Cerebral Ischemia Research Articles

Inhibition of PCSK9 Protects against Cerebral Ischemia‒Reperfusion Injury via Attenuating Microcirculatory Dysfunction.

Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24h post-reperfusion. Evolocumab (10mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway.

Extracellular vesicles derived from endothelial progenitor cells modified by Houshiheisan promote angiogenesis and attenuate cerebral ischemic injury via miR-126/PIK3R2.

Angiogenesis following cerebral ischemia is crucial for restoring blood supply to the ischemic region. Extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) offer potential therapeutic benefits in the treatment of cerebral ischemia. Houshiheisan (HSHS) has been shown to improve clinical outcomes in ischemic stroke patients, reduce cerebral ischemic damage in rats, and protect endothelial cells. However, the potential effects of HSHS-modified EPC-derived EVs (EVsHSHS) for cerebral ischemia remain unexplored. This study investigated the impact of EVsHSHS on angiogenesis using rats with permanent middle cerebral artery occlusion (pMCAO) and brain microvascular endothelial cells (BMECs) subjected to oxygen-glucose deprivation (OGD). Results demonstrated that EVsHSHS promoted the proliferation, migration, and tube formation of BMECs in vitro. In vivo, high doses of EVsHSHS exhibited better performance than equivalent doses of unmodified EPC-derived EVs in reducing cerebral infarction volume, improving cortical blood perfusion, decreasing neurological deficit scores, and increasing cortical microvessel density at day 7 post-modeling. The pro-angiogenic effects of EVsHSHS following cerebral ischemia were associated with the regulation of miR-126 and the PIK3R2/PI3K/AKT pathway.

An infected intracranial dermoid cyst at the region of torcular herophili: A case report

Background: Dermoid cysts result from embryonic fusion anomalies, with intracranial dermoid cysts being rare (0.1–0.7% of intracranial tumors). Often asymptomatic, they can manifest as midline swelling, headaches, seizures, or cerebral ischemia. Recognition and management are crucial for mitigating complications and ensuring favorable patient outcomes. Case Description: A 14-year-old girl presented with swelling at the occiput for 3 months. Initial imaging was suggestive of an extra-dural abscess in the occipital region with surrounding bone erosion. An infectious workup, including tests for tuberculosis, was non-contributory. A suboccipital craniectomy was done. On lifting, the bone flap, thick, purulent, and sebaceous contents with hair were spotted, which was adherent to the inner table of the skull and the dura overlying the torcular herophili, suggesting an infected dermoid cyst. A near-total excision was done, and culture-directed antibiotics were given. Postoperatively, the child made a complete recovery. Conclusion: The diagnosis of a dermoid cyst must be kept in mind, and it should be considered in the differential diagnosis of midline posterior fossa lesions. The risk of postoperative recurrence from incomplete excision should be weighed against the risk of injuring the venous sinuses during the extensive resection of dermoid cysts adherent to the torcular region.

Balloon angioplasty for cerebral vasospasm in preschool children.

Subarachnoid hemorrhage evolving with cerebral vasospasm and delayed cerebral ischemia may increase morbidity and mortality. Treating vasospasm with balloon percutaneous angioplasty (PTA) in adults is well known, but data in preschool children are scarce. In addition, the smaller diameters and fragility of the vessels in childhood might lead to serious complications. This study presents two cases of cerebral vasospasm in preschool children treated with balloon PTA. Therefore, it may contribute to a better understanding of the role of that technique as an effective treatment modality in this population. Balloon PTA was performed in two children (3 and 4 year-old) with aneurysmal subarachnoid hemorrhage and delayed cerebral ischemia. The procedures were uneventful, and both patients survived without complications or new infarction. Balloon PTA for proximal vasospasm may improve clinical outcomes in selected pediatric patients. Further studies are needed to clarify the best candidates, materials, and techniques.

Neuroprotection of Gueichih-Fuling-Wan on cerebral ischemia/ reperfusion injury in streptozotocin-induced hyperglycemic rats via the inhibition of the cellular apoptosis pathway and neuroinflammation

Neuroprotection of Gueichih-Fuling-Wan on cerebral ischemia/ reperfusion injury in streptozotocin-induced hyperglycemic rats via the inhibition of the cellular apoptosis pathway and neuroinflammation

Endothelial progenitor cell-derived conditioned medium mitigates chronic cerebral ischemic injury through macrophage migration inhibitory factor-activated AKT pathway.

