Compared with the MCAO Model group, [18F]FDG uptake ratios of the CsH and edaravone treatment groups were significantly higher. The CsH-treated groups also showed significant increases in [18F]FDG uptake at 144 h when compared with that of 24 h. This result indicates that like edaravone, treatment with both doses of CsH promoted the recovery of blood supply after cerebral ischemic event. Moreover, MCAO-induced cerebral ischemia significantly increased the radiouptake of [68Ga]Ga-cFLFLF at 72 h after ischemia–reperfusion operation. Compared with MCAO Model group, radiouptake values of [68Ga]-cFLFLF in both doses of CsH and edaravone groups were all decreased significantly. These results showed that both doses of CsH resulted in a similar therapeutic effect with edaravone on inhibiting neutrophil infiltration in cerebral infarction. Conclusion: Potent FPR antagonist CsH is promisingly beneficial in attenuating neuroinflammation and improving neurobehavioral function against cerebral infarction. Therefore, FPR may become a novel target for regulating neuroinflammation and improving prognosis for ischemic cerebrovascular disorders. [ABSTRACT FROM AUTHOR]

Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality. Methods: Amulti-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 µg rEGF + 3.5mg GHRP6 i.v., n=10), II (75 µg rEGF + 5mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index andmodified Rankin scale (mRS)] outcomes. Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by theirmoderate to strong effect size. At 6months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis includingmerged treated groups and utility-weightedmRS also showed a benefit of this combined therapy. Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study. [ABSTRACT FROM AUTHOR]

Background: Early identification of the severity of hypoxic-ischemic brain injury (HIBI) after cardiac arrest can be used to help plan appropriate subsequent therapy. We evaluated whether conductivity of cerebral tissue measured using magnetic resonance-based conductivity imaging (MRCI), which provides contrast derived from the concentration and mobility of ions within the imaged tissue, can reflect the severity of HIBI in the early hours after cardiac arrest. Methods: Fourteen minipigs were resuscitated after 5 min or 12 min of untreated cardiac arrest. MRCI was performed at baseline and at 1 h and 3.5 h after return of spontaneous circulation (ROSC). Results: In both groups, the conductivity of cerebral tissue significantly increased at 1 h after ROSC compared with that at baseline (P = 0.031 and 0.016 in the 5-min and 12-min groups, respectively). The increase was greater in the 12-min group, resulting in significantly higher conductivity values in the 12-min group (P = 0.030). At 3.5 h after ROSC, the conductivity of cerebral tissue in the 12-min group remained increased (P = 0.022), whereas that in the 5-min group returned to its baseline level. Conclusions: The conductivity of cerebral tissue was increased in the first hours after ROSC, and the increase was more prominent and lasted longer in the 12-min group than in the 5-min group. Our findings suggest the promising potential of MRCI as a tool to estimate the severity of HIBI in the early hours after cardiac arrest. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that experimental brain ischemia leads to dementia with an Alzheimer's disease-like type phenotype and genotype. Based on the above evidence, it was hypothesized that brain ischemia may contribute to the development of Alzheimer's disease. Brain ischemia and Alzheimer's disease are two diseases characterized by similar changes in the hippocampus that are closely related to memory impairment. Following brain ischemia in animals and humans, the presence of amyloid plaques in the extracellular space and intracellular neurofibrillary tangles was revealed. The phenomenon of tau protein hyperphosphorylation is a similar pathological feature of both post-ischemic brain injury and Alzheimer's disease. In Alzheimer's disease, the phosphorylated Thr231 motif in tau protein has two distinct trans and cis conformations and is the primary site of tau protein phosphorylation in the pre-entanglement cascade and acts as an early precursor of tau protein neuropathology in the form of neurofibrillary tangles. Based on the latest publication, we present a similar mechanism of the formation of neurofibrillary tangles after brain ischemia as in Alzheimer's disease, established on trans- and cis-phosphorylation of tau protein, which ultimately influences the development of tauopathy. [ABSTRACT FROM AUTHOR]

