Application of individual brain connectome in chronic ischemia: mapping symptoms before and after reperfusion.

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.

Chaperone-Mediated Autophagy in Brain Injury: A Double-Edged Sword with Therapeutic Potentials.

Autophagy is an intracellular recycling process that maintains cellular homeostasis by degrading excess or defective macromolecules and organelles. Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy in which a substrate containing a KFERQ-like motif is recognized by a chaperone protein, delivered to the lysosomal membrane, and then translocated to the lysosome for degradation with the assistance of lysosomal membrane protein 2A. Normal CMA activity is involved in the regulation of cellular proteostasis, metabolism, differentiation, and survival. CMA dysfunction disturbs cellular homeostasis and directly participates in the pathogenesis of human diseases. Previous investigations on CMA in the central nervous system have primarily focus on neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Recently, mounting evidence suggested that brain injuries involve a wider range of types and severities, making the involvement of CMA in the bidirectional processes of damage and repair even more crucial. In this review, we summarize the basic processes of CMA and its associated regulatory mechanisms and highlight the critical role of CMA in brain injury such as cerebral ischemia, traumatic brain injury, and other specific brain injuries. We also discuss the potential of CMA as a therapeutic target to treat brain injury and provide valuable insights into clinical strategies.

The utility of serum glucose potassium ratio as a predictive factor for haemorrhagic transformation, stroke recurrence, and mortality among ischemic stroke patients.

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 (<1.67 vs. ≥ 1.67). The primary outcome was the incidence of 30-day hemorrhagic transformation, while stroke recurrence, and all-cause mortality within twelve months, were considered secondary. Results: Among 4083 patients screened, 1047 were included in the current study. In comparison with GPR < 1.67 group, patients with ≥ 1.67 GPR had a significantly higher ratio of all-cause mortality within twelve months (aHR 2.07 [95 % CI 1.21-3.75] p = 0.01), and higher ratio of 30-day hemorrhagic transformation but failed to reach the statistical significance (aHR 1.60 [95 % CI 0.95-2.79], p = 0.08). Conclusion: Overall, baseline GPR serum is an independent predictor of all-cause mortality within twelve months in patients with acute and subacute ischemic stroke. Further clinical studies are necessary to validate these findings.

The influence of the prolactin/vasoinhibin axis on post-stroke lesion volume, astrogliosis, and survival.

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.

Improvement of neuronal and cognitive functions following treatment with 3',4' dihydroxyflavonol in experimental focal cerebral ischemia-reperfusion injury in rats.

INTRODUCTION: Ischemia/reperfusion is a pathological condition by the restoration of perfusion and oxygenation following a period of restricted blood flow to an organ. To address existing uncertainty in the literature regarding the effects of 3', 4'-dihydroxy flavonol (DiOHF) on cerebral ischemia/reperfusion injury, our study aims to investigate the impact of DiOHF on neurological parameters, apoptosis (Caspase-3), aquaporin 4 (AQP4), and interleukin-10 (IL-10) levels in an experimental rat model of brain ischemia-reperfusion injury. MATERIALS/METHODS: A total of 28 Wistar-albino male rats were used in this study. Experimental groups were formed as 1-Control, 2-Sham, 3-Ischemia-reperfusion, 4-Ischemia-reperfusion + DiOHF (10 mg/kg). The animals were anaesthetized, and the carotid arteries were ligated (ischemia) for 30 min, followed by reperfusion for 30 min. Following reperfusion, DiOHF was administered intraperitoneally to the animals at a dose of 10 mg/kg for 1 week. During the one-week period neurological scores and new object recognition tests were performed. Then, caspase 3 and AQP4 levels were determined by PCR method and IL-10 by ELISA method in hippocampus tissue samples taken from animals sacrificed under anaesthesia. RESULTS: Brain ischemia reperfusion significantly increased both caspase 3 and AQP4 values in the hippocampus tissue, while decreasing IL-10 levels. However, 1-week DiOHF supplementation significantly suppressed increased caspase 3 and AQP4 levels and increased IL-10 values. While I/R also increased neurological score values, it suppressed the ability to recognize new objects, and the administered treatment effectively ameliorated the adverse effects observed, resulting in a positive outcome. CONCLUSIONS: The results of the study show that brain ischemia caused by bilateral carotid occlusion in rats and subsequent reperfusion causes tissue damage, but 1-week DiOHF application has a healing effect on both hippocampus tissue and neurological parameters.