Chronic cerebral ischemia (CCI) is a significant health issue characterized by hypoperfusion due to damage or occlusion of the cerebral or carotid arteries. CCI may lead to progressive cognitive impairment that is considered as a prelude to neurodegenerative diseases, including dementia and Alzheimer's disease (AD). Endothelial progenitor cells (EPCs) have been implicated in vascular repair in ischemic cerebrovascular diseases, primarily by differentiating into endothelial cells (ECs) or through paracrine effects. However, the clinical transplantation of stem cell therapies remains limited. In this study, we investigated the effects of EPC-derived conditioned medium (EPC-CM) on the impaired vasculature and neurological function in a rodent model of CCI and the mechanism involved. EPC-CM was analyzed by cytokine array to identify key factors involved in angiogenesis and cellular senescence. The effects and mechanism of the candidate factors in the EPC-CM were validated in vitro using oxygen-glucose deprivation (OGD)-injured ECs and EPCs. The therapeutic effects of EPC-CM and the identified key factor were further examined in a rat model of CCI, which was induced by bilateral internal carotid artery ligation (BICAL). EPC-CM was administered via intracisternal injection one week post BICAL. The cerebral microvasculature and neurobehavior of the rats were examined three weeks after BICAL. Macrophage migration inhibitory factor (MIF) was identified as a key factor in the EPC-CM. Recombinant MIF protein promoted angiogenesis and prevented senescence in the injured EPCs and ECs. The effect was similar to that of the EPC-CM. These therapeutic effects were diminished when the EPC-CM was co-treated with MIF-specific antibody (Ab). Additionally, the vascular, motor, and cognitive improvements observed in the BICAL rats treated with EPC-CM were abolished by co-treated with MIF Ab. Furthermore, we found MIF promoted angiogenesis and anti-senescence via activating the AKT pathway. Inhibition of the AKT pathway diminished the protective effects of MIF in the in vitro study. We demonstrated that EPC-CM protected the brain from chronic ischemic injury and promoted functional recovery through MIF-mediated AKT pathway. These findings suggest EPC-CM holds potential as a novel cell-free therapeutic approach for treating CCI through the actions of MIF.

A dangerous liaison: Spreading depolarization and tissue acidification in cerebral ischemia.

Brain pH is precisely regulated, and pH transients associated with activity are rapidly restored under physiological conditions. During ischemia, the brain's ability to buffer pH changes is rapidly depleted. Tissue oxygen deprivation causes a shift from aerobic to anaerobic metabolism and the accumulation of lactic acid and protons. Although the degree of tissue acidosis resulting from ischemia depends on the severity of the ischemia, spreading depolarization (SD) events emerge as central elements to determining ischemic tissue acidosis. A marked decrease in tissue pH during cerebral ischemia may exacerbate neuronal injury, which has become known as acidotoxicity, in analogy to excitotoxicity. The cellular pathways underlying acidotoxicity have recently been described in increasing detail. The molecular structure of acid or base carriers and acidosis-activated ion channels, the precise (dys)homeostatic conditions under which they are activated, and their possible role in severe ischemia have been addressed. The expanded understanding of acidotoxic mechanisms now provides an opportunity to reevaluate the contexts that lead to acidotoxic injury. Here, we review the specific cellular pathways of acidotoxicity and demonstrate that SD plays a central role in activating the molecular machinery leading to acid-induced damage. We propose that SD is a key contributor to acidotoxic injury in cerebral ischemia.

Cell inspired delivery system equipped with natural membrane structures in applications for rescuing ischemic stroke.

