Search Results (501)

Objectives: The critical role of nerve growth factor (NGF) in neuroprotection has been demonstrated in preclinical models of neuronal injury. Here, we investigated the neuroprotective effects of intranasal CHF6467, a recombinant mutant form of human NGF lacking algogenic activity, in transient (45 min) middle cerebral artery occlusion (tMCAo). Methods: Male Wistar rats (n = 20 per group) were treated intranasally with CHF6467 (20 µg/kg, 40 µL) or vehicle (0.9% saline, 40 μL). The first dose was administered 15 min after the onset of MCAo and the second dose 24 h later. Neurological behavioral tests were performed 24 and 48 h after tMCAo. Infarct volume was measured 48 h after tMCAo. Additionally, a separate cohort of rats underwent permanent MCAo (pMCAo) and received two intranasal doses of CHF6467 or vehicle, with long-term neurological outcome assessed 7 days later using the De Simoni neuroscore (n = 13–14 per group). CHF6467 levels were measured in intact brain samples from CHF6467-treated rats (n = 5) and vehicle-treated controls (n = 4). Samples were collected 2 h after the last administration. Results: CHF6467 significantly improved neurological and sensorimotor performance compared with the vehicle-treated rats. This functional effect was associated with a reduction in infarct volume that was positively correlated with neurological deficit improvement. In the pMCAo cohort, CHF6467-treated rats were more likely to achieve a favorable neurological outcome at seven days compared with the vehicle-treated animals. Intranasal CHF6467 reached the brain but showed variable and non-uniform distribution across regions. Levels were highest in the olfactory bulbs, while the cortex and striatum had lower concentrations. In vehicle-treated rats, the drug was undetectable. Conclusions: This study demonstrates the neuroprotective effects of CHF6467 against ischemic brain injury, evidenced by both functional improvement and reduction in infarct volume. Although it reaches the brain, its distribution is heterogeneous and assessed only at one time-point. Further studies should examine its longer-term distribution and underlying mechanisms. Full article

Background: Ischemic stroke (IS) became the most common type of stroke in 2021, leading to an extreme health burden globally, and has the potential to further increase the burden in the young. However, current therapies for IS are limited, and its mechanism remains unclear. Methods: SPF C57BL/6J male mice were used to establish the middle cerebral artery occlusion (MCAO) model. The Longa’s Neurological Deficit Score and TTC staining served as evaluative metrics for the efficacy of the model. Untargeted metabolomics analysis was performed based on LC-MS technology, and PCA, PLS-DA, and KEGG analysis were used to explore the differential metabolites. Results: Compared to the Sham group, the neurological deficit score of the MCAO group was significantly higher at 2 h and 72 h after surgery (p < 0.001). There was no infarct volume in the Sham group, while the infarct volume ratio of the MCAO group significantly increased compared with that of the Sham group. In total, 1836 metabolites were identified overall, and they were clustered into 14 classifications, with “lipids and lipid-like molecules” accounting for the most (34.45%). Compared with the Sham group, 95 metabolites were up-regulated, and 107 metabolites were down-regulated in the MCAO group; 138 of 202 were identified with HMDB numbers. A further clustering and KEGG pathway analysis showed that these 138 metabolites may be involved in lipid metabolism, amino acid metabolism, and nucleotide metabolism. However, FDR was not used as extracting criteria to screen out the differential metabolites, which indicated that the outcomes should be considered for further validation. Conclusions: This discovery-stage untargeted metabolomics analysis suggests that ischemic stroke may be associated with alterations in lipid, amino acid, and nucleotide metabolism in the mouse brain, but these exploratory findings require validation in larger independent cohorts using targeted metabolomics. Full article

