Ischemic stroke is a secondary cause of mortality worldwide, imposing considerable medical and economic burdens on society. Extracellular vesicles, serving as natural nano-carriers for drug delivery, exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke. However, the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency. By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles, their delivery efficacy may be greatly improved. Furthermore, previous studies have indicated that microvesicles, a subset of large-sized extracellular vesicles, can transport mitochondria to neighboring cells, thereby aiding in the restoration of mitochondrial function post-ischemic stroke. Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components, such as proteins or deoxyribonucleic acid, or their sub-components, for extracellular vesicle-based ischemic stroke therapy. In this review, we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies. Given the complex facets of treating ischemic stroke, we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process. Moreover, given the burgeoning interest in mitochondrial delivery, we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Stroke is a serious cerebrovascular disease that is categorized into two types: ischemic and hemorrhagic. The pathological mechanisms of ischemic stroke are complex and diverse, encompassing processes such as neuroinflammation and apoptosis. The pathological processes of hemorrhagic stroke primarily involve the disruption of the blood-brain barrier and cerebral edema. Western medical treatment methods show certain effectiveness during the acute phase of stroke, but they are limited by a narrow therapeutic window and secondary injuries. Traditional Chinese medicine (TCM) has a long history and unique advantages in treating stroke. Studies confirm that active compounds derived from TCM exert multi-pathway, multi-target effects, significantly improving therapeutic outcomes and reducing adverse reactions. However, due to the complexity of the components in TCM, research on monomeric components still faces challenges. This article reviews the relevant research progress published in domestic and international journals over the past twenty years regarding the mechanisms of action of monomeric components of TCM in the treatment of stroke, aiming to provide insights and references for the clinical application of TCM in stroke treatment and further new drug development.

Alzheimer's disease (AD) and vascular dementia (VaD) are two prevalent forms of dementia. VaD is linked to cerebrovascular lesions, such as those from white matter ischemia and chronic cerebral hypoperfusion, which can also occur in AD. Nitric oxide (NO) regulates cerebral blood flow (CBF) in the central nervous system. Memantine is an NMDA receptor antagonist approved for AD treatment. This study investigated the efficacy and molecular mechanism of MN-08, a novel memantine nitrate, in one VaD model (2VO) and two AD models (APP/PS1 mice and Aβ1-42-induced mice). MN-08 increased CBF, ameliorated cognitive and memory functions in VaD and AD, and was more effective than memantine. MN-08 increased the survival rate of CA1 neurons and mitigated white matter lesions and axonal damage. Moreover, MN-08 protected neurons from OGD-induced loss and promoted axonal outgrowth in the hippocampus by upregulating phosphorylated Akt (p-Akt), glycogen synthase kinase-3β (p-GSK3β), and high-molecular-weight neurofilaments (p-NFH). The beneficial effects of MN-08 were attenuated by carboxy-PTIO, a potent NO scavenger, suggesting that MN-08-derived NO may alleviate cognitive impairment from cerebral hypoperfusion. Taken together, our studies demonstrate that MN-08 is a promising therapeutic agent for the treatment of dementia including VaD and AD.

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals. The comorbidity of the two neurological disorders represents a grave health threat to older populations. This review presents a brief background of the development of novel concepts and their clinical potentials. The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca 2+ influx is critical for neuronal function. An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca 2+ mainly via N-methyl-D-aspartate receptors, particularly of those at the extrasynaptic site. This Ca 2+ -evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity. Furthermore, mild but sustained Ca 2+ increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic, but gradually set off deteriorating Ca 2+ -dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways. Based on the Ca 2+ hypothesis of Alzheimer's disease and recent advances, this Ca 2+ -activated "silent" degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis. The N-methyl-D-aspartate receptor subunit GluN3A, primarily at the extrasynaptic site, serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity. Ischemic stroke and Alzheimer's disease, therefore, share an N-methyl-D-aspartate receptor- and Ca 2+ -mediated mechanism, although with much different time courses. It is thus proposed that early interventions to control Ca 2+ homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia. This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

The development of fibrosis after injury to the brain or spinal cord limits the regeneration of the central nervous system in adult mammals. However, the extent of fibrosis in the injured brain has not been systematically investigated in mammals in vivo. This study aimed to assess whether [18F]AlF-FAPI-42-based cerebral positron emission tomography (PET) can be utilized to assess the extent of fibrosis in ischemic regions of the brain in vivo. Sprague-Dawley rats underwent permanent occlusion of the right middle cerebral artery (MCAO). On days 3, 7, 14, and 21 after MCAO, the uptake of [18F]AlF-FAPI-42 in the ischemic region of the brain in the MCAO groups surpassed that in the control group (day 0). The specific expression of fibroblast activation protein-α (FAP) in ischemic regions of the brain was also confirmed in immunohistofluorescence experiments in vitro. [18F]AlF-FAPI-42 intensity correlated with the density of collagen deposition in the ischemic hemisphere (p < 0.001). [18F]AlF-FAPI-42 PET/CT imaging demonstrated a specific uptake of radioactivity in the infarcted area in an ischemic stroke patient. PET imaging by using [18F]AlF-FAPI-42 offers a promising non-invasive method for monitoring the progression of cerebral fibrosis caused by ischemic stroke and may facilitate the clinical management of stroke patients. Trial registration: chictr.org.cn ChiCTR2200059004. Registered April 22, 2022.

Intestinal injury as a consequence of ischemia-reperfusion injury after refractory cardiac arrest is not fully understood. This study evaluates the occurrence of clinical signs reflecting possible non-occlusive mesenteric ischemia (NOMI) to outcomes in patients with refractory cardiac arrest.

In a post-hoc analysis of a randomized, prospective Prague OHCA study comparing ECPR vs. CPR approaches in refractory out-of-hospital CA, all patients who survived longer than one hour after hospital admission were analyzed. We assessed possible NOMI based on clinical signs (mainly profuse diarrhea and abdominal distension) and their onset within 12 hours of admission. Its occurrence was correlated with neurologically unfavorable outcome (Cerebral Performance Category (CPC) Scale 3-5) at 180 days. Cox regression was used to evaluate the relationship of particular variables to adverse neurological outcomes.