Ischemic stroke (IS), accounting for 87 % of stroke incidences, constitutes a paramount health challenge owing to neurological impairments and irreversible tissue damage arising from cerebral ischemia. Chief among therapeutic obstacles are the restrictive penetration of the blood-brain barrier (BBB) and insufficient targeting precision, hindering the accumulation of drugs in ischemic brain areas. Motivated by the remarkable capabilities of natural membrane-based delivery vehicles in achieving targeted delivery and traversing the BBB, thanks to their biocompatible architecture and bioactive components, numerous membrane-engineered systems such as cells, cell membranes and extracellular vesicles have emerged as promising platforms to augment IS treatment efficacy with the help of nanotechnology. This review consolidates the primary pathological manifestations following IS, elucidates the unique functionalities of natural membrane drug delivery systems (DDSs) with nanotechnology, as well as delineates the structural characteristics of various natural membranes alongside rational design strategies employed. The review illuminates both the potential and challenges encountered when employing natural membrane DDSs in IS drug therapy, offering fresh perspectives and insights for devising efficacious and practical delivery systems tailored to IS intervention.

Preclinical safety and efficacy evaluation of the intrathecal transplantation of GMP-grade human umbilical cord mesenchymal stem cells for ischemic stroke

Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke, but its safety, effectiveness, and mechanism remain to be elucidated. In this study, good manufacturing practice–grade human umbilical cord mesenchymal stem cells (5 × 105 and 1 × 106 cells) and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats. The results showed (1) no significant difference in mortality or general conditions among the three groups. There was no abnormal differentiation or tumor formation in various organs of rats in any group. (2) Compared with saline-treated animals, those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume, with no significant differences between different human umbilical cord mesenchymal stem cell doses. (3) Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up, and the number of positive cells significantly decreased over time. (4) Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group, while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased. (5) Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+ microvessels and doublecortin-positive cells after ischemic stroke. Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+. (6) At 14 days after intrathecal administration, brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day. Taken together, these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats. The mechanisms may include alleviating the local inflammatory response in the peri-infarct region, promoting neurogenesis and angiogenesis, and enhancing the production of neurotrophic factors.

Case Report: Delayed Cerebral Ischemia with Infarction following an Undiagnosed Aneurysmal Rupture - The Diagnostic and Management Challenge

Delayed Cerebral Ischemia (DCI) typically occurs a few days after a patient suffers subarachnoid hemorrhage and can lead to a range of poor outcomes. It is primarily driven by vasospasm and its delayed and variable presentation complicates diagnosis and treatment. Here we report a case of DCI in a 31-yearold man who presented with acute onset aphasia, right-sided weakness, and difficulty swallowing. He had experienced a severe headache accompanied by nausea and vomiting 5 days prior, with an initial NIH stroke scale score of 10. Imaging revealed a left internal carotid artery aneurysm and a watershed infarct between the anterior cerebral artery and middle cerebral artery. The patient was treated with aneurysmal coiling, intraarterial verapamil, and oral nimodipine for suspected DCI secondary to subarachnoid hemorrhage. Close monitoring of the patient and treatment led to the resolution of neurological deficits over the subsequent days., with imaging confirming reperfusion. This case presents a unique challenge due to the delayed presentation and vague history. Diagnosis and treatment of DCI following aneurysmal rupture are complicated due to its delayed and variable onset. It is crucial to consider acute aneurysmal subarachnoid hemorrhage and DCI when evaluating patients who present with multiple stroke-like symptoms over several days as the management and prognosis differ from other cases of acute ischemic stroke.

Salidroside ameliorates cerebral ischemic injury and regulates the glutamate metabolism pathway in astrocytes

Background and AimSalidroside (SA) is the main active component of Rhodiola rosea L., with potential in treating cardiovascular and cerebrovascular diseases and cerebral ischemia. However, its efficacy and mechanism in cerebral ischemia remain unclear, particularly regarding its effect on glutamate (Glu) metabolism. In this paper, we aimed to investigate the efficacy of SA in treating cerebral ischemia and its pharmacological mechanism.Experimental procedureWe studied the effects of SA on SD rats with cerebral ischemia, evaluating neurobehavior, cerebral water content, infarct size, and brain microstructure. We also assessed its impact on glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and glutamate transporter 1 (GLT-1) proteins using immunohistochemistry and Western blot. Additionally, we used SVGp12 cells to simulate cerebral ischemia and measured Glu levels and used Western blot to observe the level of GS and GLT-1.ResultsSA improved neural function, reduced infarct size, and regulated GSH and Glu levels in rats. In cell experiments, SA increased cell viability and decreased Glu concentration after ischemia induction. It also regulated the expression of GFAP, GS, and GLT-1.ConclusionSA alleviates cerebral ischemia-induced injury by acting on astrocytes, possibly through regulating the glutamate metabolic pathway.