The mechanisms of cerebral ischemia–reperfusion injury (IRI) limitation by remote ischemic postconditioning (RPC) are of interest because the latter may positively influence functional recovery after cerebral ischemia. The study was aimed to assess the role of plasma proteins syndecan-1 (SDC-1) and annexin-5 (ANXA-5) in limiting cerebral IRI by RPC in a middle cerebral artery occlusion (MCAO) model in male Wistar rats. The animals were randomized into three groups: (1) control sham-operated rats (SO group), (2) rats with 30-min MCAO-induced ischemia (MCAO group), (3) rats with 30-min MCAO-induced ischemia followed by RPC (MCAO + RPC group). SDC-1 plasma levels, as assessed by ELISA, in MCAO (41.4 ± 1.3 ng/mL) and MCAO + RPC (67.8 ± 5.8 ng/mL) rats were, respectively, by 30% (p < 0.05) and 112% (p < 0.01) higher than in SO control (31.9 ± 1.1 ng/mL). No intergroup differences in ANXA-5 plasma levels were detected. Cerebral infarct volume in MCAO and MCAO + RPC rats accounted for 32.0 ± 2.5 and 13.6 ± 1.3% of the total brain volume, respectively (p < 0.05). Cerebral edema volume in MCAO and MCAO + RPC rats were 47.0 ± 3.3 and 16.0 ± 2.1%, respectively (p < 0.05). In MCAO + RPC animals, correlation analysis revealed a high direct correlation between infarct size and right forelimb muscular strength (grip strength test, 3.9 ± 0.8 H, p > 0.5; KK = 0.72, p < 0.05) and a very high inverse correlation between infarct size and right hindlimb capillary blood flow (Doppler flowmetry, r = –0.98, p < 0.01). Animals' neurologic deficits were assessed by the Garcia scoring scale, while their locomotor coordination was assessed in the Rotarod test. It is assumed that SDC-1 plasma protein may serve as a potential regulator of the infarct size-limiting effect of remote ischemic postconditioning, which is determinative for functional recovery. [ABSTRACT FROM AUTHOR]

Since the first description of the possible utilization of the internal maxillary artery for bypass surgery, there are some reports of its use in aneurysm cases; however, there is no information about the possible advantages of this type of bypass for cerebral ischemic disease. We present a 77-year-old man with a history of diabetes, hypertension, systemic atherosclerosis, and two acute myocardial infarctions with left hemiparesis. Imaging studies reported total occlusion of the right internal carotid artery and 75% occlusion on the left side, with an old opercular infarction and repeated transient ischemic attacks in the right middle cerebral artery territory despite medical treatment. After a consensus, we decided to perform a bypass from the internal maxillary artery to the M2 segment of the middle cerebral artery using a radial artery graft. After performing the proximal anastomosis, the calculated graft's free flow was 216 ml/min. Subsequently, after completing the bypass, the patency was confirmed with fluorescein videoangiography and intraoperative Doppler. Postoperatively, imaging studies showed improvement in the perfusion values and the hemiparesis from 3/5 to 4+/5. The patient was discharged one week after the operation, with a modified Rankin scale of 1, without added deficits. The use of revascularization techniques in steno-occlusive disease indicates a select group of patients that may benefit from this procedure. In addition, internal maxillary artery bypass has provided a safe option for large areas of ischemia that cannot be supplied with a superficial temporal artery - middle cerebral artery bypass. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose: To evaluate the neuroprotective effect of resveratrol, urapidil, and a combined administration of these drugs against middle cerebral artery occlusion (MCAO) induced ischemia/reperfusion (IR) injury model in rats. Methods: Thirty-five rats were divided into five groups of seven animals each. Animals in IR, IR resveratrol (IRr), IR urapidil (IRu), and IR + combination of resveratrol and urapidil (IRc) were exposed to MCAO induced cerebral ischemia reperfusion injury model. Rats in IRr and IRu groups received 30-mg/kg resveratrol and 5-mg/kg urapidil respectively. Animals in IRc received a combined treatment of both drugs. At the end of the study, brain tissues were used for oxidative stress (malondialdehyde, glutathione, and superoxide dismutase), pro-apoptotic caspase-3, anti-apoptotic Bcl-2, and pro-inflammatory tumor necrosis factor-α cytokine level measurements. Results: The MCAO model successfully replicated IR injury with significant histopathological changes, elevated tissue oxidative stress, and upregulated apoptotic and inflammatory protein expression in IR group compared to control group (p < 0.001). All parameters were significantly alleviated in IRr group compared to IR group (all p < 0.05). In IRu group, all parameters except for caspase-3 and Bcl-2 were also significantly different than IR group (all p < 0.05). The IRc group showed the biggest difference compared to IR group in all parameters (all p < 0.001). The IRc had higher superoxide dismutase and Bcl-2 levels, and lower caspase-3 levels compared to both IRr and IRu groups (all p < 0.05). Also, the IRc group had lower MDA and TNF-α levels compared to IRu group (all p < 0.05). Conclusions: The results indicate that combined treatment of resveratrol and urapidil may be a novel strategy to downregulate neurodegeneration in cerebral IR injury.