STZ-induced gestational diabetes exposure alters PTEN/AKT/mTOR-mediated autophagy signaling pathway leading to increase the risk of neonatal hypoxic-ischemic encephalopathy.

Exposure to gestational diabetes mellitus (GDM) during pregnancy has significant consequences for the unborn baby and newborn infant. However, whether and how GDM exposure induces the development of neonatal brain hypoxia/ischemia-sensitive phenotype and the underlying molecular mechanisms remain unclear. In this study, we used a late GDM rat model induced by administration of streptozotocin (STZ) on gestational day 12 and investigated its effects of GDM on neonatal brain development. The pregnant rats exhibited increased blood glucose levels in a dose-dependent manner after STZ administration. STZ-induced maternal hyperglycemia led to reduced blood glucose levels in neonatal offspring, resulting in growth restriction and an increased brain to body weight ratio. Importantly, GDM exposure increased susceptibility to hypoxia/ischemia (HI)-induced brain infarct sizes compared to the controls in both male and female neonatal offspring. Further molecular analysis revealed alterations in the PTEN/AKT/mTOR/autophagy signaling pathway in neonatal male offspring brains, along with increased ROS production and autophagy-related proteins (Atg5 and LC3-II). Treatment with the PTEN inhibitor bisperoxovanadate (BPV) eliminated the differences in HI-induced brain infarct sizes between the GDM-exposed and the control groups. These findings provide novel evidence of the development of a brain hypoxia/ischemia-sensitive phenotype in response to GDM exposure and highlight the role of the PTEN/AKT/mTOR/autophagy signaling pathway in this process.

Apoptosis, Autophagy, and Mitophagy Genes in the CA3 Area in an Ischemic Model of Alzheimer's Disease with 2-Year Survival.

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.

Thyroid hormones and stroke, the gap between clinical and experimental studies.

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.

Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial.

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: A 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. 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 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. Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study. Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

Electroacupuncture at the Dazhui and Baihui acupoints and different frequencies (10 and 50 Hz) protects against apoptosis by up-regulating ERK1/2-mediated signaling in rats after global cerebral ischemia.

Objectives: 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.

Oxidized mitochondrial DNA activates the cGAS-STING pathway in the neuronal intrinsic immune system after brain ischemia-reperfusion injury.

In the context of stroke and revascularization therapy, brain ischemia-reperfusion injury is a significant challenge that leads to oxidative stress and inflammation. Central to the cell's intrinsic immunity is the cGAS-STING pathway, which is typically activated by unusual DNA structures. The involvement of oxidized mitochondrial DNA (ox-mtDNA)-an oxidative stress byproduct-in this type of neurological damage has not been fully explored. This study is among the first to examine the effect of ox-mtDNA on the innate immunity of neurons following ischemia-reperfusion injury. Using a rat model of transient middle cerebral artery occlusion and a cellular model of oxygen-glucose deprivation/reoxygenation, we have discovered that ox-mtDNA activates the cGAS-STING pathway in neurons. Importantly, pharmacologically limiting the release of ox-mtDNA into the cytoplasm reduces inflammation and improves neurological functions. Our findings suggest that targeting ox-mtDNA release may be a valuable strategy to attenuate brain ischemia-reperfusion injury following revascularization therapy for acute ischemic stroke.

The effect of calpain inhibitor-I on copper oxide nanoparticle-induced damage and cerebral ischemia-reperfusion in a rat model.

