Search Results (4,987)

The objective of this study is to mitigate the bottom-out failure and improve the energy absorption of conventional helmet liners during high-energy impacts, thereby reducing the risk of head injuries. To this end, a locally reinforced Primitive-type triply periodic minimal surface (P-TPMS) energy-absorbing liner is proposed for the helmet forehead region, which facilitates progressive energy dissipation through layer-by-layer buckling deformation. A finite element model of a helmet–head coupling was created based on a previously verified high-fidelity head model and subsequently validated against the ECE 22.06 standard drop-test methodology. Three critical design parameters—outer protective layer thickness, triply periodic minimal surface (TPMS) unit cell size, and wall thickness—were optimized employing the Box–Behnken Design (BBD) response surface methodology, resulting in quadratic regression models for the head injury criteria (HIC) and peak linear acceleration (PLA) with good fit ($R^2$ > 0.97). Optimal parameter combinations were established using multi-objective optimization, with protective efficacy carefully assessed from both head dynamic response and biomechanical response perspectives. The ideal P-TPMS liner possesses an outer protective layer thickness of 14.95 mm, a TPMS unit cell size of 12.23 mm, and a wall thickness of 3.93 mm. Compared to the traditional expanded polystyrene (EPS) liner, the optimized P-TPMS liner significantly reduces HIC (by ∼16%) and PLA (by ∼14%) while extending the impact duration. More critically, it transitions both intracranial pressure and brain tissue strain below their respective clinical injury thresholds, substantially lowering the risks of skull fracture and mild traumatic brain injury (mTBI). The P-TPMS construction facilitates continuous energy dissipation during impacts via incremental layer-by-layer buckling deformation, hence extending impact duration and markedly improving helmet protective efficacy. These findings offer theoretical foundations and technical direction for the creation of localized heterogeneous liner designs in advanced high-performance helmets, although the results are limited to frontal flat-anvil impact conditions. Full article

Background: Intracranial pressure (ICP) monitoring remains the cornerstone of neurocritical care in severe traumatic brain injury (TBI), yet its prognostic value as a standalone metric is limited. The Pressure Reactivity Index (PRx), a continuous measure of cerebrovascular reactivity derived from ICP and arterial blood pressure, may offer additional or complementary prognostic information. This systematic review aimed to compare the prognostic performance of PRx-derived metrics versus standard ICP monitoring for mortality and functional outcome in patients with TBI. Methods: A systematic search of PubMed, Web of Science, and Scopus was conducted for studies published between January 2000 and December 2025. Studies were eligible if they included adult TBI patients with continuous multimodal monitoring and reported comparative prognostic data for PRx- and ICP-based metrics. Risk of bias within the studies was appraised via the QUIPS tool, and the GRADE system was used to rate the strength of the evidence. Due to methodological heterogeneity, findings were synthesized narratively. Results: Nine studies were included. Applying a maximum-cohort estimation to account for overlapping registries, the pooled sample comprised a minimum of 1240 unique patients. In the majority of included studies, direct within-cohort head-to-head comparisons demonstrated that specific PRx-derived metrics—such as the individualized ICP threshold (iICP), Longest Continuous Duration of Autoregulatory Impairment (LCAI), Lower Limit of Reactivity (LLR), and time-integrated burdens (%Time > Threshold)—yielded stronger prognostic discrimination compared to standard ICP thresholds for both mortality (PRx: AUC 0.747–0.648 and ICP: AUC 0.660–0.614) and functional outcome. When added to established predictive models, PRx-derived metrics provided clinically meaningful incremental improvements in prognostic accuracy, with descriptive incremental AUC gains ranging from +0.039 to +0.170 across the six studies reporting model augmentation. Due to heterogeneity in baseline models, PRx-derived metrics, and patient populations, these findings are presented strictly as a descriptive range. Conclusions: PRx and PRx-derived cerebrovascular reactivity metrics-namely iICP, LCAI, LLR, and time-integrated burdens of autoregulatory failure—show potential to offer additive prognostic value beyond standard ICP monitoring in severe TBI. However, because current evidence is strictly observational and likely influenced by institutional confounders, it cannot currently support definitive clinical recommendations. Further prospective, multicenter studies utilizing standardized thresholds are necessary to confirm these associative findings and isolate their true prognostic value. Full article