Despite plenty of human studies on changes in thyroid hormones after stroke and some animal studies that assessed the effects of thyroid hormone administration on stroke, conclusive evidence for clinical application is lacking. This review aimed to determine the consistency of the results between clinical and preclinical studies. This article reviewed the PubMed, Embase, web of Knowledge, and Google Scholar databases up to June 2023 using the MeSH terms “stroke, cerebral ischemia, cerebral infarction, brain ischemia, brain infarction, triiodothyronine (T3), tetraiodothyronine (T4), thyroxine (T4), and thyroid hormone''. The results of clinical and preclinical studies related to T3 substantially confirm each other. That is, in most human studies lower T3 was associated with poor outcomes, and in experimental studies, T3 administration also had therapeutic effects. However, the results of experimental studies related to T4 could not support those of clinical studies. There seem to be some conflicts between experimental and human studies, especially regarding changes and effects of T4 after stroke. The gap between experimental and clinical studies may lead to non-applicable results, wasting time and money, and unnecessary killing of animals.

Abstract How brain functions in the distorted ischemic state before and after reperfusion is unclear. It is also uncertain whether there are any indicators within ischemic brain that could predict surgical outcomes. To alleviate these issues, we applied individual brain connectome in chronic steno‐occlusive vasculopathy (CSOV) to map both ischemic symptoms and their postbypass changes. A total of 499 bypasses in 455 CSOV patients were collected and followed up for 47.8 ± 20.5 months. Using multimodal parcellation with connectivity‐based and pathological distortion‐independent approach, areal MR features of brain connectome were generated with three measurements of functional connectivity (FC), structural connectivity, and PageRank centrality at the single‐subject level. Thirty‐three machine‐learning models were then trained with clinical and areal MR features to obtain acceptable classifiers for both ischemic symptoms and their postbypass changes, among which, 11 were deemed acceptable (AUC > 0.7). Notably, the FC feature‐based model for long‐term neurological outcomes performed very well (AUC > 0.8). Finally, a Shapley additive explanations plot was adopted to extract important individual features in acceptable models to generate “fingerprints” of brain connectome. This study not only establishes brain connectomic fingerprint databases for brain ischemia with distortion, but also provides informative insights for how brain functions before and after reperfusion.

Background and Objective: Glucose-Potassium Ratio (GPR) has emerged as a biomarker in several pathophysiological conditions. However, the association between GPR and long-term outcomes in stroke patients has not been investigated. Our study evaluated the applicability of baseline GPR as a predictive prognostic tool for clinical outcomes in ischemic stroke patients. Methods: The multicenter retrospective cohort study included acute-subacute adult ischemic stroke patients who had their baseline serum GPR levels measured. Eligible patients were categorized into two sub-cohorts based on the baseline GPR levels (

Embolization is one of the four approaches to the treatment of arteriovenous malformations. Typical complications of endovascular interventions include intraoperative or postoperative hemorrhage, ischemic stroke, perforation or dissection of a vessel, forced retention of a microcatheter in vessels due to polymerization of embolic material. Infectious complications after endovascular interventions and brain abscesses caused by Escherichia coli have been reported quite rarely. Although abscess formation after embolization is extremely rare, it is a serious condition that requires immediate treatment. This is a case of a unique clinical picture of a spontaneous brain abscess caused by Escherichia coli on the background of a giant arteriovenous malformation in an adult man without a typical route of infection and immunosuppression. This possibility should be taken into account in the treatment of arteriovenous malformation of the brain. A 37-year-old patient complained of convulsive attacks, increased body temperature, impaired speech, and right-sided hemiparesis. A brain abscess developed 1 month after the third stage of embolization of a giant arteriovenous brain malformation. Cultures of the contents of the abscess showed a positive result for Escherichia coli. During the long course of treatment, relapses of the abscess were registered several times, with each of them a complex approach to solving the problem was used ‒ a combination of surgical intervention and antibiotic therapy. Choosing the most effective method of treatment makes it possible to prevent or reduce the likelihood of complications and improve the patient's quality of life. Long and repeated procedures, partial exclusion of the malformation, repeated passages with microinstrumentation, use of a significant amount of substance for embolization can cause the development of inflammation, thrombus formation in the vessels of arteriovenous malformations and increase the risk of developing purulent-infectious complications after endovascular neurosurgical interventions. Consideration of the given clinical case will contribute to deepening the understanding of this pathology.