Lack of additional benefit from slow rewarming after therapeutic hypothermia for ischaemic brain injury in near-term fetal sheep.

The optimal rate of rewarming after therapeutic hypothermia is unclear. Slow rewarming may reduce cardiovascular instability and rebound seizures, but there is little controlled evidence to support this. The present study aimed to determine whether slow rewarming can improve neuroprotection after 72h of hypothermia. Fetal sheep (0.85 gestation) received sham occlusion (n=8) or 30min of global cerebral ischaemia followed by normothermia (n=7), or hypothermia from 3 to 72h with either fast, spontaneous rewarming within 1h (n=8) or slow rewarming at 0.5°Ch-1 over 10h (n=8). Hypothermia improved EEG and spectral edge recovery, with no significant difference between fast and slow rewarming. Hypothermia reduced the number of seizures, with no significant difference in seizure activity between fast and slow rewarming. Hypothermia improved neuronal survival in the cortex, CA1, CA3, CA4 and dentate gyrus regions of the hippocampus, with no significant difference between fast and slow rewarming. Hypothermia attenuated microglia counts in the cortex, with no significant difference between fast and slow rewarming. The rate of rewarming after a clinically relevant duration of hypothermia did not affect neurophysiological recovery, neuronal survival or attenuation of microglia after global cerebral ischaemia in term-equivalent fetal sheep. KEY POINTS: The rate of rewarming after 72h of hypothermia did not affect recovery of EEG or spectral edge. There was no difference in the occurrence of seizures as a result of the rate of rewarming after hypothermia. The rate of rewarming after 72h of hypothermia did not affect neuronal survival in the cortex or hippocampus.

Modulation of Ca2+ oscillation following ischemia and nicotinic acetylcholine receptors in primary cortical neurons by high-throughput analysis.

Calcium oscillations in primary neuronal cultures and iPSCs have been employed to investigate arrhythmogenicity and epileptogenicity in drug development. Previous studies have demonstrated that Ca2+ influx via NMDA and nicotinic acetylcholine receptors (nAChRs) modulates Ca2+ oscillations. Nevertheless, there has been no comprehensive investigation into the impact of ischemia or nAChR-positive allosteric modulators (PAM) drugs on Ca2+ oscillations at a level that would facilitate high-throughput screening. We investigated the effects of ischemia and nAChR subtypes or nAChR PAM agonists on Ca2+ oscillations in high-density 2D and 3D-sphere primary neuronal cultures using 384-well plates with FDSS-7000. Ischemia for 1 and 2h resulted in an increase in the frequency of Ca2+ oscillations and a decrease in their amplitude in a time-dependent manner. The NMDA and AMPA receptor inhibition significantly suppressed Ca2+ oscillation. Inhibition of NR2A or NR2B had the opposite effect on Ca oscillations. The potentiation of ischemia-induced Ca2+ oscillations was significantly inhibited by the NMDA receptor antagonist, MK-801, and the frequency of these oscillations was suppressed by the NR2B inhibitor, Ro-256981. In the 3D-neurosphere, the application of an α7nAChR agonist increased the frequency of Ca2+ oscillations, whereas the activation of α4β2 had no effect. The combination of nicotine and PNU-120596 (type II PAM) affected the frequency and amplitude of Ca2+ oscillations in a manner distinct from that of type I PAM. These systems may be useful not only for detecting epileptogenicity but also in the search for neuroprotective agents against cerebral ischemia.