Background/Objectives: Extracranial–intracranial (EC-IC) bypass, particularly superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis, is used to augment cerebral perfusion in selected patients with moyamoya disease or atherosclerotic steno-occlusive disease. This study evaluated the impact of STA-MCA bypass on regional cerebral perfusion using a semi-quantitative SPECT area-based method. Methods: Of 40 patients screened between June 2018 and June 2022, 15 with complete paired pre- and postoperative CTA and SPECT data were included. Postoperative imaging was performed at a median of 12 months (range, 6–15 months). Proportional perfusion area in the basal ganglia and temporal regions was calculated using Labelme annotation, Canny edge detection, and Green’s theorem, normalized to total brain area. Paired comparisons and exploratory subgroup analyses were performed. Normality was assessed by Shapiro–Wilk test; Wilcoxon signed-rank tests served as sensitivity analyses. Results: Mean age was 56 ± 15.7 years (40% female). All 16 anastomoses were patent. Postoperative perfusion area increased significantly in the basal ganglia (mean difference 0.24, 95% CI 0.13–0.35, p = 0.0003) and temporal regions (0.34, 95% CI 0.08–0.60, p = 0.012). Wilcoxon tests confirmed these findings (basal ganglia p = 0.0003; temporal p = 0.008). In unilateral cases, ipsilateral and contralateral basal ganglia improvements did not differ significantly (p = 0.839). Results should be interpreted as exploratory given the limited sample size. Conclusions: STA-MCA bypass was associated with significant increases in semi-quantitative perfusion area on SPECT, particularly in the basal ganglia. The lack of ipsilateral–contralateral difference is consistent with a possible global hemodynamic effect, but this interpretation remains hypothesis-generating. The pragmatic SPECT method is feasible for perioperative monitoring yet requires further validation. Larger prospective studies with standardized protocols are warranted. Full article

Cerebral ischemia–reperfusion injury is a key determinant of a poor outcome after stroke. The mitochondrial uncoupling protein 2 (UCP2) has been implicated in cerebral ischemia-reperfusion injury and in the outcome of ischemic stroke, although its role remains controversial. In C57BL/6J and B6.129S4-Ucp2^tm1Lowl/J (UCP2^−/−) mice, we analyzed cognitive function and lifespan. In an MCAO model induced for one hour, infarct volumes, neurological deficits, and gene expression patterns were determined after 24 h. The UCP2 inhibitor genipin was used in an oxygen-glucose deprivation (OGD) model to investigate synaptic transmission in the hippocampus. Compared to controls, UCP2^−/− mice exhibited a reduced lifespan and displayed impaired cognition. However, in 6-month-old UCP2^−/− mice, the infarct volume was reduced, primarily due to a smaller core size, but not in 18-month-old animals. In both strains, ischemia induced upregulation of antioxidant defense genes, including catalase and SOD1. In the ex vivo ODG model, synaptic transmission was depressed, but pretreatment with genipin prevented the tissue from this impairment. Our findings indicate an infarct-reducing effect of UCP2 deficiency, especially in young-adult mice, and, mechanistically, a neuroprotective effect by genipin in hippocampal slices. Full article

Background: Danshen–Gegen is a classic herb pair in traditional Chinese medicine, which has been used to treat cardiovascular and cerebrovascular diseases. Ischemic stroke (IS) is a prevalent cerebrovascular condition; ferroptosis is one of the contributing factors driving the progression of IS. This study aims to determine the underlying mechanism and examine if Danshen–Gegen (DG) extract may prevent cerebral ischemia–reperfusion injury by preventing ferroptosis. Methods: The comprehensive compositional characterization of DG was analyzed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-orbitrap MS). The experiments were conducted in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/re-oxygenation (OGD/R) cells. The neuroprotective effects of DG on IS were assessed by examining rat survival rates, infarct volume, behavioral scores, and cerebral water content. Then, we tested the accumulation of Fe²⁺ and lipid peroxidation products such as reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and 4-hydroxynonenal (4-HNE) in rats and cells. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), Solute Carrier Family 7 Member 11 (-xCT), Glutathione peroxidase 4 (GPX4), Cyclooxygenase-2 (COX-2), Transferrin Receptor 1 (TFR1), and Long-chain-fatty-acid–CoA ligase 4 (ACSL4) was also assessed in vivo and in vitro. Results: UPLC-Q-orbitrap MS analysis was performed to characterize the chemical profile of DG, and a total of 33 chemical constituents were successfully identified. DG significantly alleviated the ischemic damage to brain tissue, reduced infarct volume, and improved neurological dysfunction. The content of Fe²⁺ and lipid peroxidation products was markedly decreased. Furthermore, DG could restore the expression of Nrf2, -xCT, and GPX4 with the inhibition of COX-2, TFR1, and ACSL4, thus achieving a suppressive effect on ferroptosis. Conclusions: The regulatory influence of DG via the Nrf2/System xc-/GPX4 axis may play a crucial role in alleviating ferroptosis and enhancing recovery from cerebral ischemia injury. Full article

Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive “smart” hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care. Full article

Hyperbaric oxygen (HBO) shows neuroprotective potential in cerebral ischemia–reperfusion (CIR) injury, but its variable efficacy suggests that the underlying cellular mechanisms remain incompletely defined. We previously showed that HBO suppresses microglial NLRP3 inflammasome activation after CIR injury in a reactive oxygen species (ROS)-dependent manner; yet, how ROS couples to this effect remains unclear. Since mitochondria regulate ROS and inflammasome signaling, we investigated whether HBO modulates microglial mitochondrial dynamics in CIR injury. In adult male ICR mice (n = 71, 8–12 weeks) subjected to 60 min middle cerebral artery occlusion followed by 24 h reperfusion, HBO improved neurological function, reduced infarct area, and decreased ASC-positive microglia/macrophages. In lipopolysaccharide/nigericin-stimulated primary microglia, HBO suppressed IL-1β release, reduced mitochondrial fragmentation, preserved mitochondrial membrane potential, maintained mitofusin 2 (MFN2) protein level, and reduced DRP1 Ser616 phosphorylation without altering total DRP1 or FIS1 expression. MitoTEMPOL abolished HBO-mediated protection against mitochondrial fragmentation, MFN2 reduction, and DRP1 Ser616 phosphorylation in vitro. Edaravone, when combined with HBO, attenuated HBO-mediated neuroprotection and counteracted HBO-induced regulation of MFN2 and DRP1 Ser616 phosphorylation in vivo. These findings support ROS-dependent remodeling of microglial mitochondrial dynamics as a mechanism contributing to HBO-mediated suppression of inflammasome-associated inflammation after CIR injury. Full article

Reperfusion after acute ischemic stroke (AIS) triggers a series of ferroptosis-related molecular events, including iron dyshomeostasis, oxidative/nitrative stress, antioxidant depletion, and membrane lipid peroxidation. Conventional ferroptosis assays mainly rely on ex vivo or endpoint measurements, limiting their ability to dynamically monitor the spatiotemporal evolution of these events during ischemia–reperfusion. Recent advances in chemical sensing and optical imaging have enabled in situ detection of key ferroptosis-related nodes, such as Fe²⁺/labile iron pool, ROS/ONOO⁻, GSH/Cys/GPX4, H₂S/Cys–Met metabolism, and lipid peroxidation. In this review, we summarize sensing targets, reaction-based probe design, near-infrared and two-photon imaging, photoacoustic imaging, and multimodal validation strategies for AIS-related ferroptosis. Representative probes for H₂O₂, ONOO⁻, H₂S, Fe²⁺, and lipid peroxidation are discussed in the context of cellular models, oxygen-glucose deprivation/reoxygenation, middle cerebral artery occlusion/reperfusion, and in vivo brain imaging. We emphasize that a single probe signal cannot independently confirm ferroptosis and should be interpreted together with GPX4/ACSL4 alterations, MDA/4-HNE levels, tissue injury, neurological outcomes, and Fer-1/Lip-1 rescue experiments. Finally, we discuss current challenges, including limited tissue penetration, blood–brain barrier delivery, quantitative stability, probe safety, and clinical translation, and highlight future directions involving ratiometric, NIR/NIR-II, two-photon, multitarget, and imaging-guided validation strategies. Full article