One of the ischemic stroke prevention methods is reconstructive surgery on the carotid arteries, during which there is a risk of ischemia-reperfusion phenomenon. Nevertheless, there is still a high risk of stroke at all stages of the surgery, which equally depends on the atherosclerotic plaque structure and on the technique and tactics of surgery. The aim of this study was to investigate the dynamics of redox homeostasis and nitric oxide production in the blood taken from the internal jugular vein in patients with carotid arteries pathology against the episode of cerebral blood flow restriction during carotid surgery. This prospective cohort study involved 56 patients which required carotid reconstructive surgery. The markers dynamics of oxygen metabolism, redox homeostasis and nitric oxide production in blood from the internal jugular vein on the side of surgery were studied. It was found that the activity of free radical processes is proportional to the level of jugular hypoxemia. Bidirectional dynamics of lactate concentration during intraoperative transient cerebral ischemia was revealed. In some patients, lactate production activates with an increase in free radical processes activity in proportion to the intensification of nitric oxide synthesis against a decrease in peroxynitrite production and activation of molecular compensatory mechanisms increasing concentrations of L-arginine and reduced glutathione. In others, the extraction of oxygen from the blood increases without lactate production, activation of nitric oxide synthesis and development of oxidative stress. This indicates good adaptive reserves against acute restriction of cerebral blood flow.

Background and Objective: The alteration of mitochondrial functions, especially the opening of the mitochondrial permeability transition pore (mPTP), has been proposed as a key mechanism in the development of lesions in cerebral ischemia, wherefore it is considered as an important target for drugs against ischemic injury. In this study, we aimed to investigate the effects of mitochondrial complex I inhibitors as possible regulators of mPTP using an in vitro brain ischemia model of the pentobarbital/ketamine (PBK)-anesthetized rats. Results: We found that PBK anesthesia itself delayed Ca2+-induced mPTP opening and partially recovered the respiratory functions of mitochondria, isolated from rat brain cortex and cerebellum. In addition, PBK reduced cell death in rat brain slices of cerebral cortex and cerebellum. PBK inhibited the adenosine diphosphate (ADP)-stimulated respiration of isolated cortical and cerebellar mitochondria respiring with complex I-dependent substrates pyruvate and malate. Moreover, pentobarbital alone directly increased the resistance of isolated cortex mitochondria to Ca2+-induced activation of mPTP and inhibited complex I-dependent respiration and mitochondrial complex I activity. In contrast, ketamine had no direct effect on functions of isolated normal cortex and cerebellum mitochondria. Conclusions: Altogether, this suggests that modulation of mitochondrial complex I activity by pentobarbital during PBK anesthesia may increase the resistance of mitochondria to mPTP opening, which is considered the key event in brain cell necrosis during ischemia.

Background: Accurate longitudinal risk prediction for DCI (delayed cerebral ischemia) occurrence after subarachnoid hemorrhage (SAH) is essential for clinicians to administer appropriate and timely diagnostics, thereby improving treatment planning and outcome. This study aimed to develop an improved longitudinal DCI prediction model and evaluate its performance in predicting DCI between day 4 and 14 after aneurysm rupture. Methods: Two DCI classification models were trained: (1) a static model based on routinely collected demographics and SAH grading scores and (2) a dynamic model based on results from laboratory and blood gas analysis anchored at the time of DCI. A combined model was derived from these two using a voting approach. Multiple classifiers, including Logistic Regression, Support Vector Machines, Random Forests, Histogram-based Gradient Boosting, and Extremely Randomized Trees, were evaluated through cross-validation using anchored data. A leave-one-out simulation was then performed on the best-performing models to evaluate their longitudinal performance using time-dependent Receiver Operating Characteristic (ROC) analysis. Results: The training dataset included 218 patients, with 89 of them developing DCI (41%). In the anchored ROC analysis, the combined model achieved a ROC AUC of 0.73 ± 0.05 in predicting DCI onset, the static and the dynamic model achieved a ROC AUC of 0.69 ± 0.08 and 0.66 ± 0.08, respectively. In the leave-one-out simulation experiments, the dynamic and voting model showed a highly dynamic risk score (intra-patient score range was 0.25 [0.24, 0.49] and 0.17 [0.12, 0.25] for the dynamic and the voting model, respectively, for DCI occurrence over the course of disease. In the time-dependent ROC analysis, the dynamic model performed best until day 5.4, and afterwards the voting model showed the best performance. Conclusions: A machine learning model for longitudinal DCI risk assessment was developed comprising a static and a dynamic sub-model. The longitudinal performance evaluation highlighted substantial time dependence in model performance, underscoring the need for a longitudinal assessment of prediction models in intensive care settings. Moreover, clinicians need to be aware of these performance variations when performing a risk assessment and weight the different model outputs correspondingly.