This study aimed to investigate the effects of the calpain inhibitor N-Acetyl-Leu-Leu-norleucinal (ALLN) on neuroapoptotic cell damage caused by Copper Oxide Nanoparticles (CuO-NP) and exacerbation of damage through brain ischemia/reperfusion (I/R) in a rat model. Male Wistar Albino rats (n=80) were divided into eight groups: Control, I/R, CuO-NP, CuO-NP+I/R, I/R+ALLN, CuO-NP+ALLN, CuO-NP+I/R+ALLN, and DMSO. Biochemical markers (MBP, S100B, NEFL, NSE, BCL-2, Cyt-C, Calpain, TNF-α, Caspase-3, MDA, and CAT) were measured in serum and brain tissue samples. Histological examinations (H&E staining), DNA fragmentation analysis (TUNEL) were performed, along with Caspase-3 assessment. The ALLN-treated groups exhibited significant improvements in biochemical markers and a remarkable reduction in apoptosis compared to the damaged groups (CuO-NP and I/R). H&E and Caspase-3 staining revealed damage-related morphological changes and reduced apoptosis in the ALLN-treated group. However, no differences were observed among the groups with TUNEL staining. The findings suggest that ALLN, as a calpain inhibitor, has potential implications for anti-apoptotic treatment, specifically in mitigating neuroapoptotic cell damage caused by CuO-NP and I/R.

Trans- and Cis-Phosphorylated Tau Protein: New Pieces of the Puzzle in the Development of Neurofibrillary Tangles in Post-Ischemic Brain Neurodegeneration of the Alzheimer's Disease-like Type.

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.

Deviation From Personalized Blood Pressure Targets Correlates With Worse Outcome After Successful Recanalization.

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.

Methylene blue and its potential in the treatment of traumatic brain injury, brain ischemia, and Alzheimer's disease.

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.

A Brain Ischemia-Reperfusion Model for the Study of Tau Phosphorylation and O-GlcNAcylation.

Cerebral ischemia produces a decrease, loss, or instability of the assembly processes in the neuronal cytoskeleton, related to the alteration in the normal processes of phosphorylation of the Tau protein, triggering its hyperphosphorylation and altering the normal processes of formation of neuronal microtubules. Here we describe the methods used to study the impact of middle cerebral artery occlusion (MCAo) on neurological functions and Tau phosphorylation in Wistar rat brain.

Emerging artificial intelligence-aided diagnosis and management methods for ischemic strokes and vascular occlusions: A comprehensive review.

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.

Catalpol attenuates ischemic stroke by promoting neurogenesis and angiogenesis via the SDF-1α/CXCR4 pathway.

BACKGROUND: Stroke is a leading cause of disability and death worldwide. Currently, there is a lack of clinically effective treatments for the brain damage following ischemic stroke. Catalpol is a bioactive compound derived from the traditional Chinese medicine Rehmannia glutinosa and shown to be protective in various neurological diseases. However, the potential roles of catalpol against ischemic stroke are still not completely clear. PURPOSE: This study aimed to further elucidate the protective effects of catalpol against ischemic stroke. METHODS: A rat permanent middle cerebral artery occlusion (pMCAO) and oxygen-glucose deprivation (OGD) model was established to assess the effect of catalpol in vivo and in vitro, respectively. Behavioral tests were used to examine the effects of catalpol on neurological function of ischemic rats. Immunostaining was performed to evaluate the proliferation, migration and differentiation of neural stem cells (NSCs) as well as the angiogenesis in each group. The protein level of related molecules was detected by western-blot. The effects of catalpol on cultured NSCs as well as brain microvascular endothelial cells (BMECs) subjected to OGD in vitro were also examined by similar methods. RESULTS: Catalpol attenuated the neurological deficits and improved neurological function of ischemic rats. It stimulated the proliferation of NSCs in the subventricular zone (SVZ), promoted their migration to the ischemic cortex and differentiation into neurons or glial cells. At the same time, catalpol increased the cerebral vessels density and the number of proliferating cerebrovascular endothelial cells in the infracted cortex of ischemic rats. The level of SDF-1α and CXCR4 in the ischemic cortex was found to be enhanced by catalpol treatment. Catalpol was also shown to promote the proliferation and migration of cultured NSCs as well as the proliferation of BMECs subjected to OGD insult in vitro. Interestingly, the impact of catalpol on cultured cells was inhibited by CXCR4 inhibitor AMD3100. Moreover, the culture medium of BMECs containing catalpol promoted the proliferation of NSCs, which was also suppressed by AMD3100. CONCLUSION: Our data demonstrate that catalpol exerts neuroprotective effects by promoting neurogenesis and angiogenesis via the SDF-1α/CXCR4 pathway, suggesting the therapeutic potential of catalpol in treating cerebral ischemia.