Background/Objectives: Ischemic stroke remains a major global health challenge, yet therapeutic options are severely restricted by narrow treatment windows and the risk of hemorrhagic transformation. Natural small molecules represent a valuable reservoir for discovering novel neuroprotective leads with favorable safety profiles. Cinchonidine, a natural quinoline alkaloid, has shown anti-inflammatory and cytoprotective properties, but its potential in treating ischemic stroke is largely unexplored. This study aimed to evaluate the neurovascular protective effects and hemostatic safety of cinchonidine in preclinical stroke models. Methods: We evaluated cinchonidine using a mouse model of middle cerebral artery occlusion (MCAO) and in vitro oxygen–glucose deprivation (OGD) models in cerebral endothelial cells (CECs) and Neuro2A cells. Infarct volume, brain edema, and neurological recovery were assessed. Blood–brain barrier (BBB) integrity was measured via Evans blue extravasation. Mechanistic markers, including microglial activation, pro-inflammatory mediators (iNOS, COX-2), and apoptosis-related signaling, were examined. Additionally, cinchonidine’s effect on platelet aggregation was also tested. Results: Cinchonidine significantly reduced infarct volume and brain edema while improving neurological functional recovery. It effectively preserved BBB integrity and enhanced cell viability under OGD conditions. Furthermore, cinchonidine suppressed microglial activation and decreased the expression of pro-inflammatory mediators. These protective effects were associated with the modulation of apoptotic signaling pathways. These protective effects were accompanied by reduced p53-associated stress signaling in endothelial cells and ischemic brain tissue. Importantly, cinchonidine did not significantly interfere with platelet aggregation, suggesting a potentially favorable hemostatic profile. Conclusions: Cinchonidine attenuates ischemic brain injury and is associated with endothelial protection, preservation of BBB integrity, and modulation of inflammatory and apoptotic responses. As a natural lead compound that does not compromise hemostasis, cinchonidine represents a promising lead compound for further development as a neurovascular protective strategy in ischemic stroke. Full article

Background: Scutellaria baicalensis (Scu) extract has been traditionally used in the treatment of stroke-related syndromes, yet its underlying molecular mechanisms, particularly those involving ferroptosis, remain to be fully elucidated. Purpose: This study aims to validate the hypothesis that Scu extract improves cerebral ischemia-reperfusion injury (CIRI) by inhibiting ferroptosis through the PI3K/AKT signaling pathway. Methods: This study employed middle cerebral artery occlusion (MCAO) in male Sprague-Dawley (SD) rats and oxygen–glucose deprivation/reoxygenation (OGD/R) models to evaluate the protective effects of Scu extract against CIRI. Multiple approaches were integrated to elucidate the underlying mechanisms. Furthermore, a range of experimental techniques, including neurological function assessment, TTC staining, histopathological analysis, biochemical assays, qPCR, transmission electron microscopy (TEM), reactive oxygen species (ROS) detection, Western blotting, and immunofluorescence, were used to comprehensively validate its neuroprotective effects. Results: Scu extract significantly improved neurological outcomes and attenuated brain injury in MCAO rats. Proteomic analysis revealed significant enrichment of ferroptosis-related pathways, which was supported by reduced mitochondrial damage, decreased iron accumulation, and restoration of the SLC7A11/GPX4 axis. Subsequently, UPLC/Q-TOF-MS analysis revealed that four major bioactive components were absorbed in MCAO rats. KEGG pathway analysis based on network pharmacology further indicated that the PI3K/AKT signaling pathway is a key regulatory target. Notably, pharmacological inhibition of PI3K with LY294002 markedly abolished the anti-ferroptotic effects of Scu extract, which was further confirmed in vitro. Conclusions: This study demonstrates that Scu extract confers neuroprotection against CIRI in MCAO rats potentially through inhibiting ferroptosis via activation of the PI3K/AKT pathway. Full article