Coenzyme CoQ10 (CoQ10) is an endogenous lipid-soluble antioxidant that effectively protects lipids, proteins, and DNA from oxidation due to its ability to undergo redox transitions between oxidized and reduced forms. Various oxidative stress-associated infectious and somatic diseases have been observed to disrupt the balance of CoQ10 concentration in tissues. As a high molecular weight polar lipophilic compound, CoQ10 exhibits very limited oral bioavailability, which restrains its therapeutic potential. Nevertheless, numerous studies have confirmed the clinical efficacy of CoQ10 therapy through oral administration of high doses over extended time periods. Experimental studies have demonstrated that in emergency situations, intravenous administration of both oxidized and reduced-form CoQ10 leads to a rapid increase in its concentration in organ tissues, offering protection for organ tissues in ischemic conditions. This suggests that the cardio- and neuroprotective efficacy of intravenously administered CoQ10 forms could present new opportunities in treating acute ischemic conditions. Based on these findings, the review provides reasoning supporting further research and implementation of CoQ10 dosage forms for intravenous administration in emergency situations into clinical practice. [ABSTRACT FROM AUTHOR]

Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood–brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders. [ABSTRACT FROM AUTHOR]

Introduction: The ischemic cerebrovascular disease has a high frequency due to the population aging mainly. Objective: To compare clinical characteristics of patients with ischemic cerebrovascular of two age groups. Methods: A descriptive, cross-sectional, retrospective study was carried out in the Neurology and Neurosurgery Institute in Havana, from January to December, 2017 in patients with ischemic cerebrovascular disease; 36 individuals of both age groups. In this regard, demographic variables, risk factors, clinical manifestations, coma scale and neurological deficiency, etiology and localization of the ischemic ictus were analyzed. Results: The 65 years group had a significant increase of hypertensive patients (88.9%). The average of the National Institute of Health stroke scale was superior in these patients (median [10-90 percentile]: 9.5 [4-19]). There was statistical increment of over 65 years patients with partial paralysis of the look and ataxia, but monoparesis and visual extinction in the age under 65 years. Such a scale had a statistical increase in the atherothrombotic and cardioembolic ictus in comparison with other etiologies in both patient groups. The over 65 years patients with just one risk factor or and those with hypertension had a higher punctuation of the scale. Conclusions: The degree of neurological affectation was higher in over 65 years patients that had a risk factor and in those with hypertension. As a result it could be suggested that the molecular and pathophysiolologic mechanisms of these patients vary with the age. [ABSTRACT FROM AUTHOR]

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Ischemic stroke is a common degenerative disease in Indonesia caused by interrupted or restricted blood supply to part of brain, preventing it from getting oxygen and nutrients. Without sufficient blood supply, brain cells begin to die. Various treatments for ischemic stroke patients have been developed and implemented, but are still ineffective in treating or preventing brain damage. Curcumin is one of the bioactive compounds which mostly found in turmeric which is one of the main spices resource in Indonesia that has many benefits as a medicine. People have been making use of curcumin as a medicine for various diseases, one of which is stroke. Therefore, this systematic review analysed qualitatively the effect of curcumin on the brain condition after ischemic stroke. The method used in this study was a systematic review of 8 databases in the last 10 years, from 2012 to August 2022. Study included was only experimental study on rats. Based on 19 articles gathered, there was a decrement in ROS, COX-2, iNOS, NF-kB, TNF-a, IL-6, Bax, Caspase-9, Caspase-3, ICAM-1, MMP-9, neurological deficit score, and an increment in BCL-2, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) in rats receiving curcumin intervention either orally or intravenously. Curcumin affects the ischemic brain in a number of ways, namely as an antioxidant, anti-inflammatory, anti-apoptotic, Blood-Brain-Barrier (BBB) protector, increasing neurogenesis, and reducing neurological deficits. It is concluded that curcumin has an elevating effect in protecting brain condition after an ischemic stroke. [ABSTRACT FROM AUTHOR]