Abstract 4140169: Neonatal Electroencephalogram Alpha:Delta changes precede neurologic injury during Antegrade Cerebral Perfusion and Deep Hypothermic Circulatory Arrest

Background: Although neurologic injury commonly occurs following neonatal aortic arch reconstruction, the mechanism(s) are poorly understood. A decrease or inter-hemispheric difference in the electroencephalogram (EEG) Alpha:Delta ratio (A:D) precedes cerebral ischemia during antegrade cerebral perfusion (ACP). However, it is unknown if A:D changes precede neurologic injury during deep hypothermic circulatory arrest (DHCA). We hypothesized during DHCA, the A:D would decrease and that a significant A:D inter-hemispheric difference would precede neurologic injury. Methods: Neonates requiring aortic arch reconstruction underwent simultaneous quantitative EEG monitoring. Left vs. right hemispheric, anterior, and posterior A:Ds were recorded at baseline, arterial cannulation, cooling, ACP vs. DHCA, and the rewarming phases of the operation. Left vs. right A:D differences > 25% were considered significant for ischemia and the cumulative duration of a significant A:D inter-hemispheric difference was calculated. Post-operative neurologic injury was defined as either stroke or seizure. Results: From 86 neonates, 16.2 % (14) required DHCA and 83.8 % (72) ACP. There were no significant differences in the pre-operative demographics or baseline A:Ds between groups. Although the A:Ds remained similar during ACP, after 15 minutes the hemispheric A:Ds decreased significantly during DHCA (Figure 1). Eleven neonates (ACP-7 vs. DHCA-4) developed neurologic injury. The duration of an anterior A:D inter-hemispheric difference > 25% was significantly greater within neonates that developed neurologic injury (25 {IQR:0,65 minutes} vs. 5 {IQR: 0, 15 minutes}; p<0.001). Multivariate analysis demonstrated that the duration of an anterior A:D difference > 25% was independently associated with neurologic injury using either ACP or DHCA (Odds Ratio:1.081, 95% CI: 1.025, 1.141; p-value=0.004). Conclusion: Unlike ACP, the A:D decreased significantly during DHCA. During either DHCA or ACP, a significant anterior inter-hemispheric A:D difference was independently associated with neurologic injury and suggests the importance of quantifying the A:D during neonatal arch reconstruction.

Alpha‑Asarone Ameliorates Neuronal Injury After Ischemic Stroke and Hemorrhagic Transformation by Attenuating Blood-Brain Barrier Destruction, Promoting Neurogenesis, and Inhibiting Neuroinflammation.

Recombinant tissue-type plasminogen activator (rt-PA), the primary drug for acute ischemic stroke (IS), has a narrow therapeutic window and carries a potential risk of hemorrhagic transformation (HT). Without rt-PA administration, patients may suffer permanent cerebral ischemia. Alpha-asarone (ASA), a natural compound derived from Acorus tatarinowii Schott, exhibits diverse neuropharmacological effects. This study aims to investigate whether ASA could improve outcomes in IS and be used to mitigate HT induced by rt-PA. We employed models of permanent middle cerebral artery occlusion (pMCAO) and photothrombotic cortical injury (PCI) to investigate both the therapeutic efficacy and underlying mechanisms of ASA during the acute and recovery periods following IS, respectively. Additionally, Sprague-Dawley rats were subjected to rt-PA treatment at 6-h post-PCI to mimic HT (rt-PA-HT). Our results revealed three key findings: (1) ASA demonstrated therapeutic effects in the acute phase of pMCAO rats by alleviating blood-brain barrier damage through inhibition of glial cell-mediated neuroinflammation; (2) administration of ASA 24 h after stroke ameliorated the neurological damage during the recovery phase in PCI mice by promoting neurogenesis via activation of the BDNF/ERK/CREB signaling pathway; (3) ASA attenuated rt-PA-HT injury by modulating the NLRP3/Caspase1/IL-1β and IL-18 pathways. Overall, our findings suggest that ASA mitigates neuronal injury following IS and HT, positioning it as a promising candidate for treating these conditions.

Neuroprotective Effects of Ethanol Extract Polyscias guilfoylei (EEPG) Against Glutamate Induced Neurotoxicity in HT22 Cells