Of the 256 study participants, 61 developed possible NOMI: 46 (51.7%) in the ECPR group and 15 (16.5%) in the CPR group. Adverse neurological outcomes occurred in 41 (89%) and nine (60%) patients, respectively. The number of patients developing possible NOMI was higher in those treated with ECPR (p>0.01). Its occurrence correlated with cardiac arrest length, elevated levels of neuron-specific enolase and procalcitonin at 48 and 72 hours. It was independently associated with adverse outcomes. In Cox regression, possible NOMI was associated with poor neurological outcomes in ECPR patients.

The development of profuse diarrhea, abdominal distension and other signs suggesting non-occlusive mesenteric ischemia in patients with refractory out-of-hospital cardiac arrest are observed more frequently in patients with poor neurological outcome at day 180, especially in patients treated with ECPR.

ClinicalTrials.gov: NCT01511666.

Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A significant pathological feature of IS impaired energy metabolism. Astrocytes, as the most prevalent glial cells in the brain, sit in between neurons and the microvasculature. By taking advantage of their special anatomical location, they play a crucial part in regulating cerebral blood flow (CBF) and metabolism. Astrocytes can withstand hypoxic and ischemic conditions better than neurons do. Additionally, astrocytes are essential for maintaining the metabolism and function of neurons. Therefore, the "neurocentric" perspective on neuroenergetics is gradually giving way to a more comprehensive perspective that takes into account metabolic interaction between astrocytes and neurons. Since neurons in the core region of the infarct are unable to undergo oxidative metabolism, the focus of attention in this review is on neurons in the peri-infarct region. We'll go over the metabolic crosstalk of astrocytes and neurons during the acute phase of IS using three different types of metabolites: lactate, fatty acids (FAs), and amino acids, as well as the mitochondria. After IS, astrocytes in the peri-infarct zone can produce lactate, ketone bodies (KBs), glutamine (Gln), and l-serine, shuttling these metabolites, along with mitochondria, to neurons. This process helps maintain the energy requirements of neurons, preserves their redox state, and regulates neurotransmitter receptor activity.

The nuclear Overhauser enhancement (NOE)-mediated saturation transfer effect at -1.6 ppm, termed NOE(-1.6 ppm), has demonstrated potential for detecting ischemic stroke. However, the quantification of the NOE(-1.6 ppm) effect usually relies on a multiple-pool Lorentzian fit method, which necessitates a time-consuming acquisition of the entire chemical exchange saturation transfer (CEST) Z-spectrum with high-frequency resolution, thus hindering its clinical applications.

This study aims to assess the feasibility of employing asymmetry analysis, a rapid CEST data acquisition and analysis method, for quantifying the NOE(-1.6 ppm) effect in an animal model of ischemic stroke.

We examined potential contaminations from guanidinium/amine CEST, NOE(-3.5 ppm), and asymmetric magnetization transfer (MT) effects, which could reduce the specificity of the asymmetry analysis of NOE(-1.6 ppm). First, a Lorentzian difference (LD) analysis was used to mitigate direct water saturation and MT effects, providing separate estimations of the contributions from the guanidinium/amine CEST and NOE effects. Then, the asymmetry analysis of the LD fitted spectrum was compared with the asymmetry analysis of the raw CEST Z-spectrum to evaluate the contribution of the asymmetric MT effect at -1.6 ppm.

Results show that the variations of the LD quantified NOE(-1.6 ppm) in stroke lesions are much greater than that of the CEST signals at +1.6 ppm and NOE(-3.5 ppm), suggesting that NOE(-1.6 ppm) has a dominating contribution to the asymmetry analysis at -1.6 ppm compared with the guanidinium/amine CEST and NOE(-3.5 ppm) in ischemic stroke. The NOE(-1.6 ppm) variations in the asymmetry analysis of the raw CEST Z-spectrum are close to those in the asymmetry analysis of the LD fitted spectrum, revealing that the NOE(-1.6 ppm) dominates over the asymmetric MT effects.

Our study demonstrates that the asymmetry analysis can quantify the NOE(-1.6 ppm) contrast in ischemic stroke with high specificity, thus presenting a viable alternative for rapid mapping of ischemic stroke.

Ischemic stroke represents one of the leading cerebrovascular diseases with a high rate of mortality and disability globally. To date, there are no effective clinical drugs available to improve long-term outcomes for post-stroke patients. A novel nucleic acid agent circSCMH1 which can promote sensorimotor function recovery in rodent and nonhuman primate animal stroke models has been found. However, there are still delivery challenges to overcome for its clinical implementation. Besides, its effects on post-stroke cognitive functions remain unexplored. Herein, lipid nanoparticle circSCMH1@LNP1 is established to deliver circSCMH1 and explore its therapeutic efficacy comprehensively. Distribution experiments demonstrate that intranasal administration of circSCMH1@LNP1 significantly increases circSCMH1 distribution in the peri-infarct region and reduces its non-specific accumulation in other organs compared to intravenous injection. Therapeutic results indicate that circSCMH1@LNP1 promotes synaptic plasticity, vascular repair, neuroinflammation relief, and myelin sheath formation, thereby achieving enhanced sensorimotor and cognitive function recovery in post-stroke mice. In conclusion, this research presents a simple and effective LNP system for efficient delivery of circSCMH1 via intranasal administration to repair post-stroke brain injury. It is envisioned that this study may bridge a crucial gap between basic research and translational application, paving the way for clinical implementation of novel circSCMH1 in post-stroke patient management.

Stroke significantly impacts global health, being a primary cause of disability, dementia, and mortality. The interplay of nutritional deficiency and systemic inflammation plays a pivotal role in determining stroke outcomes. While the Prognostic Nutritional Index (PNI) and the Advanced Lung Cancer Inflammation Index (ALI) have been recognized for their prognostic value in various diseases, their relevance in stroke prognosis necessitates further exploration.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018, analyzing 908 stroke survivors to examine the associations between PNI, ALI, and mortality outcomes. Weighted Cox proportional hazards models were applied to assess the associations, controlling for demographic and health-related variables. Kaplan-Meier curves and restricted cubic splines were used to evaluate survival differences and non-linear relationships, respectively. Additionally, subgroup and sensitivity analyses were conducted to verify the robustness of the associations.