Background: Ischemic stroke remains a leading cause of mortality and disability worldwide. Despite extensive preclinical research, most neuroprotective strategies have failed to translate into clinical benefit, partly due to methodological variability. The transient intraluminal filament middle cerebral artery occlusion (tifMCAO) model is widely used, yet its implementation lacks consistency. This review aimed to characterize tifMCAO methodologies in adult rats and examine how experimental variability relates to reported outcomes. Methods: A systematic review was conducted following PRISMA guidelines. Studies using tifMCAO in adult rats were included. MEDLINE (PubMed), Web of Science, and Scopus were searched up to March 2025. Risk of bias was assessed using the SYRCLE tool and reporting quality using the ARRIVE checklist. The protocol was registered in PROSPERO (CRD420251140869). Results were synthesized narratively. Results: A total of 125 studies were included. A commonly used framework involved male Sprague–Dawley rats (6–12 weeks), silicone-coated monofilaments, occlusion durations of 60–120 min (most frequently 90 min), and isoflurane anesthesia, although this reflects methodological convergence rather than true standardization. Substantial variability was observed across methodological parameters. Variations in ischemia duration, filament properties, and anesthesia were associated with differences in infarct size, blood–brain barrier disruption, and functional outcomes. Conclusions: The tifMCAO model shows partial methodological convergence alongside significant variability influencing outcomes. Improved standardization and reporting are essential to enhance reproducibility and translational relevance. Full article

Background: Mitochondrial dysfunction is a central event in the pathogenesis of ischemic stroke. The roles of specific mitochondrial complex subunits, such as NDUFA4 and NDUFB3, in cerebral ischemia–reperfusion injury remain poorly defined. This study aims to investigate the dynamic expressions and functional impact of NDUFA4 and NDUFB3 in ischemic stroke. Methods: A transient middle cerebral artery occlusion (MCAO) model was established in male C57BL/6J mice. Label-free quantitative proteomics and Western blotting were employed to analyze protein expression in the ischemic penumbra. Highly differentiated PC12 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) or glutamate excitotoxicity to mimic ischemic injury in vitro. The functional consequences of NDUFB3 knockdown and overexpression were assessed by measuring ATP levels, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptosis. The involvement of the JNK-mediated mitochondrial apoptotic pathway was also examined. Results: Proteomic analysis revealed a significant upregulation of NDUFA4 and NDUFB3 in the ischemic penumbra of MCAO mice, as verified by western blot. In highly differentiated PC12 cells, both OGD/R and glutamate exposure induced a time-dependent increase in these proteins in mitochondrial fractions. Functional studies demonstrated that NDUFB3 knockdown significantly rescued OGD/R-induced mitochondrial dysfunction, as indicated by restored ATP production, reduced ROS generation, and stabilized ΔΨm. Furthermore, NDUFB3 silencing attenuated apoptosis by inhibiting JNK phosphorylation and decreasing BAX levels. Conversely, overexpression of NDUFB3 alone was sufficient to induce mitochondrial abnormalities, including loss of ΔΨm and elevated oxidative stress in highly differentiated PC12 cells. Conclusions: Ischemic injury triggers the upregulation of mitochondrial complex subunits NDUFA4 and NDUFB3. While this may initially act as a compensatory response, our findings identify NDUFB3 as a critical mediator of ischemic stroke pathology, whose overexpression drives mitochondrial dysfunction and apoptosis. In contrast, the suppression of NDUFB3 provides protection against ischemic injury. Therefore, NDUFB3 may be a potential candidate therapeutic target for reducing mitochondrial damage in ischemic stroke, but this role requires further validation in additional experimental and translational models. Full article