Introduction: Raspberries are cerebral microvascular formations of unknown origin, defined as three or more transversally sectioned vascular lumina surrounded by a common perivascular space. We have previously demonstrated an increased raspberry density in the cortex of patients with vascular dementia and cerebral atherosclerosis, while studies by other authors on overlapping and synonymously defined vascular entities mainly associate them with advancing age. The aim of the present study was to examine the relationship between raspberries and age in a large study sample while including multiple potential confounding factors in the analysis. Materials and methods: Our study sample consisted of 263 individuals aged 20–97 years who had undergone a clinical autopsy including a neuropathological examination. The cortical raspberry density had either been quantified as part of a previous study or was examined de novo in a uniform manner on haematoxylin- and eosin-stained tissue sections from the frontal lobe. The medical records and autopsy reports were assessed regarding neurodegeneration, cerebral infarcts, cerebral atherosclerosis and small vessel disease, cardiac hypertrophy, nephrosclerosis, hypertension, and diabetes mellitus. With the patients grouped according to 10-year age interval, non-parametric tests (the Kruskal–Wallis test, followed by pairwise testing with Bonferroni-corrected P values) and multiple linear regression models (not corrected for multiple tests) were performed. Results: The average raspberry density increased with advancing age. The non-parametric tests demonstrated statistically significant differences in raspberry density when comparing the groups aged 60–99 years and 70–99 years to those aged 20–29 years (P < 0.012) and 30–59 years (P < 0.011), respectively. The multiple linear regression models demonstrated positive associations with age interval (P < 0.001), cerebral atherosclerosis (P = 0.024), cardiac hypertrophy (P = 0.021), hypertension subgrouped for organ damage (P = 0.006), and female sex (P = 0.004), and a tendency towards a negative association with Alzheimer's disease neuropathologic change (P = 0.048). Conclusion: The raspberry density of the frontal cortex increases with advancing age, but our results also indicate associations with acquired pathologies. Awareness of the biological and pathological context where raspberries occur can guide further research on their origin. [ABSTRACT FROM AUTHOR]

Explaining changes at the gene level that occur during neurodegeneration in the CA3 area is crucial from the point of view of memory impairment and the development of post-ischemic dementia. An ischemic model of Alzheimer's disease was used to evaluate changes in the expression of genes related to amyloid transport in the CA3 region of the hippocampus after 10 min of brain ischemia with survival of 2, 7 and 30 days and 12, 18 and 24 months. The quantitative reverse transcriptase PCR assay revealed that the expression of the LRP1 and RAGE genes involved in amyloid transport was dysregulated from 2 days to 24 months post-ischemia in the CA3 area of the hippocampus. LRP1 gene expression 2 and 7 days after ischemia was below control values. However, its expression from day 30 to 24 months, survival after an ischemic episode was above control values. RAGE gene expression 2 days after ischemia was below control values, reaching a maximum increase 7 and 30 days post-ischemia. Then, after 12, 18 and 24 months, it was again below the control values. The data indicate that in the CA3 area of the hippocampus, an episode of brain ischemia causes the increased expression of the RAGE gene for 7–30 days during the acute phase and that of LRP1 from 1 to 24 months after ischemia during the chronic stage. In other words, in the early post-ischemic stage, the expression of the gene that transport amyloid to the brain increases (7–30 days). Conversely, in the late post-ischemic stage, amyloid scavenging/cleaning gene activity increases, reducing and/or preventing further neuronal damage or facilitating the healing of damaged sites. This is how the new phenomenon of pyramidal neuronal damage in the CA3 area after ischemia is defined. In summary, post-ischemic modification of the LRP1 and RAGE genes is useful in the study of the ischemic pathways and molecular factors involved in the development of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

ObjectiveThis study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.MethodsA multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18–80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.ResultsThe study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8–11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06–1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03–1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.ConclusionEGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.Clinical Trial RegistrationRPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

Background Personalized blood pressure (BP) management for patients with acute ischemic stroke after successful endovascular thrombectomy lacks evidence. We aimed to investigate whether the deviation of BP from cerebral autoregulation limits is associated with worse outcomes. Methods and Results We determined autoregulation by measuring mean velocity index and calculated the percentage of time and the burden (defined as the time‐BP area) with BP outside the autoregulatory limits of each subject within 48 hours after endovascular thrombectomy. In total, 91 patients with large vessel occlusion stroke who had achieved successful recanalization were prospectively enrolled between May 2020 and February 2022. The burden with BP outside the autoregulatory limits was associated with poor outcome (modified Rankin Scale score 3–6) at 90 days (adjusted odds ratio, 1.28 [95% CI, 1.03–1.59]). The percentage of time with BP out of the autoregulatory limits was correlated with early neurological deterioration (National Institute of Health Stroke Scale scores increased ≥2 at 7 days) (adjusted odds ratio, 1.38 [95% CI, 1.04–1.83]). The burden of BP that decreased below the autoregulatory lower limit was associated with significant infarct growth (volume of infarct growth >11.6 mL) at 7 days (adjusted odds ratio, 1.21 [95% CI, 1.01–1.44]). The percentage of time that BP exceeded the autoregulatory upper limit was associated with symptomatic intracranial hemorrhage within 48 hours (adjusted odds ratio, 1.55 [95% CI, 1.02–2.34]). Conclusions Both the percentage of time and the burden of BP that deviates from the autoregulation‐preserved range are associated with unfavorable clinical outcomes. This study highlights the potential benefits of autoregulation‐guided BP management strategy after successful recanalization.