Effects of Banhabaekchulcheonma-Tang on Brain Injury and Cognitive Function Impairment Caused by Bilateral Common Carotid Artery Stenosis in a Mouse Model.

Vascular dementia (VD) is the second most prevalent dementia type, with no drugs approved for its treatment. Here, the effects of Banhabaekchulcheonma-Tang (BBCT) on ischemic brain injury and cognitive function impairment were investigated in a bilateral carotid artery stenosis (BCAS) mouse model. Mice were divided into sham-operated, BCAS control, L-BBCT (40 ml/kg), and H-BBCT (80 ml/kg) groups. BBCT's effects were characterized using the Y-maze test, novel object recognition test (NORT), immunofluorescence staining, RNA sequencing, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses. The NORT revealed cognitive function improvement in the H-BBCT group, while the Y-maze test revealed no significant difference among the four groups. The CD68+ microglia and GFAP+ astrocyte numbers were reduced in the H-BBCT group. Furthermore, H-BBCT treatment restored the dysregulation of gene expression caused by BCAS. The major BBCT targets were predicted to be cell division cycle protein 20 (CDC20), Epidermal growth factor (EGF), and tumor necrosis factor receptor-associated factor 1 (TRAF1). BBCT regulates the neuroactive ligand-receptor interaction and neuropeptide signaling pathways, as predicted by KEGG and GO analyses, respectively. BBCT significantly improved cognitive impairment in a BCAS mouse model by inhibiting microglial and astrocyte activation and regulating the expression of CDC20, EGF, TRAF1, and key proteins in the neuroactive ligand-receptor interaction and neuropeptide signaling pathways.

Anti-miRNA103/107 encapsulated in transferrin-conjugated lipid nanoparticles crosses blood-brain barrier and reduces brain ischemic damage.

MicroRNA (miRNA), by post-transcriptionally regulating the expression of genes involved in stroke response, represents important effectors in stroke pathophysiology. Recently, the 103/107 miRNA family emerged as a possible therapeutic target in stroke, as it controls the expression of sodium calcium exchanger 1, a plasma membrane transporter that plays a fundamental role in stroke pathophysiology. Although the neuroprotective properties of this and other miRNAs are promising, several pharmacokinetic drawbacks remain to be faced for the development of a translatable therapy based on small RNAs in CNS diseases. In the present study, to overcome these limitations, the anti-miRNA103/107 was encapsulated in specific preparations of lipid nanoparticles (LNPs), and their effectiveness was evaluated both in an in vitro model of hypoxia represented by primary neuronal cortical cultures exposed to oxygen and glucose deprivation followed by reoxygenation, and in an in vivo model of stroke obtained in rats exposed to transient occlusion of the middle cerebral artery. The results of the present study demonstrated that the encapsulation of anti-miRNA103/107 in transferrin-conjugated PEG-stabilized LNPs allowed the blood-brain barrier crossing and significantly reduced brain ischemic damage. The present achievements pave the way for the exploitation of a systemic intravenous miRNA delivery strategy in stroke therapy.