Objectives: This study aimed to develop a prognostic model for isolated moderate-to-severe traumatic brain injury (TBI) (Glasgow Coma Scale [GCS] ≤ 12) using readily available variables and to explore paired blood–cerebrospinal fluid (CSF) metabolomic signatures. Methods: Consecutive TBI patients admitted between January 2019 and June 2025 were retrospectively analyzed. Multivariate logistic regression with bootstrap internal validation identified predictors of 6-month unfavorable outcome and in-hospital mortality. Untargeted metabolomics was performed on paired blood and CSF samples from 30 matched male patients. Results: Among 405 patients, 266 (65.7%) had unfavorable outcomes and 54 (13.3%) died in hospital. Rotterdam CT Score (odds ratio [OR] 10.59, 95% confidence interval [CI] 6.19–18.14), initial lactate (OR 1.81, 95% CI 1.38–2.36), and blood glucose (OR 1.40, 95% CI 1.21–1.64) predicted unfavorable outcome (area under the receiver operating characteristic curve [AUC] 0.97). GCS motor score (OR 0.50, 95% CI 0.37–0.66), initial lactate (OR 1.57, 95% CI 1.31–1.91), and follow-up lactate (OR 1.57, 95% CI 1.34–1.88) predicted mortality (AUC 0.96). Blood metabolomics revealed enrichment in energy and lipid metabolism pathways. CSF metabolomics highlighted neurotransmitter pathway dysregulation and neuroinflammatory markers, with depleted kynurenic acid in both biofluids. Conclusions: Readily available admission variables enable early bedside risk stratification in TBI. Metabolomic profiling links unfavorable outcomes to systemic energy–lipid dysregulation and central neuroinflammatory–neurotransmitter disturbances, with the tryptophan–kynurenine axis as a potential therapeutic target for neuroprotective strategies. Full article

Alzheimer’s disease (AD) is characterized by Tau hyperphosphorylation, β-amyloid (Aβ) accumulation, and progressive neuronal loss. Gastrodia elata (G. elata), a traditional Chinese medicine with well-established neuroprotective properties, was investigated. Two G. elata-derived miRNAs, Gas-miR04-3p and Gas-miR19-5p, were identified as regulators of JNK3. By means of Western blot, RT-qPCR, and assessments of antioxidant indices, it was demonstrated that Gas-miR04-3p and Gas-miR19-5p can suppress JNK3 expression, reduce Tau phosphorylation at Ser202 and Ser396, enhance antioxidant capacity, and attenuate apoptosis in AD-related cellular and molecular pathology models. These miRNAs were also detectable in murine brain tissues following oral administration of total RNA extracted from G. elata. Their administration was associated with decreased JNK3 activation, alleviated Tau hyperphosphorylation, and improved expression of apoptosis-related proteins in AD mouse models. These results suggest that G. elata miRNAs may exert neuroprotective effects through regulation of JNK3 signaling, thereby attenuating Tau-related pathological changes and neuronal injury in AD-related models. Full article

Traumatic brain injury (TBI) is a global public health problem which causes long-term neurologic damage caused by both primary mechanical injury and secondary pathological processes. Extracellular vesicles (EVs) such as exosomes, microvesicles (MVs) and apoptotic bodies (ApoBDs) serve as critical vehicles mediating intercellular communication in the central nervous system (CNS) following TBI. The biogenesis and the content of EVs, including proteins, lipids and RNAs, are greatly changed and involved in the evolution of inflammation or tissue repairing after TBI. In this overview, we recapitulate the cellular origin of EVs and the function of EVs in the neuroinflammatory process after TBI, highlighting the dual regulatory roles of EVs in the biological response to TBI, whereby certain EV populations amplify secondary injury cascades, while others promote endogenous repair and recovery processes. We next investigate the progress in EV engineering and targeted delivery systems and report the potential mechanisms, emphasize the prospects and potential of engineered EVs for therapy, and comment on challenges and perspectives for clinical application in TBI. Full article