Large-vessel occlusion (LVO) stroke is a promising field for the use of AI, especially machine learning (ML) because optimal results are highly dependent on timely diagnosis, communication, and treatment. In order to better understand the current state of artificial intelligence (AI) in relation to LVO strokes, its efficacy, and potential future applications, we searched relevant literature to perform a comprehensive evaluation of the topic. The databases PubMed, Embase, and Scopus were extensively searched for this review. Studies were then screened using title and abstract criteria and duplicate studies were excluded. By using pre-established inclusion and exclusion criteria, it was decided whether or not to include full-text papers in the final analysis. The studies were analyzed, and the relevant information was retrieved. In recognizing LVO on computed tomography, ML approaches were very accurate. There is a shortage of AI applications for thrombectomy patient selection, despite the fact that certain research accurately evaluates individual patient eligibility for endovascular therapy. Machine learning algorithms may reasonably predict clinical and angiographic outcomes as well as associated factors. AI has shown promise in the diagnosis and treatment of people who have just suffered a stroke. However, the usefulness of AI in management and forecasting remains restricted, necessitating more studies into machine learning applications that can guide decision making in the future.

During brain ischemia, excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage. Indeed, anoxic depolarization, consisting of massive neuronal depolarization due to the loss of membrane ion gradients, occurs in vivo or in vitro during an energy failure. The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors, namely: A1, A2A, A2B, and A3. The A2A receptor subtype is highly expressed in striatal medium spiny neurons, which are particularly susceptible to ischemic damage. Evidence indicates that the A2A receptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours. We recently added new knowledge to the mechanisms by which the adenosine A2A receptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation. We demonstrated that the selective block of A2A receptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+ channel modulation and a presynaptic inhibition of glutamate release by the A2A receptor antagonist. The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2A receptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.

Background Stroke is a cardiovascular disease that seriously endangers human health, which is characterized by high prevalence, disability and mortality rates. Peony bark is the dried root bark of peony in the buttercup family, which has the effect of clearing heat and cooling blood, activating blood circulation and resolving blood stasis. Paeonol (PAE) is the main active ingredient of peony bark, has been confirmed to have neuroprotective effect under hypoglycemia and hypoxia conditions. Objective To observe the effect and neurobiological mechanism of gastric administration of paeonol solution on improving behavioral dysfunction caused by middle cerebral artery occlusion (MCAO) , a kind of stroke, in a mouse model. Methods The study was conducted from December 2019 to December 2021. Twenty SPF male C57BL/6 mice were randomized into SHAM group (n=10) and model group (MCAO group, n=10) . The MCAO model was formed by intraluminal suture method. After 24 hours of modeling, the neurological function of each group was evaluated by Longa Score. Laser Speckle Contrast Imaging was used to monitor the changes of cerebral blood flow after MCAO. TTC staining was used in the pathological examination of cerebral infarction in MCAO mice. For investigating the protective effect of PAE on behavioural dysfunction of MCAO mice, 50 SPF male C57BL/6 mice were randomly grouped into SHAM group (n=10) , model+corn oil group (n=20) , and model+PAE group (n=20) . After the verification of model stability at 24 hours following the modeling, the model+PAE group received intragastric administration of PAE and corn oil solution in a concentration of 100 mg·kg-1· d-1, and the other two groups were gavaged with equal amounts of corn oil. Then on the 28th day after of modelling, survival curve was plotted to assess the survival status of mice in the three groups; the neurological recovery of mice was determined using the Longa Score; the area of cerebral infarction was examined by Nissl staining. The behavioural changes in motor sensory function were tested at five time points: the day before modeling, and 7, 14, 21 and 28 days after modelling. For exploring the mechanism of PAE improving behavioural dysfunction in MCAO mice, 30 SPF male C57BL/6 mice were randomly divided into SHAM group (n=6) , model+corn oil group (n=12) and model+PAE group (n=12) . After verifying the model stability at 24 hours following the modeling, the model+PAE group received intragastric administration of PAE and corn oil solution in a concentration of 100 mg·kg-1· d-1, and the other two groups were gavaged with an equal amount of corn oil. The expression of interleukin 1β (IL-1β) protein in the striatum of mouse brain was measured by Western blotting on the second day after modelling to investigate whether PAE could reduce the inflammatory response in the brain during the acute period. The expression of ionized calcium-binding adapter molecule 1 (IBA1) and glial fibrillary acidic protein (GFAP) in the penumbra was measured by immunofluorescence on the 14th day after modelling. Results The 28-day survival rate was 66.47% for the model+corn oil group, and 81.43% for model+PAE group. Log-rank test showed that the 28-day survival curve significantly differed across SHAM group, model+corn oil group, and model+PAE group (χ2=1.436, P