Objective: Cerebral ischemia/reperfusion (I/R) injury triggers oxidative stress, neuroinflammation, neuronal degeneration, and white matter damage not only in directly affected cerebral regions but also in remote brain areas such as the cerebellum. Skimmianine, a naturally occurring furoquinoline alkaloid, has been reported to possess antioxidant and anti-inflammatory properties. This study investigated the protective effects of skimmianine pretreatment against secondary cerebellar injury following experimental cerebral I/R. Materials and Methods: Thirty-two female Wistar rats were randomly assigned to sham, Skimmianine, I/R, and I/R + Skimmianine groups (n = 8/group). Cerebral I/R was induced by transient middle cerebral artery occlusion for 60 min followed by 23 h reperfusion. Skimmianine (40 mg/kg/day, intraperitoneally) was administered for 14 days before ischemia induction. Oxidative stress markers, neuroinflammatory mediators, histopathological alterations, behavioral outcomes, and ultrastructural changes were evaluated. In addition, network pharmacology and molecular docking analyses were performed to explore potential molecular mechanisms. Results: Cerebral I/R significantly decreased TAS levels compared with sham (0.89 ± 0.15 vs. 1.52 ± 0.18 mmol Trolox Eq/L) and increased TOS (15.60 ± 3.03 vs. 6.80 ± 1.41 µmol H₂O₂ Eq/L), OSI (17.48 ± 0.50 vs. 4.43 ± 0.47), TNF-α (68.4 ± 10.2 vs. 18.6 ± 4.4 pg/mL), Iba1 (41.3 ± 9.7 vs. 11.7 ± 1.6 pg/mL), and GFAP levels (334.5 ± 12.5 vs. 87.7 ± 9.5 ng/mL; all p < 0.001). I/R also impaired motor performance, as shown by increased beam crossing time (11.7 ± 2.2 vs. 4.8 ± 0.7 s) and grid foot fault rate (18.6 ± 4.0% vs. 3.4 ± 1.1%). Skimmianine pretreatment significantly improved these alterations, increasing TAS to 1.29 ± 0.20 mmol Trolox Eq/L and reducing TOS, OSI, TNF-α, Iba1, and GFAP levels to 9.20 ± 2.04, 7.07 ± 0.47, 34.9 ± 7.4, 24.2 ± 6.9, and 237.0 ± 7.9, respectively, compared with the untreated I/R group. Histopathological scores for Purkinje cell loss, edema, vascular congestion, and TNF-α expression were also significantly reduced by skimmianine. Quantitative TEM analysis showed that I/R reduced myelin thickness (0.29 ± 0.05 vs. 0.53 ± 0.07 µm), increased G-ratio values (0.75 ± 0.05 vs. 0.63 ± 0.04), and increased vacuolized fibers (24.70 ± 4.20% vs. 3.20 ± 1.10%), whereas skimmianine partially restored myelin thickness (0.42 ± 0.07 µm), reduced the G-ratio (0.68 ± 0.05), and decreased vacuolized fibers (11.20 ± 2.80%; p < 0.05 vs. I/R). Molecular docking demonstrated favorable binding between skimmianine and TNF-α, with a predicted binding energy of −6.953 kcal/mol. Conclusions: These findings indicate that skimmianine exerts neuroprotective effects against secondary cerebellar injury following cerebral I/R through coordinated modulation of oxidative stress, systemic neuroinflammatory responses, astroglial injury-associated pathways, and inflammation-related mechanisms. Full article

