Pre-ischaemic empagliflozin treatment attenuates blood–brain barrier disruption via β-catenin mediated protection of cerebral endothelial cells

Cardiovascular Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Abstract Aims Microvascular endothelial cells dysfunction can significantly worsen ischaemic stroke outcomes by disrupting tight junctions and increasing the acquisition of adhesion molecules, accelerating blood–brain barrier (BBB) disruption pro-inflammatory response. The identification drugs that improve cell function may be crucial for stroke. It has been validated empagliflozin (EMPA), a novel antidiabetic drug, protects regardless diabetic status patient. However, impact EMPA on is unclear. We hypothesized would exert beneficial effect outcome protecting microvascular against junction increase molecules. Methods results Young adult male mice were administered with or vehicle (dimethyl sulfoxide) daily 7 days before being subjected to transient middle cerebral artery occlusion (tMCAO). Neurological deficits evaluated up 28 post-tMCAO. Infarct volume, BBB disruption, inflammatory assessed 1 day after tMCAO.bEnd.3 primary brain treated under oxygen glucose deprivation/reperfusion (OGD/R), lactate dehydrogenase release, transendothelial electrical resistance, leakage fluorescein isothiocyanate-dextran, molecules proteins examined. Mechanistic studies probing conducted RNA-seq. treatment ischaemia markedly improved infarct inflammation 1-day post-tMCAO, further enhanced neurobehavioral days. Pre-treatment attenuated OGD/R conditions. In mechanistic terms, RNA-seq data from isolated microvessels revealed Wnt/β-catenin signalling pathway was preserved in group, contrast group. inhibited β-catenin ubiquitination promoted translocation cytoplasm nucleus function. Importantly, inhibitor XAV-939 eliminated this protective EMPA. Conclusion administration tMCAO ischaemia/reperfusion-induced via β-catenin-mediated protection cells. Therefore, shows potential improving as an adjunctive preventive strategy.

Language: Английский

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Empagliflozin-activated AMPK elicits neuroprotective properties in reserpine-induced depression via regulating dynamics of hippocampal autophagy/inflammation and PKCζ-mediated neurogenesis

Psychopharmacology, Journal Year: 2024, Volume and Issue: 241(12), P. 2565 - 2584

Published: Aug. 19, 2024

Abstract Rationale Major depression has been an area of extensive research during the last decades, for it represents a leading cause disability and suicide. The stark rise rates influenced by life stressors, economic threats, pandemic era, resistance to classical treatments, made disorder rather challenging. Adult hippocampal neurogenesis plasticity are particularly sensitive dynamic interplay between autophagy inflammation. In fact, intricate balance two processes contributes neuronal homeostasis survival. Objectives Having demonstrated promising potentials in AMPK activation, major metabolic sensor regulator, empagliflozin (Empa) was investigated possible antidepressant properties reserpine rat model depression. Results While protocol elicited behavioral, biochemical, histopathological changes relevant depression, Empa outstandingly hindered these pathological perturbations. Importantly, autophagic response markedly declined with which disrupted AMPK/mTOR/Beclin1/LC3B machinery and, conversely, neuro-inflammation prevailed under influence NLRP3 inflammasome together oxidative/nitrative stress. Consequently, AMPK-mediated neurotrophins secretion obviously deteriorated through PKCζ/NF-κB/BDNF/CREB signal restriction. restored monoamines autophagy/inflammation balance, driven activation. By promoting atypical PKCζ phosphorylation (Thr403) subsequently phosphorylates NF-κB at Ser311, successfully reinforced BDNF/CREB neuroplasticity. latter finding supported CA3 toluidine blue staining reveal intact neurons. Conclusion current study highlights interesting role as regulator inflammatory responses pathology also pinpoints unusual contribution via AMPK/PKCζ/NF-κB/BDNF/CREB transduction. Accordingly, can have special benefits diabetic patients depressive symptoms. Limitations p -NF-κB (Ser311) on assembly activation not investigated, represent point further research. Graphical abstract

Language: Английский

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Empagliflozin demonstrates neuroprotective and cardioprotective effects by reducing ischemia/reperfusion damage in rat models of ischemic stroke and myocardial infarction

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 15, 2025

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated potential neuroprotective and cardioprotective effects in preliminary studies. This study evaluates the efficacy of empagliflozin (EMPA) reducing ischemia/reperfusion damage both brain heart using rat models. Ischemic stroke myocardial infarction (MI) were induced male Sprague-Dawley rats, which randomized into three groups: (1) Control (no EMPA), (2) Acute treatment (EMPA, 10 mg/kg IV, administered min before ischemia 1 reperfusion), (3) Chronic 20 food for 7 days ischemia). Stroke was by middle cerebral artery occlusion (MCAO) one hour, followed 3 h reperfusion, MI left coronary 30 min, reperfusion. Brain tissues analyzed anatomic size stroke. In brain, significantly smaller EMPA groups compared to controls (acute: 3.7 ± 1.2%, chronic: 6.9 2.1% vs. control: 14.5 2.5%, p < 0.05). Edema also reduced 5.5 0.9%, 5.9 0.8% 9.6 heart, 46.9 2.0%, 48.8 5.8% 70.0 2.6%, 0.05), no-reflow 36.3 3.3%, 33.9 4.3% 53.4 treatment, acute chronic, reduces infarct volume edema, as well models ischemic ischemia/reperfusion, indicating substantial effects.