Background/Objectives: Assisted verticalization and supported upright activity are relevant components of rehabilitation in adults with severe acquired brain injury (sABI), although patient selection and implementation remain challenging. This retrospective observational study aimed primarily to describe the implementation feasibility and documented safety of GRILLO-based training in routine inpatient multidisciplinary rehabilitation, and secondarily to report exploratory pre–post functional changes. Methods: We reviewed clinical records of 34 adults screened or considered for GRILLO-based training at Centro Cardinal Ferrari KOS, Italy, between June 2022 and December 2024. GRILLO training was delivered as part of standard care and not as an experimental intervention. Functional outcomes included the Barthel Index (BI), Trunk Control Test (TCT), Tinetti Balance Scale, and Tinetti Gait subscale, extracted from routine documentation. Non-parametric descriptive analyses were used. Results: Of 34 screened patients, 4 did not meet diagnostic criteria for ABI, 5 interrupted training because of pain or poor tolerance to prolonged upright positioning, and 3 were not included because of poor compliance/motivation or an incomplete clinical pathway. The paired functional-analysis cohort comprised 22 patients: 20 (91%) completed 15 sessions and 2 (9%) completed 10 sessions. No serious device-related adverse events were documented in available clinical records, although minor adverse events were not systematically monitored. Among patients with paired observations, median BI increased from 16 to 22.5 (median change, +3; p = 0.008; n = 20), median TCT from 72 to 74 (median change, +12; p < 0.001; n = 21), and median Tinetti Balance Scale from 1 to 2 (median change, +1; p = 0.006; n = 22). Individual responses were heterogeneous and floor effects were evident, especially for balance and gait-related measures. Conclusions: In this retrospective real-world cohort, GRILLO-based training could be implemented in selected severely impaired inpatients, but feasibility may be overestimated if interrupted and non-completing cases are not considered. The non-completion cases may suggest that feasibility depends not only on initial clinical indication, but also on the appropriate timing of introduction, tolerance to prolonged upright physical effort, pain/discomfort, motivation, and behavioral engagement. The retrospective design, survivorship bias, non-systematic adverse-event monitoring, concurrent multidisciplinary rehabilitation, and absence of a comparator group preclude conclusions regarding device-specific safety or efficacy. Nevertheless, these preliminary findings support further prospective controlled studies. Full article

Background: Meta-analyses suggest an association between patent foramen ovale (PFO) and white-matter hyperintensities (WMH), but pooled effect sizes do not clarify applicability to routine transthoracic echocardiography (TTE) or provide patient-level risk estimates. Objective: The objective of this study was to evaluate the association between TTE-detected PFO and MRI-defined WMH in routine practice and to develop a practice-anchored framework (PAMAP) that translates literature-derived evidence into individualized risk. Methods: We performed a retrospective, single-center, propensity-matched analysis of 149 adults undergoing TTE and brain MRI (37 PFO-positive, 112 controls). The primary endpoint was WMH (Fazekas ≥ 1). PAMAP synthesized 12 studies; 4 eligible studies were pooled using random-effects meta-analysis to derive a locked shunt coefficient (OR 3.65). The locked model used age and shunt (H); embolic context (E), and atrial stress (A) were neutral until refit. Transportability was assessed at the cohort level (expected vs. observed prevalence) and patient level (calibration, discrimination), followed by a minimal prespecified refit. Results: WMH was more frequent in PFO-positive versus control participants (54% vs. 32%). Literature-based expected prevalence approximated observed prevalence, supporting transportability. The locked model showed acceptable performance (calibration intercept 0.106; slope 0.912; Brier 0.188; AUC 0.756). A parsimonious refit improved performance (Brier 0.176; AUC 0.783), with the shunt term remaining significant (OR 2.45, 95% CI 1.23–4.88). Conclusions: PAMAP translates meta-analytic associations into a transportable patient-level risk framework. In routine TTE-defined PFO populations, the WMH association is preserved, suggesting that incidental PFO may mark early subclinical cerebral injury and enabling calibrated, individualized risk assessment. 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