In our cohort, elevated PNI was associated with significantly lower risks of all-cause mortality (Hazard Ratio [HR]: 0.53, 95 % Confidence Interval [CI]: 0.37-0.75, p < 0.001) and cardiovascular mortality (HR: 0.60, 95 % CI: 0.38-0.94, p = 0.028). Similarly, higher ALI levels correlated with a reduced risk of all-cause mortality (HR: 0.53, 95 % CI: 0.37-0.72, p < 0.001), though its impact on cardiovascular mortality did not reach statistical significance after adjustment. Subgroup analysis revealed that gender, age, and diabetes status modulated the relationship between PNI/ALI and mortality outcomes, with significant interactions observed especially in diabetic patients (PNI: P for interaction = 0.025 and ALI: P for interaction = 0.007).

This study confirms that higher PNI and ALI are associated with lower all-cause mortality in stroke survivors. Elevated PNI also reduces cardiovascular mortality risk. Gender, age, and diabetes status influence these associations. These findings highlight the importance of monitoring nutritional and inflammatory status in stroke recovery.

Neural glutamate homeostasis is important for health and disease. Ischemic conditions, like stroke, cause imbalances in glutamate release and uptake due to energy depletion and depolarization. We here used the glutamate sensor SF-iGluSnFR(A184V) to probe how chemical ischemia affects the extracellular glutamate dynamics in slice cultures from mouse cortex. SF-iGluSnFR imaging showed spontaneous glutamate release indicating synchronous network activity, similar to calcium imaging with GCaMP6f. Glutamate imaging further revealed local, atypically large, and long-lasting plume-like release events. Plumes occurred with low frequency, independent of network activity, and persisted in tetrodotoxin (TTX). Blocking glutamate uptake with TFB-TBOA favored plumes, whereas blocking ionotropic glutamate receptors (iGluRs) suppressed plumes. During chemical ischemia plumes became more pronounced, overly abundant and contributed to large-scale glutamate accumulation. Similar plumes were previously observed in cortical spreading depression and migraine models, and they may thus be a more general consequence of glutamate uptake dysfunctions in neurological and neurodegenerative diseases.

Pediatric stroke is a significant cause of childhood mortality and morbidity. The clinical research in this field bears certain limitations that do not exist in the pre-clinical setting. Experimental models of ischemic stroke show differences in lesion evolution and blood-brain barrier (BBB) permeability between adult and neonatal rats. However, little is known about these factors in the juvenile stage. Here, we characterize the evolution of the lesion, penumbra and degree of BBB permeability in a photothrombotic ring model of juvenile stroke using a mixed longitudinal and cross-sectional study. Fourteen Sprague Dawley juvenile rats (weight 130-189 g), lesion, penumbra volume and blood-brain barrier (BBB) leakage were measured longitudinally on days 0, 2, and 7 following photothrombotic stroke. Magnetic resonance imaging (MRI) techniques were used to measure lesion and penumbra volumes (T2-weighted imaging [T2]), water restriction (diffusion-weighted imaging [DWI]) and BBB leakage (with dynamic contrast-enhanced imaging [DCE]). To confirm stroke, histology was performed (n = 9) with Triphenyltetrazolium chloride staining (TTC) (n=9), (Haemotoxylin and Eosin (H&E) staining (n=3); andn Evans Blue (EB) staining to assess BBB permeability (n=9). We found the volume of the penumbra to be larger and better delineated on MRI and histology in the acute compared to the subacute and chronic stages. The lesion was smaller in volume and increased over time following same time trajectory. The BBB was most compromised at the hyperacute stage (day 0) and decreasingly, yet persistently, disrupted to day 7. Our in vivo and ex vivo findings provide insight into the evolution of stroke and could serve as a study model to test blood-brain barrier stabilization agents in the pediatric setting.

Acute ischemic stroke disrupts communication between neurons and blood vessels in penumbral areas. How neurons and blood vessels cooperate to achieve blood-brain barrier repair remains unclear. Here, we reveal crosstalk between ischemic penumbral neurons and endothelial cells (ECs) mediated by circular RNA originating from oxoglutarate dehydrogenase (CircOGDH).

We analyzed clinical data from patients with acute ischemic stroke to explore the relationship between CircOGDH levels and hemorrhagic transformation events. In addition, a middle cerebral artery occlusion and reperfusion mouse model with neuronal CircOGDH suppression was used to assess endothelial permeability. ECs with increased CircOGDH expression were analyzed for changes in COL4A4 (collagen type IV alpha 4) levels, and in vitro coculture experiments were conducted to examine small extracellular vesicle-mediated CircOGDH transfer between neurons and ECs.

Clinical data indicated that reduced CircOGDH levels were correlated with increased hemorrhagic transformation in patients with acute ischemic stroke. In the middle cerebral artery occlusion and reperfusion model, neuronal CircOGDH suppression impaired the restoration of endothelial permeability. ECs with increased CircOGDH expression exhibited higher COL4A4 levels, which helped maintain vascular stability. In vitro, hypoxic neurons transferred CircOGDH to ECs via small extracellular vesicles, leading to elevated COL4A4 expression and enhanced endothelial integrity.

Our findings highlight the significance of CircOGDH in neuron-EC crosstalk via small extracellular vesicles in the ischemic penumbra, emphasizing the need for balanced intervention strategies in acute ischemic stroke management.

The application of existing radical treatments for stroke is limited to a small number of cases, with current practices predominantly focusing on conservative therapy. This review examines the pathophysiology of excitotoxicity, oxidative stress, and inflammation during brain ischemia caused by stroke, highlighting insights into each pathology and reporting the latest therapeutic developments that are expected to serve as new treatment options. Finally, we outline the recent attention given to the relationship between periodontal disease and stroke. We propose addressing the limitations of existing treatments for stroke and suggest novel therapeutic approaches while also presenting the potential contribution of periodontal disease treatment to the prevention of stroke.