This study investigated the effects of different doses of ranolazine in a middle cerebral artery occlusion/reperfusion (MCAO-I/R) model by evaluating histopathological changes and serum Sirtuin 1 (SIRT1), Apela peptide (APELA), and Apelin-13 (APL13) levels. A total of 47 male Sprague Dawley rats (250 ± 20 g) were randomly assigned to five groups: Sham (n = 7), MCAO (n = 10), MCAO+RAN10 (n = 10), MCAO+RAN30 (n = 10), and MCAO+RAN50 (n = 10). MCAO-I/R was induced by transient filament occlusion of the right middle cerebral artery for 90 min followed by reperfusion. Ranolazine was administered intraperitoneally once daily for 21 days in the treatment groups. Serum SIRT1, APELA, and APL13 levels were measured using enzyme-linked immunosorbent assay (ELISA), and brain tissues were evaluated histopathologically for neuronal degeneration and apoptotic cell counts. Histopathological analysis revealed significant neuronal degeneration and increased apoptosis in the MCAO group compared with the Sham group. Ranolazine treatment did not demonstrate significant histopathological improvement compared with the untreated MCAO group. Among the treatment groups, the MCAO+RAN50 group showed higher apoptotic cell counts and lower serum biomarker levels than the other ranolazine-treated groups. Serum SIRT1, APELA, and APL13 levels were lowest in the MCAO+RAN50 group, with selected pairwise differences reaching statistical significance. Under the present experimental conditions, clear evidence of neuroprotection could not be demonstrated. None of the ranolazine-treated groups showed significant histopathological improvement compared with the untreated MCAO group. These findings indicate that higher-dose ranolazine was not associated with neuroprotection under the conditions of this study. However, given the limited sample size, absence of infarct volume analysis, lack of neurological functional assessment, and absence of tissue-level molecular validation, further studies are required to clarify the biological significance and potential clinical relevance of the observed biomarker changes. Full article

Background/Objectives: Carotid perivascular adipose tissue (PVAT) density on computed tomography angiography (CTA) is a noninvasive surrogate marker of local vascular inflammation, but its relevance to stroke etiology in a homogeneous cohort of patients undergoing mechanical thrombectomy (MT) remains unclear. Methods: We retrospectively analyzed 146 consecutive patients with acute ischemic stroke treated with MT for acute middle cerebral artery (MCA) occlusion between May 2018 and August 2024. Baseline CTA was used to quantify carotid PVAT density with two 2–3 mm² circular regions of interest per internal carotid artery (ICA), placed ≥1 mm from the vessel wall. Measurements were performed bilaterally, and the ICA ipsilateral to the occluded MCA was defined as the stroke-side ICA. Etiology was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system and grouped as large-artery atherosclerosis (LAA), cardioembolism (CE), and other/undetermined (OD/UD). Interobserver agreement was assessed using the intraclass correlation coefficient. Results: The mean age was 72.21 ± 12.39 years; 83.6% of patients achieved successful recanalization (mTICI ≥ 2b), and 47.9% had a favorable 90-day outcome (mRS ≤ 2). In the LAA subgroup (n = 38), ipsilateral PVAT density was significantly higher (less negative) than contralateral PVAT density (−64.24 ± 11.74 vs. −78.22 ± 9.13 HU; p < 0.001). Ipsilateral PVAT density differed significantly across TOAST groups (ANOVA p = 0.004), being higher in LAA than in CE (Δ = 11.19 HU; p = 0.003) and OD/UD (Δ = 9.54 HU; p = 0.004). ROC analysis showed modest discrimination for LAA versus non-LAA stroke (AUC 0.67, 95% CI 0.58–0.75), with an optimal cutoff of −79 HU (sensitivity 92.1%, specificity 40.7%). In multivariable logistic regression, higher ipsilateral PVAT density was independently associated with LAA etiology (per 1-HU increase: OR 1.048, 95% CI 1.018–1.079; p = 0.0016). PVAT density was not associated with recanalization success or 90-day functional outcome. Conclusions: In patients with acute MCA occlusion undergoing MT, higher carotid PVAT density on the stroke side was independently associated with LAA stroke etiology but had limited value for predicting MT success or short-term clinical outcome. Full article