Background Although cycling has definite health benefits, it is certainly not a risk-free activity; its increasing use is associated with a rise in accidents. This study aims to characterize cycling injuries and their associated factors in a tertiary trauma center, including injury severity, accident circumstances, and in-hospital costs. Methods: A retrospective observational study was conducted on patients over 15 years of age hospitalized after a cycling accident. Collected variables included the characteristics of the accident, the epidemiology of musculoskeletal injuries, helmet use, injury severity as assessed using the Abbreviated Injury Scale (AIS), the Injury Severity Score (ISS), and costs. Results: A total of 131 patients were included, of whom 90.8% were male, with a mean age of 43.2 ± 14.1 years. Most accidents were due to falls (83.7%). Accidents occurred in urban areas (56.3%), inter-urban roads (28.1%), and rural areas (15.6%). Upper limb fractures, particularly clavicle fractures (13.7%), were the most frequent injuries (31.0%). Traumatic brain injury (TBI) was present in 30.0% of patients, and 17.6% were polytraumatized. Injury severity was higher in males (p = 0.009) and in collisions compared with falls (p = 0.033). It was also correlated with length of hospital stay (r = 0.376). Patients with TBI exhibited significantly higher ISSs (p < 0.001). Helmet use was reported in 71.1% of patients and was more frequent in rural areas (p < 0.001) and associated with lower neurological AIS scores (p = 0.031). The mean cost per patient was €8545 ± 15,298, increasing with severity of injury (p < 0.001), and was higher in polytraumatized patients (p < 0.001) and in those with TBI. Conclusions: Cycling accidents most frequently resulted in upper limb fractures. Helmet use was more common where mandatory and was associated with less severe neurological injuries but not with a lower incidence of TBI. Costs increased with injury severity, particularly in patients with TBI and longer hospital stays. Full article

Early diagnosis of post-traumatic epilepsy (PTE) is crucial for timely intervention. However, it is hampered by the lack of reliable biomarkers. In this review, we provide a comprehensive summary of current advances in PTE biomarker research, drawing primarily on evidence from human cohort studies, with selective support from experimental animal models where mechanistic insights are required. We cover (i) neuroimaging, including CT, MRI, and EEG/qEEG, which reveal structural and functional alterations associated with epileptogenesis; (ii) molecular biomarkers, including RNAs, proteins, metabolites, and extracellular vesicle (EV)-derived molecules that reflect neuroinflammation, blood–brain barrier (BBB) dysfunction, neuronal injury, and synaptic remodeling; and (iii) artificial intelligence (AI)-assisted approaches, which integrate multimodal datasets to identify complex predictive patterns. While individual modalities offer valuable but incomplete prognostic information, AI-driven analytics hold the greatest promise for early predictive power by combining multimodal data. Future progress will depend on the integration of high-resolution imaging, multi-omics profiling, and rigorous validation to deliver clinically actionable biomarker panels and ultimately reduce the burden of PTE. Full article