Acute brain injuries (ABI) caused by various emergencies can lead to structural and functional damage to brain tissue. Common causes include traumatic brain injury, cerebral hemorrhage, ischemic stroke, and heat stroke. Globally, ABI represent a significant portion of neurosurgical cases. Previous studies have emphasized the significant therapeutic potential of stem cell-derived extracellular vesicles (EVs). Recent research indicates that EVs extracted from resident cells in the central nervous system (CNS) also show therapeutic potential following brain injury. Microglia, as innate immune cells of the CNS, respond to changes in the internal environment by altering their phenotype and secreting EVs that impact various CNS cells, including neurons, astrocytes, oligodendrocytes, endothelial cells, neural stem cells (NSCs), and microglia themselves. Notably, under different external stimuli, microglia can either promote neuronal survival, angiogenesis, and myelin regeneration while reducing glial scarring and inflammation, or they can exert opposite effects. This review summarizes and evaluates the current research findings on how microglia-derived EVs influence various CNS cells after ABI under different external stimuli. It analyzes the interaction mechanisms between EVs and resident CNS cells and discusses potential future research directions and clinical applications.

Transforming growth factor-β-activated kinase 1 binding protein 2 (TAB2) plays a vital role in inflammatory pathways. It has also been considered a potential target for the enhancement of the the antiestrogen effects. Previous evidence has indicated that TAB2 gene variants are associated with several diseases, whereas their potential correlation with endometrial cancer (EC) is unclear. This study aims to initially explore the association between TAB2 gene polymorphisms (rs237028 /AG, rs521845 T/G, and rs652921 T/C) and EC.

Polymerase chain reaction-restriction fragment length polymorphism was applied to determine the genotype composition and the allele frequencies of TAB2 gene variant polymorphisms in 270 EC patients and 294 healthy controls.

The G allele of rs521845 was related to the increase of EC risk [p=0.08, odds ratio (OR): 0.72, 95% confidence interval (CI): 0.56-0.91]. Moreover, EC risk was associated with rs521845 in different genetic models (p=0.017, OR: 0.63, 95% CI: 0.44-0.91 in the codominant model; p=0.0051, OR: 0.61, 95% CI: 0.43-0.87 in the dominant model). For rs237028, the percentage of AG genotype in patients with highly differentiated tumours (G1) was significantly higher than that in moderately, poorly differentiated patients (G2/G3) (p=0.031, OR: 0.77, 95% CI: 0.45-1.30).

Our results showed that the rs521845 polymorphism of TAB2, was associated with EC risk, suggesting that TAB2 may play a crucial role in EC prognosis.

The neuroprotective and proangiogenic potential of ghrelin in acute ischemic stroke has been demonstrated in experimental studies. However, the transferability of these results is limited as ghrelin was administered either before or very early after stroke onset and follow-up was limited to the first days after stroke. The aim of this study was therefore to close and extend this knowledge gap. To this end, we investigated the effect of ghrelin in two different translational animal models, one investigating acute and one investigating long-term structural and functional recovery after experimental stroke.

Middle cerebral artery occlusion (MCAO) or photothrombotic stroke was induced in 65 adult male Wistar rats. Eleven sham-operated animals served as controls. The rats were treated with either ghrelin, the ghrelin receptor antagonist [D-Lys]-GHRP-6 or a control substance. Up to four weeks after ischemia, behavioral tests such as the cylinder test, the tape removal test, and the rotarod test were performed to examine sensorimotor deficits, and the Morris water maze was performed to examine effects on the acquisition and consolidation of new memories. The structural outcome was determined by a differential analysis of neurogenesis in relation to survival and proliferation of newborn neurons in the post-ischemic brain, angiogenesis and determination of infarct size.

Ghrelin treatment improved motor and somatosensory functions and preserved the consolidation of new memories after photothrombotic stroke. As a structural correlate, long-term survival and sustained proliferation of neuronal cells after stroke was significantly increased in ghrelin-treated rats, while angiogenesis remained unaffected. In contrast to these neuroregenerative mechanisms, ghrelin did not induce immediate neuroprotective effects after MCAO.

Our results suggest that ghrelin has a significant pro-neuroregenerative effect by enhancing long-term survival and sustained proliferation of neurons in the dentate gyrus and peri-infarct area, thus promoting functional recovery. Overall, ghrelin represents a promising target in the subacute and chronic phase after ischemic stroke.

Microvascular dysfunction and no-reflow are considered a major cause of secondary damage despite revascularization in acute ischemic stroke (AIS), ultimately affecting patient outcomes. We used quantitative PET-MRI imaging to characterize early microvascular damages in a preclinical non-human primate model mimicking endovascular mechanical thrombectomy (EVT). During occlusion, PET perfusion and MRI diffusion were used to measure ischemic and lesion core volumes respectively. Following revascularization, multiparametric PET-MRI included perfusion, diffusion, blood-brain barrier (BBB) permeability MRI, and 15O-oxygen metabolism PET. Lesion growth on MRI was evaluated at one week, and the neurological score was assessed daily; a poor outcome was defined as a score>6 (0-normal, 60-death) after one week. Early after recanalization, the gold-standard PET ischemic threshold (<0.2 ​mL/min/g) identified post-EVT hypoperfusion in 67 ​% of the cases (14/21) located in the occlusion acute lesion. Acquired 110 ​min post-EVT, the area of MRI Tmax hypoperfusion was larger and even more frequent (18/20) and was also located within the acute lesion. Eight of the total cases (38 ​%) had a poor outcome, and all of them had no-reflow (7/8 MRI no-reflow and 6/8 ​PET no-reflow). Diffusion ADC alterations and post-EVT oxygen extraction fraction (OEF) values were significantly different in PET no-reflow cases compared to those without no-reflow, exhibiting an inverse correlation. Independently of no-reflow, long perfusion Tmax and post-EVT high BBB Ktrans in the lesion core were the hallmarks of poor outcome and infarct growth. This early quantitative imaging signature may predict infarct growth and poor outcome and help to identify neuroprotection targets.