Language: Английский

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Dl-3-n-Butylphthalide Promotes Neurogenesis in Ischemic Stroke Mice Through Wnt/β-Catenin Signaling Activation and Neurotrophic Factor Production

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Synchronized neurogenesis and angiogenesis after stroke have been well documented, inducing neurovascular remodeling may provide a promising strategy to promote tissue repair functional recovery. Dl-3-n-Butylphthalide (NBP) was reported exert potent angiogenic activity in rodent models of stroke. However, little is currently known regarding the effects mechanisms NBP on ischemic This study aimed determine whether how promotes cerebral injury. Adult C57BL/6 mice, subjected distal middle artery occlusion (dMCAO), were treated with NBP. The efficacy assessed using neurologic deficits infarct volume. Immunofluorescent staining applied evaluate neurogenesis. regulation Wnt/β-catenin signaling pathway expression neurotrophic factors detected by western blotting qRT-PCR. Administration reduced volume ameliorated neurological promoted proliferation NSCs SVZ, migration neuroblasts along corpus callosum, differentiation toward neurons peri-infarct zone, resulting restored neural function. Moreover, we revealed that NBP-induced associated activation pathway, which reversed DKK1. In addition, increased production VEGF BDNF. Our data unveiled potentials recovery stroke, depending factor production. Thus, be candidate for delayed treatment

Language: Английский

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Keep your guard up: blood–brain barrier protection by empagliflozin after acute ischaemic stroke

Cardiovascular Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

Language: Английский

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Meta-analysis of the efficacy and safety of SGLT-2 inhibitors in patients with heart failure and type 2 diabetes mellitus

Medicine, Journal Year: 2025, Volume and Issue: 104(18), P. e42196 - e42196

Published: May 2, 2025

Background: To investigate the efficacy and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in patients with heart failure (HF) type diabetes mellitus (T2DM). Methods: A manual search was conducted 3 prestigious English databases, Cochrane Library, PubMed, Web Science, for studies published within last decade, from July 2014 to 2024. The extracted literature synthesized analyze outcomes, survival prognostic indicators, profiles SGLT-2 HF T2DM. bias risk assessment scale used as a tool evaluate quality literature, Review Manager 5.4 software create chart. Data analysis merging were completed help Stata 15.0 statistical software. Results: Twelve encompassing 9509 included meta-analysis. results revealed that compared control group, inhibitor-treated group demonstrated significantly greater reductions left ventricular end-diastolic volume index [mean difference (MD) = -7.25, 95% confidence intervals [95% CI] (-9.83, -4.67)], brain natriuretic peptide levels [MD -36.96, CI (-63.51, -10.41)], N-terminal pro-brain -519.27, (-660.77, -377.78)]. Furthermore, exhibited higher increases Kansas City Cardiomyopathy Questionnaire scores 3.32, (3.30, 3.34)], indicating improved life. Additionally, incidence adverse events lower [OR 0.78, (0.69, 0.88)]. pooled meta-analysis indicated inhibitor therapy reduced cardiovascular death or hospitalization by 23%, 19%, all-cause mortality 9%. Conclusion: risks mortality, death, improve cardiac function, decrease events, enhance life these patients.

Language: Английский

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Sodium-glucose cotransporter protein 2 inhibition, plasma proteins, and ischemic stroke: A mediation Mendelian randomization and colocalization study

Journal of Stroke and Cerebrovascular Diseases, Journal Year: 2024, Volume and Issue: 34(1), P. 108136 - 108136

Published: Nov. 12, 2024

To determine the effect of sodium-glucose cotransporter protein 2 (SGLT2) inhibition on ischemic stroke (IS) and investigate circulating proteins that mediate effects SGLT2 IS.

Language: Английский

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Central SGLT2 mediate sympathoexcitation in hypertensive heart failure via attenuating subfornical organ endothelial cGAS ubiquitination to amplify neuroinflammation: Molecular mechanism behind sympatholytic effect of Empagliflozin

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 145, P. 113711 - 113711

Published: Dec. 7, 2024

Language: Английский

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Bibliometric and visual analysis of SGLT2 inhibitors in cardiovascular diseases

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 30, 2024

Cardiovascular diseases (CVD) pose a significant threat to human health due their high mortality and morbidity rates. Despite advances in treatments, the prevalence impact of cardiovascular disease continue increase. Sodium-glucose transporter 2 inhibitors (SGLT2i), initially approved for treatment type diabetes, have important research value promising applications reducing CVD risk, especially heart failure (HF) atherosclerosis patients with (ASCVD). This study aims comprehensively review latest progress, trends, cutting-edge hot spots, future development directions SGLT2i field through bibliometric analysis.

Language: Английский

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The SGLT2 inhibitor empagliflozin exerts neuroprotective effect against hydrogen peroxide-induced toxicity on primary neurons

Metabolic Brain Disease, Journal Year: 2024, Volume and Issue: 40(1)

Published: Nov. 19, 2024

Language: Английский

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