Background The incidence, mortality and disability rates of ischemic stroke are high, and the reperfusion injury after thrombolytic therapy has a great impact on patients. Acupuncture is a characteristic therapy for the treatment of the disease, but the action mechanism remains unclear. Objective To observe the effect of Tongdu Tiaoshen electroacupuncture (EA) pretreatment on miR-124-3p/glycogen synthase kinase β (GSK-3β) /cyclin D (Cyp-D) signaling pathway and mitochondrial permeability transition pore (MPTP) of cerebral ischemia-reperfusion injury (CIRI) rats, and explore its possible mechanism of prevention and control of CIRI. Methods From June to August 2022, a total of 100 clean SD rats were randomly divided into the sham operation group, model group, EA group, agonist group and EA + inhibitor group, with 20 rats in each group. For 7 d of intervention before modeling, in the EA group and EA + inhibitor group, "Baihui" (GV 20) , "Fengfu" (GV 16) and "Dazhui" (GV 14) were selected to perform electroacupuncture 1 time a day for 7 days. For 24 h before modeling, miR-124 agonist and inhibitor (5 nmol) were injected into the lateral ventricles in the EA + agonist group and inhibitor group. Except for the sham operation group, the right cerebral ischemia-reperfusion model of rats was prepared by the modified suture method in the rest groups. The right cerebral cortex of rats was taken, the degree of neurological impairment in each group was observed using mNSS scale and TTC staining, the nerve cell injury was observed by TUNEL staining and transmission electron microscopy. The expressions of GSK-3β, p-GSK-3β, Cyp-D, Cyt-C and Caspase-3 in cerebral cortex of each group were detected by immunofluorescence staining, Western blot and real-time quantitative PCR. The degree of MPTP openness was detected by flow cytometry, the higher rate of MPTP-positive cells indicated greater degress of MPTP openness. Results Except for the sham operation group, all rest groups of rats were successfully modeled. Compared with the sham operation group, mNSS score and infarct volume of brain tissue were increased, mitochondrial structure was seriously damaged, cell apoptosis index was increased, p-GSK-3β positive expression was reduced, Cyp-D positive expression was enhanced, miR-124-3p, Cyp-D, Cyt-C and Caspase-3 mRNA expressions were increased, p-GSK-3β/ GSK-3β ratio was decreased, relative Cyp-D, Cyt-C, and Caspase-3 protein expressions were increased, and MPTP openness degree was increased in the model group (P

Objective To investigate the protective effect of remimazolam on cerebral nerves in a rat model of cerebral ischemia/reperfusion injury and its mechanism. Methods A total of 50 male Sprague-Dawley rats were randomly divided into sham-operation group (Sham group), cerebral ischemia/reperfusion group (I/R group), I/R+remimazolam (RE) group, I/R+RE+LY294002 (LY) group, and I/R+LY group. Neurological deficit score was used to evaluate the degree of neurological dysfunction. After arterial blood samples and brain tissue pathological sections were collected from the rats in each group, 2,3,5-trip-henyltetrazolium chloride staining was performed for the brain tissue sections to calculate cerebral infarct volume ratio; ELISA was used to measure the serum levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α); Western blotting was used to measure the relative expression levels of protein kinase B (AKT), phosphorylated AKT (p-AKT), nuclear factor-kappa B p65 (NF-κB p65), and phosphorylated NF-κB p65 (p-NF-κB p65) in brain tissue, and then immunofluorescence assay was used to measure the expression level of p-NF-κB p65 inside and outside the nucleus of cells in brain tissue. Results There were significant differences between these groups in cerebral infarct volume ratio, neurological deficit score, the serum levels of IL-6, IL-1β, and TNF-α, the relative expression levels of p-AKT and p-NF-κB p65, p-AKT/AKT ratio, and p-NF-κB p65/NF-κB p65 ratio (F=72.41-654.90,P

Carotid free⁃floating thrombus (CFFT) is significantly associated with ischemic stroke. Thrombosis occludes the artery or falls off, leading to massive cerebral infarction or multiple embolism. In severe cases, cerebral hernia or even death may occur. The diagnosis of CFFT is gradually based on CT angiography (CTA). Early identification can help in etiological treatment. This article reviews the progress of the diagnosis and treatment of CFFT, in order to improve chinical diagnosis and treatment.