Acute ischemic stroke (AIS) is a significant brain disease with a high mortality and disability rate. Additional therapies for AIS are urgently needed, and neuroplasticity mechanisms by agents are expected to be neuroprotective for AIS. As a major active component of Salvia miltiorrhiza, salvianolic acid A (SAA) has shown potential for preventing cardiovascular diseases. However, there is no evidence of the long-term effect of SAA on ischemic injury or its mechanism. Therefore, using rats and mice, we systematically investigated the impact of SAA on AIS from the perspective of neuroprotective and neuroplasticity. Here, we report that SAA induces a long-term depression (LTD)-like process in synapses. This antiexcitotoxicity action supports the SAA effect, including alleviating infarction and promoting blood circulation in photothrombosis and middle cerebral artery occlusion (MCAO) models. Furthermore, repeated positron emission tomography/computed tomography (PET/CT) imaging and behavioral assessments two months after AIS induction reveal that acute treatment of SAA promotes recovery from disrupted whole-brain glucose metabolism and impaired spatial memory. These data suggest that acute treatment of SAA is neuroprotective by improving long-term functional outcomes through a synaptic LTD-like process, providing a promising adjunct to current therapies to enable better recovery for AIS.

Neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries. Schizophrenia is not as common as other mental disorders, affecting approximately 24 million people worldwide. All these disorders have in common that still there is not an effective pharmacological treatment to cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention as a potential therapeutic target due to its important role in learning and memory and also due to its implication in excitotoxicity processes. Some drugs targeting NMDARs are already being used to treat symptoms of disorders affecting the central nervous system (CNS). Here, we aim to review the implications of NMDAR in these CNS pathologies, its role as a potential therapeutic target, and the future perspectives for developing new treatments focused on these receptors.

Wogonin, an O-methylated flavonoid extracted from Scutellaria baicalensis, has demonstrated profound neuroprotective effects in a range of central nervous system (CNS) diseases. This review elucidates the pharmacological mechanisms underlying the protective effects of wogonin in CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, epilepsy, anxiety, neurodegenerative diseases, and CNS infections. Wogonin modulates key signaling pathways, such as the MAPK, NF-κB, and ROS pathways, contributing to its anti-inflammatory, antioxidant, and antiapoptotic properties. In ischemic stroke models, wogonin reduces infarct size and enhances neurological outcomes by mitigating inflammation and oxidative stress. For patients with hemorrhagic stroke and traumatic brain injury, it accelerates hematoma regression, mitigates secondary brain damage, and promotes neurogenesis, making it an entirely new treatment option for patients with limited access to this type of therapy. Its anticonvulsant and anxiolytic effects are mediated through GABA-A receptor modulation. Moreover, wogonin shows promise in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease by promoting autophagy and reducing neuroinflammation. Additionally, it exhibits antiviral properties, offering potential benefits against CNS infections. Despite extensive preclinical evidence, further clinical studies are warranted to confirm its efficacy and safety in humans. This review highlights the great therapeutic potential of wogonin in terms of CNS protection. However, despite the substantial preclinical evidence, further large-scale clinical studies are necessary. Future researchers need to further explore the long-term efficacy and safety of wogonin in clinical trials and translate it for early application in the clinical treatment of true CNS disorders.

A fluorescence quenching mechanism using linear diselenides was proposed for the first time through a combination of intramolecular charge transfer (ICT) and Förster resonance energy transfer (FRET). Herein, we synthesized and screened a two-photon fluorescent probe AFC-SeSe, demonstrating a remarkable 300-fold increase in response to glutathione (GSH). Additionally, AFC-SeSe enabled real-time observation of increased thiol levels following treatment within a short timeframe in a mouse model of stroke.

Nelonemdaz selectively antagonizes the 2B subunit of the N-methyl-d-aspartate glutamate receptor and scavenges free radical species.

To evaluate whether nelonemdaz enhances the clinical outcomes of patients with acute ischemic stroke undergoing emergent reperfusion therapy.

This multicenter double-blind placebo-controlled randomized phase 3 trial (December 25, 2021, to June 30, 2023, in South Korea) recruited patients with acute ischemic stroke who met the following criteria: National Institutes of Health Stroke Scale score greater than or equal to 8, Alberta Stroke Program Early Computed Tomography score greater than or equal to 4, and endovascular thrombectomy within 12 hours after stroke onset.

Patients were assigned in a 1:1 ratio to receive intravenous infusions of nelonemdaz twice a day for 5 days or a matching placebo.

The primary end point was a favorable shift in the modified Rankin scale (mRS) 12 weeks after stroke onset. The secondary end points included various composites of the mRS at 5 and 12 weeks, symptomatic intracranial hemorrhage, and infarct volume. Both intention-to-treat and per-protocol analyses were conducted.

A total of 496 patients were enrolled across 24 Korean stroke centers, of whom 39 dropped out (254 men [55.6%]; mean [SD] age, 72.9 [12.1] years). Baseline characteristics of study participants did not significantly differ. For the primary end point, the distribution of the mRS scores at 12 weeks did not significantly differ between the nelonemdaz and placebo groups (common odds ratio, 0.95; 95% CI, 0.69-1.31). For the secondary end points, a median of mRS at 5 weeks (3 vs 3) and mRS 0 at 12 weeks (18.1% vs 18.2%) did not differ substantially between groups. The occurrence of symptomatic intracranial hemorrhage (2.7% vs 0.9%) and infarct volume within 24 hours of the last trial drug infusion (42 vs 38 mL) did not differ significantly between groups. No serious adverse events were reported regarding the trial drug and placebo.

In this randomized clinical trial, nelonemdaz did not meet the primary efficacy end point compared with placebo.

ClinicalTrials.gov Identifier: NCT05041010.