Oxidative stress induced by glutamate is a significant contributor to neuronal cell damage and can lead to neurodegenerative diseases such as Alzheimer’s, Huntington’s, and ischemic brain injury. At the cellular level, oxidative stress increases Ca2+ ion influx and reactive oxygen species (ROS), which activate the MAPK signaling pathway. Additionally, the generation of ROS causes mitochondrial dysfunction, triggering apoptosis by promoting the translocation of AIF to the nucleus from the mitochondria. The neuroprotective potential of Polyscias guilfoylei has not yet been reported. Therefore, in this study, the ethanol extract of Polyscias guilfoylei (EEPG) was examined for its protective effect against oxidative cell damage caused by glutamate in neuronal cells. EEPG treatment increased the viability of HT22 cells exposed to high concentrations of glutamate. Cellular Ca2+ ion influx and ROS generation decreased with EEPG treatment in glutamate-treated HT22 cells. EEPG treatment inhibited MAPK activation and AIF nuclear translocation. In an in vivo study, EEPG attenuated brain cell death in an ischemic brain injury rat model. This study demonstrates the potential therapeutic effects of Polyscias guilfoylei in the treatment of ischemic brain injury.

Raloxifene Protects Oxygen-Glucose-Deprived Astrocyte Cells Used to Mimic Hypoxic-Ischemic Brain Injury

Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5–10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen–glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O2 for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival—65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen–glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen–glucose-deprived astrocyte cells, used to mimic hypoxic–ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion.

NIMG-64. SURVIVAL IMPLICATIONS OF POSTOPERATIVE RESTRICTED DIFFUSION IN HIGH-GRADE GLIOMA AND LIMITATIONS OF INTRAOPERATIVE MRI DETECTION

Abstract AIMS In glioma surgery, surgically induced cerebral ischemia may poorly affect overall survival. While intraoperative MRI (iMRI) is an established tool used to maximize extent of resection, its ability to detect cerebral ischemia during surgery has not been studied. Here we evaluate both the association of post-surgical cerebral ischemia on survival independent of new functional deficits and the sensitivity of iMRI in detecting cerebral ischemia. METHODS We retrospectively reviewed 361 cranial surgeries that used a 3 Tesla iMRI. 165 patients met all inclusion criteria and were included in the final analysis. Diffusion weighted imaging (DWI) obtained during iMRI was compared to postoperative DWI obtained within 7 days of the operation in cases where no further resection occurred after the iMRI. RESULTS 42 of 165 patients (25%) showed evidence of restricted diffusion on postoperative (poMRI); 37 of these 42 (88%) lacked evidence of restricted diffusion on iMRI (false-negative rate of 88%, sensitivity of 12%). In high-grade gliomas, poMRI restricted diffusion volume was predictive of overall survival independent of new functional deficit (p = 0.011). CONCLUSION Here we present the largest case series to date analyzing the sensitivity of iMRI in detecting ischemia. In high-grade gliomas, increased volume of ischemia correlated with worsening median overall survival (OS) irrespective of postoperative neurologic deficits. Future work will focus on improving intraoperative detection of ischemia during the hyperacute phase when interventions such as blood pressure modulation or direct application of vasodilator agents may be effective.

Research progress of ferroptosis in brain injury

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a key contributor to neuronal damage in various types of brain injury, including traumatic brain injury (TBI) and ischemic brain injury caused by brian ischemia (BI). This review summarizes the underlying mechanisms of ferroptosis in brain injuries and highlights its role in exacerbating neuronal loss, inflammation, and secondary damage. After TBI, the release of free iron and oxidative stress after injury triggers ferroptosis, contributing to long-term neurological deficits. Similarly, in BI, ferroptosis is initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction during ischemia and reperfusion, further amplifying neuronal damage. The current review provides a comprehensive overview of the interplay between ferroptosis and brain injury, with an emphasis on the potential of targeting ferroptosis to improve recovery outcomes in patients. Future research directions include the development of novel ferroptosis inhibitors and the integration of ferroptosis-targeting strategies with existing treatment modalities.

Differential vulnerability among cell types in the neurovascular unit: Description and mechanisms.

Currently, successful preclinical cerebroprotective agents fail to translate effectively into clinical practice suggesting the need for a comprehensive evaluation of all aspects of brain function. Selective vulnerability refers to the specific regional response of the brain following global ischemia, with observed patterns of vulnerability attributed to the distribution of neuronal subtypes and the functions of respective brain regions. Conversely, the concept of differential vulnerability pertains to the cell-type-specific reactions to cerebral ischemia, dictated by the biological characteristics of individual cells. This review aims to explore these vulnerability hypotheses and elucidate potential underlying cellular mechanisms.