Background: Traumatic brain injury (TBI) and substance use disorder (SUD) frequently co-occur due to shared risk factors and a potentially bidirectional relationship. However, epidemiological patterns in rural populations remain understudied despite known disparities in access and outcomes. This study aimed to characterize the relationship between TBI and SUD in a rural Southwestern population, including demographic and clinical patterns of diagnostic sequencing. Methods: A retrospective observational study was conducted using electronic health records and trauma registry data (2022–2023) from a rural trauma center. Cohort one included 24,389 emergency department encounters with ICD-10 codes for TBI or SUD. Cohort two included 248 trauma registry patients with TBI and SUD diagnoses. Descriptive statistics and multinomial logistic regression models were used to evaluate diagnostic patterns and associated demographic factors. Results: Males were more likely to have co-occurring TBI and SUD (Relative Risk Ratio [RRR] = 1.35), while increasing age was associated with TBI-only diagnoses. Among patients with multiple visits and diagnoses, 16% had co-diagnoses, while 9% had sequential diagnoses. American Indian/Alaska Native patients had higher co-diagnosis risk compared to White patients (RRR = 2.21, p < 0.001). Higher blood alcohol concentration was associated with lower Glasgow Coma Scale scores (r = −0.15, p = 0.022), indicating greater severity. Conclusions: TBI and SUD frequently co-occur in rural populations, with notable disparities by sex and race/ethnicity. Emergency Departments are critical points of care for interventions such as screening for both substance use and head injury when either is suspected, and employing culturally responsive education and referral pathways upon discharge. Full article

Exposure to electromagnetic fields (EMFs) at different frequencies has been reported to induce apoptotic changes in brain tissue. Apoptosis is commonly evaluated using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) method; however, conventional semi-quantitative scoring is subjective and may vary between observers. Therefore, this study aimed to evaluate the feasibility of transfer learning-based convolutional neural network (CNN) models for the objective and automated classification of apoptotic damage in TUNEL-stained brain sections. A total of 92 light microscopy images of TUNEL-stained rat brain tissue, obtained from experimental groups, were analyzed. Apoptotic damage was categorized into three classes (0: no, +1: slight, +2: moderate) based on semi-quantitative scoring. Pre-trained convolutional neural network models, including AlexNet, SqueezeNet, GoogLeNet, Inception-v3, and ResNet-101, were applied for image classification. All models were able to classify apoptotic damage levels, defined by the extent of TUNEL staining, from images with varying performance. The best-performing model achieved high classification accuracy and demonstrated strong agreement with manual scoring, as determined by visual assessments by experts. The models successfully distinguished between different levels of apoptotic damage observed across experimental groups. The findings suggest that transfer learning-based CNN models may provide an objective and reproducible approach for the classification of apoptotic damage in TUNEL-stained histopathological images, thereby reducing observer-dependent variability. This approach may also support histopathological evaluation in experimental models, including studies investigating EMF-induced brain injury. Full article

Hypoxic–ischemic brain injury remains the leading cause of death and neurological disability after cardiac arrest. Although targeted temperature management (TTM) and other neuroprotective strategies have demonstrated promising results in preclinical studies, large randomized controlled trials have largely failed to show consistent clinical benefit. This review examines two major limitations that may contribute to these translational failures: delayed initiation of therapy beyond a time-limited therapeutic window and the lack of baseline injury severity stratification. Evidence from both experimental and clinical studies suggests that the opportunity to modify neurological injury may be confined to the first few hours after return of spontaneous circulation (ROSC). Delayed intervention may occur after irreversible neuronal injury, microvascular dysfunction, and impaired cerebrovascular autoregulation have already become established. In addition, cardiac arrest survivors represent a heterogeneous population. Patients with minimal injury may recover with standard supportive care, whereas those with severe irreversible injury are unlikely to benefit from neuroprotective interventions. Patients with moderate-severity brain injury may represent the subgroup most likely to respond to targeted therapies. Ultra-early stratification using neuroimaging, electroencephalography, circulating biomarkers, and clinical risk scores may help identify patients with therapeutic potential. This review proposes that future post-cardiac arrest research should integrate both time-sensitive intervention strategies and early injury severity stratification. Large prospective studies and randomized controlled trials are needed to determine not only whether interventions are effective, but also when they should be initiated and which patients are most likely to benefit. Full article