Blood-brain barrier (BBB) damage significantly affects the prognosis of ischemic stroke patients. This project employed multi-omics analysis to identify key factors regulating BBB disruption during cerebral ischemia-reperfusion. An integrated analysis of three transcriptome sequencing datasets from mouse middle cerebral artery occlusion/reperfusion (MCAO/R) models identified eight downregulated genes in endothelial cells. Additionally, transcriptome analysis of BBB (cortex) and non-BBB (lung) endothelium of E13.5 mice revealed 2,102 upregulated genes potentially associated with BBB integrity. The eight downregulated genes were intersected with the 2,102 BBB-related genes and mapped using single-cell RNA sequencing data, revealing that solute carrier family 22 member 8 (Slc22a8) is specifically expressed in endothelial cells and pericytes and significantly decreases after MCAO/R. This finding was validated in the mouse MCAO/R model at both protein and mRNA levels in this study. External overexpression of Slc22a8 using a lentivirus carrying Tie2 improved Slc22a8 and tight junction protein levels and reduced BBB leakage after MCAO/R, accompanied by Wnt/β-catenin signaling activation. In conclusion, this study suggested that MCAO/R-induced downregulation of Slc22a8 expression may be a crucial mechanism underlying BBB disruption. Interventions that promote Slc22a8 expression or enhance its function hold promise for improving the prognosis of patients with cerebral ischemia.

Ischemic stroke is a devastating disease in which mitochondrial damage or dysfunction substantially contributes to brain injury. Mitochondrial uncoupling protein-2 (UCP2) is a member of the UCP family, which regulates production of mitochondrial superoxide anion. UCP2 is reported to be neuroprotective for ischemic stroke-induced brain injury. However, the molecular mechanisms of UCP2 in ischemic stroke remain incompletely understood. In this study, we investigated whether and how UCP2 modulates neuroinflammation and regulates neuronal ferroptosis following ischemic stroke in vitro and in vivo. Wild-type (WT) and UCP2 knockout (Ucp2-/-) mice were subjected to middle cerebral artery occlusion (MCAO). BV2 cells (mouse microglial cell line) and HT-22 cells (mouse hippocampal neuronal cell line) were transfected with small interfering (si)-RNA or overexpression plasmids to knockdown or overexpress UCP2 levels. Cells were then exposed to oxygen-glucose deprivation and reoxygenation (OGD/RX) to simulate hypoxic injury in vitro. We found that UCP2 expression was markedly reduced in a time-dependent manner in both in vitro and in vivo ischemic stroke models. In addition, UCP2 was mainly expressed in neurons. UCP2 deficiency significantly enlarged infarct volumes, aggravated neurological deficit scores, and exacerbated cerebral edema in mice after MCAO. In vitro knockdown of Ucp2 and in vivo genetic depletion of Ucp2 (Ucp2-/- mice) increased neuronal ferroptosis-related indicators, including Fe2+, malondialdehyde, glutathione, and lipid peroxidation. Overexpression of UCP2 in neuronal cells resulted in reduced ferroptosis. Moreover, knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ischemic stroke models, suggesting that endogenous UCP2 inhibits neuroinflammation following ischemic stroke. Upregulation of UCP2 expression in microglia appeared to decrease the release of pro-inflammatory factors and increase the levels of anti-inflammatory factors. Further investigation showed that UCP2 deletion inhibited expression of AMPKα/NRF1 pathway-related proteins, including p-AMPKα, t-AMPKα, NRF1, and TFAM. Thus, UCP2 protects the brain from ischemia-induced ferroptosis by activating AMPKα/NRF1 signaling. Activation of UCP2 represents an attractive strategy for the prevention and treatment of ischemic stroke.

The endogenous neuromodulator adenosine is massively released during hypoxic/ischemic insults and differentially modulates post-ischemic damage depending on the expression and recruitment of its four metabotropic receptor subtypes, namely A1, A2A, A2B and A3 receptors (A1Rs, A2ARs, A2BRs and A3Rs). We previously demonstrated, by using a model of transient middle cerebral artery occlusion (tMCAo) in rats, that selective activation of A2ARs, as well as A2BRs, ameliorates post-ischemic brain damage in contrast to neuroinflammation. In the present study, we investigated whether the multitarget nucleoside MRS3997, a full agonist at both A2ARs and A2BRs, would afford higher neuroprotection in post-ischemic damage. Chronic systemic treatment with MRS3997 reduced neurological deficit, body weight loss and infarct volume in the cortex and striatum measured 7 days after ischemia. The dual agonist counteracted neuronal loss, reduced myelin damage, and prevented morphological changes indicative of microglia and astrocyte activation. Finally, MRS3997 shifted plasma cytokine levels to an anti-inflammatory profile. These effects were preceded, at 2 days after the insult, by a reduced granulocyte infiltration in the ischemic cortex and, differently from what was observed with selective A2AR or A2BR agonism, also in striatum. In summary, we demonstrate here that MRS3997, systemically administered for 7 days after tMCAO, protects ischemic areas from neuronal and glial damage and inhibits neuroinflammation, therefore representing an attractive strategy to ameliorate post-stroke damage and neurological symptoms.

Neuroprotection, defined as safeguarding neurons from damage and death by inhibiting diverse pathological mechanisms, continues to be a promising approach for managing a range of central nervous system (CNS) disorders, including acute conditions such as ischemic stroke and traumatic brain injury (TBI) and chronic neurodegenerative diseases like Parkinson's disease (PD), Alzheimer's disease (AD), and multiple sclerosis (MS). These pathophysiological conditions involve excessive glutamatergic (Glu) transmission activity, which can lead to excitotoxicity. Inhibiting this excessive Glu transmission has been proposed as a potential therapeutic strategy for treating the CNS disorders mentioned. In particular, ligands of G protein-coupled receptors (GPCRs), including metabotropic glutamatergic receptors (mGluRs), have been recognized as promising options for inhibiting excessive Glu transmission. This review discusses the complex interactions of mGlu receptors with their subtypes, including the formation of homo- and heterodimers, which may vary in function and pharmacology depending on their protomer composition. Understanding these intricate details of mGlu receptor structure and function enhances researchers' ability to develop targeted pharmacological interventions, potentially offering new therapeutic avenues for neurological and psychiatric disorders. This review also summarizes the current knowledge of the neuroprotective potential of ligands targeting group III mGluRs in preclinical cellular (in vitro) and animal (in vivo) models of ischemic stroke, TBI, PD, AD, and MS. In recent years, experiments have shown that compounds, especially those activating mGlu4 or mGlu7 receptors, exhibit protective effects in experimental ischemia models. The discovery of allosteric ligands for specific mGluR subtypes has led to reports suggesting that group III mGluRs may be promising targets for neuroprotective therapy in PD (mGlu4R), TBI (mGlu7R), and MS (mGlu8R).

Antagonizing excessive glutamate-induced neuroexcitatory toxicity is one of the treatments for brain and retinal nerve damage in ischemic stroke patients. In this work, a series of 3-benzoyl-4-phenyl-spiropyrrolidone (spiroheterocyclic) compounds were designed and synthesized by modifying the Michael receptor of chalcone to reduce its toxicity. Several compounds with superior protective effects on PC12 cells were screened through an experimental model of glutamate-induced damage, and a quantitative evaluation of the structure-activity relationship (QSAR) model with a regression coefficient of R2 = 0.90723 was established through the random forest (RF) algorithm. Among these compounds, E38 significantly increased the survival rate of damaged cells, promoted colony formation, and inhibited LDH release and apoptosis, and the protective effect of E38 was possibly partly through the HO-1/SIRT1 pathway. More importantly, in mice model of middle cerebral artery occlusion (MCAO), E38 decreased cerebral infarct size, improved neurological scores, and mitigated retinal damage. In conclusion, this work presents a novel class of chalcone derivatives with neuroprotective activity and offers potential compounds for the treatment of ischemic stroke.

Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood-brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-beta peptides within cerebral blood vessels, leading to neurovascular complications. Ischemic strokes result from acute disruptions in cerebral blood flow, triggering metabolic disturbances and neurodegeneration. Both conditions often co-occur and are associated with respiratory dysfunctions. The retrotrapezoid nucleus (RTN), which is crucial for CO2 sensing and breathing regulation in the brainstem, may play a key role in breathing disorders seen in these conditions. This study aims to investigate the role of Transforming Growth Factor Beta (TGF-β) signaling in the RTN on respiratory and cognitive functions in CAA, both with and without concurrent ischemic stroke. Adult male Tg-SwDI (CAA model) mice and C57BL/6 wild-type controls underwent stereotaxic injections of lentivirus targeting TGF-βR2 in the RTN. Stroke was induced by middle cerebral artery occlusion using a monofilament. Respiratory functions were assessed using whole-body plethysmography, while cognitive functions were evaluated through the Barnes Maze and Novel Object Recognition Test (NORT). Immunohistochemical analysis was conducted to measure TGF-βR2 and GFAP expressions in the RTN. CAA mice exhibited significant respiratory dysfunctions, including reduced respiratory rates and increased apnea frequency, as well as impaired cognitive performance. TGF-βR2 silencing in the RTN improved respiratory functions and cognitive outcomes in CAA mice. In CAA mice with concurrent stroke, TGF-βR2 silencing similarly enhanced respiratory and cognitive functions. Immunohistochemistry confirmed reduced TGF-βR2 and GFAP expressions in the RTN following silencing. Our findings demonstrate that increased TGF-β signaling and gliosis in the RTN contribute to respiratory and cognitive dysfunctions in CAA and CAA with stroke. Targeting TGF-βR2 signaling in the RTN offers a promising therapeutic strategy to mitigate these impairments. This study is the first to report a causal link between brainstem gliosis and both respiratory and cognitive dysfunctions in CAA and stroke models.

Cerebrovascular diseases (CVDs), comprising predominantly ischemic stroke and chronic cerebral hypoperfusion (CCH), are a significant threat to global health, often leading to disability and mortality. Remote ischemic conditioning (RIC) has emerged as a promising, non-pharmacological strategy to combat CVDs by leveraging the body's innate defense mechanisms. This review delves into the neuroprotective mechanisms of RIC, categorizing its effects during the acute and chronic phases of stroke recovery. It also explores the synergistic potential of RIC when combined with other therapeutic strategies, such as pharmacological treatments and physical exercise. Additionally, this review discusses the pathways through which peripheral transmission can confer central neuroprotection. This review concludes by addressing the challenges regarding and future directions for RIC, emphasizing the need for standardized protocols, biomarker identification, and expanded clinical trials to fully realize its therapeutic potential.

Previously, we reported that transplantation of regeneration-associated cells (RACs) via the ipsilateral external carotid artery reduced stroke volume in mice with permanent occlusion of the middle cerebral artery (MCA). However, intracarotid arterial transplantation is invasive and requires skill, and severe complications may occur, such as thromboembolism, infection, and decreased cerebral blood flow. This study aimed to investigate the efficacy of intravenous injection of RACs in reducing stroke volume and increasing anti-inflammatory and angiogenic factors in mice with focal cerebral ischemia. Mice with occluded MCAs received intravenous injections of phosphate-buffered saline (PBS) (control), low-dose RACs, or high-dose RACs. The proximal part of the left MCA was occluded to induce permanent focal ischemia. After 3 days, we administered PBS or low-dose (1 × 104 /50 µL) or high-dose RACs (1 × 105 /50 µL) through the tail vein and assessed the infarct volume on day 7. High-dose RACs significantly decreased infarct volume compared to PBS, whereas low-dose RACs showed no effect. The number of interleukin-10 (IL-10)-positive and vascular endothelial growth factor (VEGF)-positive cells in the peri-infarct area on day 7 was significantly higher in mice treated with low-dose and high-dose RACs than in the PBS control group. Intravenous injection of RACs can reduce ischemic stroke volume; however, a higher dose of RACs is required than the dose used in intraarterial transplantation. By assessing IL-10 and VEGF expression, the study sheds light on the underlying mechanisms of RAC therapy, revealing its potential anti-inflammatory and angiogenic properties in the treatment of cerebral ischemia.