Background: Moderate-to-severe preterm brain injury (PBI), including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), remains an important cause of adverse neurodevelopmental outcomes in preterm infants. Early risk stratification using routinely collected clinical data may help prioritize surveillance in vulnerable infants. Methods: We retrospectively included 318 preterm infants admitted between 2015 and 2024 as the development cohort. Thirty-three candidate predictors derived from perinatal factors, first laboratory tests within 24 h of admission, and selected early hospitalization variables were evaluated. Seven machine-learning algorithms were developed using stratified 10 × 5 nested cross-validation with prespecified preprocessing, class-balancing, and feature-selection procedures. Candidate models were compared primarily using the mean fold-level area under the receiver operating characteristic curve (AUROC). After model selection, the finalized LightGBM model was calibrated using Platt scaling, and its pooled out-of-fold (OOF) performance was summarized. Two prespecified thresholds (Youden and high-sensitivity) were used for risk stratification. A small independent temporal cohort of 35 infants was used for preliminary external validation. Results: PBI occurred in 62/318 infants (19.5%) in the development cohort and 6/35 infants (17.1%) in the temporal external cohort. During candidate-model comparison, LightGBM achieved the highest mean fold-level AUROC (0.768, 95% CI 0.708–0.825). The finalized 14-feature LightGBM model, evaluated using pooled OOF predictions after Platt calibration, yielded an AUROC of 0.747 (95% CI 0.679–0.811), a PR-AUC of 0.392, and a Brier score of 0.136. At the Youden threshold (0.18), sensitivity was approximately 0.70 and specificity approximately 0.85; at the high-sensitivity threshold (0.10), sensitivity was approximately 0.95 and specificity approximately 0.50. Key predictors included ventilation status and early physiologic and laboratory indicators. In the small temporal external cohort (n = 35), the AUROC was 0.897 (95% CI 0.672–1.000); however, this high point estimate should not be overinterpreted because of the limited sample size, wide confidence interval, and suboptimal calibration, and should therefore be considered preliminary. Conclusions: We developed an interpretable LightGBM model using routinely available early postnatal and early hospitalization data to support risk stratification for PBI in preterm infants. The model showed moderate internal discrimination and a positive net benefit across clinically relevant thresholds. Preliminary temporal external validation in a small cohort yielded highly uncertain estimates; larger multicenter studies are needed to confirm generalizability, refine calibration, and determine the most appropriate implementation strategy before routine clinical use. Full article

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that regulates key cellular processes, like proliferation, apoptosis, inflammation, and vascular homeostasis. S1P acts as a signaling molecule both inside and outside cells by interacting with five G-protein-coupled S1P receptors (S1PR1–S1PR5). Accumulating evidence indicates that dysregulation of S1P signaling is implicated in the pathophysiology of cerebral ischemia/reperfusion (I/R) injury and Alzheimer’s disease (AD). In I/R injury, S1P signaling regulates vascular permeability, immune cell infiltration, and neuronal survival and death. In AD, alterations in S1P metabolism are associated with β-amyloid deposition, tau hyperphosphorylation, synaptic dysfunction, and sustained neuroinflammation. S1P receptor (S1PR) modulators represent promising therapeutic agents in both preclinical and clinical studies. Fingolimod was the first oral disease-modifying therapy approved for the treatment of multiple sclerosis and, at the same time, the first S1PR modulator introduced into clinical practice. New selective S1PR-targeting agents, including siponimod and ozanimod (S1PR1 and S1PR5), as well as the S1PR1-selective agent ponesimod, have also been approved for clinical use. In addition to their immunomodulatory properties, S1PR modulators have direct effects in the central nervous system, facilitating the maintenance of blood–brain barrier integrity, reducing microglial activation, and enhancing neuronal survival pathways. Building on this knowledge, we discuss the role of S1P signaling, highlighting recent advances in S1PR modulators as promising therapeutic agents for cerebral I/R injury and AD. Full article