The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) plays an essential role in glycolysis and in the antioxidant pathway associated with glutathione. Therefore, we investigated the effects of PFKFB3 on oxidative and ischemic damage. We synthesized a fusion protein of transactivator of transcription (Tat)-PFKFB3 to facilitate its passage into the intracellular space and examine its effects against oxidative stress induced by hydrogen peroxide (H2O2) treatment and ischemic damage caused by occlusion of the common carotid arteries for 5 min in gerbils. The Tat-PFKFB3 protein was efficiently delivered into HT22 cells in a concentration- and time-dependent manner, with higher levels observed 18 h after treatment. Furthermore, treatment with 6 µM Tat-PFKFB3 demonstrated intracellular delivery into HT22 cells, as analyzed through immunocytochemical staining. Moreover, it significantly ameliorated the reduction of cell viability induced by 200 µM H2O2 treatment. Tat-PFKFB3 treatment also alleviated H2O2-induced DNA fragmentation and reactive oxygen species formation in HT22 cells. In gerbils, the intraperitoneal administration of 2 mg/kg Tat-PFKFB3 efficiently delivered the substance to all hippocampal areas, including the hippocampal CA1 region. This administration significantly mitigated ischemia-induced hyperlocomotion, long-term memory deficits, and ischemic neuronal death in the hippocampal CA1 region after ischemia. Additionally, treatment with 2 mg/kg Tat-PFKFB3 significantly ameliorated the translocation of Cdk5 from the cytosol to the nucleus in the hippocampal CA1 region 24 h after ischemia, but not in other regions. The treatment also significantly reduced reactive oxygen species formation in the CA1 region. These findings suggest that Tat-PFKFB3 reduces neuronal damage in the hippocampal CA1 region after ischemia through the reduction of Cdk5 signaling and reactive oxygen species formation. Therefore, Tat-PFKFB3 may have potential applications in reducing ischemic damage.

Reperfusion therapy, which substantially promotes the vessel recanalization rate and improves clinical outcomes, remains the most effective treatment of acute ischemic stroke (AIS). However, a substantial number of patients are either unsuitable for recanalization therapy or experience limited recovery postreperfusion. There is growing recognition that adjunctive neuroprotective therapies may further improve the outcomes in AIS patients by protecting brain tissue during ischemia. Recent advancements in neuroprotective approaches, including pharmacologic agents such as nerinetide edaravone, and uric acid, as well as nonpharmacological interventions, such as remote ischemic conditioning and normobaric hyperoxia, offer promising potentials in stroke care. This review provides an overview of the current neuroprotective therapies, examines recent clinical evidence, and discusses the strengths and weaknesses of certain clinical trials aimed at cerebral protection.

Nanozymes are a new kind of material which has been applied since the beginning of this century, and its birth has promoted the development of chemistry, materials science, and biology. Nanozymes can be used as a substitute for natural enzyme and has a wide range of applications; therefore, it has attracted extensive attention from all sectors of the community, and the number of studies has constantly increasing. In this paper, we introduced the outstanding achievements in the field of nanozymes in recent years from the main function, the construction of nanozyme-based biosensors, and the treatment of ischemic stroke, and we also illustrated the internal mechanism and the catalytic principle. In the end, the obstacles and challenges in the future development of nanozymes were proposed.

The serum lactate level has been confirmed to be an independent risk factor for the occurrence of acute kidney injury (AKI) in many diseases. However, the correlation between serum lactate level and AKI in critical patients with acute ischemic stroke (AIS) has not been clear. Moreover, limited studies have examined the mediating effect of serum glucose on the association between serum lactate and AKI.

We identified 1,435 AIS patients from the Medical Information Mart for Intensive Care (MIMIC-III) database and divided them into AKI or No-AKI groups. We used a propensity score matching method to reduce confounding factors. Linear regression, logistic regression, and restricted cubic splines (RCS) plots were used to evaluate relationships between serum lactate levels and AKI. Finally, the mediating role of serum glucose on the relationship between serum lactate and AKI was investigated utilizing the mediation analysis.

In the present study, a total of 634 critical patients aged ≥ 18 years with AIS were included after propensity score matching (1:1). We used RCS plotting to reveal a linear association between serum lactate levels and AKI (P for nonlinearity < 0.001). After full adjustment for potential confounders (Model 3), high lactate levels increased the risk of AKI (odds ratio, 2.216; 95 % confidence interval, 1.559-3.271; P-value < 0.001). Serum glucose explained 14.9 % of the association between serum lactate and AKI among critical patients with AIS (P-value < 0.001), 16.4 % among patients with AIS and diabetes mellitus (DM) (P-value = 0.24), and 19.5 % among patients with AIS and without DM (P-value < 0.001).

Serum lactate was independently associated with increased risk-adjusted AKI in critical patients with AIS. The increase in serum glucose may have mediated this effect, especially in patients without DM.

Acute ischemic stroke (AIS) is an acute brain injury caused by sudden occlusion of a blood vessel. Endovascular therapy is the most effective way to restore blood flow. However, despite the restoration of blood flow in some patients, their clinical prognosis often remains unsatisfactory. Albumin has shown neuroprotective effects in animal models of AIS. Therefore, this study aims to evaluate the safety, feasibility, and efficacy of local arterial infusions of 20% human serum albumin solution as an adjuvant therapy after endovascular therapy in patients with AIS.

This study is a prospective, therapeutic exploratory, non-randomized, open-label, phase 1 clinical trial testing the use of 20% human serum albumin solution injected via the artery immediately after successful reperfusion in patients with AIS. The study is divided into two stages. In the first stage, a single-dose-finding will explore the maximum safe dose according to the 3 + 3 dose escalation principle;, with the maximum dose being 0.60 g/kg. After recanalizing the occluded blood vessel, human serum albumin solution will be injected into the internal carotid artery region through a guiding catheter for 30 min. The second stage involves an albumin adjuvant therapy cohort (AT) and an endovascular treatment lonely cohort (ET). The AT cohort will encompass at least 15 additional participants to complete safety trials at the maximum safe dose determined in the first stage. The ET cohort will include well-matched patients receiving endovascular therapy alone, derived from a contemporaneous prospective registry, who will be excluded from having cardiopulmonary disorders and from receiving any neuroprotective therapy. The primary outcome of this study will be symptomatic intracranial hemorrhage. Efficacy outcomes will include the proportion of patients with the progression of cerebral infarction volume, a modified Rankin Scale of 0-2 on day 90 after randomization. An exploratory secondary outcome will be the analysis of thromboinflammatory and neuroprotective molecule profiles.

This pilot trial aims to explore the safety and efficacy of arterial infusion of an albumin solution after occlusive vessel opening in AIS. The results will provide data parameters for subsequent tests on the arterial infusion of albumin solutions.

ClinicalTrials.gov, NCT05953623.