Academic Journal
Danshensu derivative mitigate cerebral ischemia-reperfusion injury via the PI3K-AKT-CREB signaling pathway.
| Τίτλος: | Danshensu derivative mitigate cerebral ischemia-reperfusion injury via the PI3K-AKT-CREB signaling pathway. |
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| Συγγραφείς: | Bai F; Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China., Liu T; Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China., Yang R; Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China., Qu Y; Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China., Liu X; Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China., Wang J; Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China. Electronic address: wangjinhui@hrbmu.edu.cn., Li C; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China. Electronic address: lichunli_2014@126.com. |
| Πηγή: | Journal of ethnopharmacology [J Ethnopharmacol] 2026 Sep 15; Vol. 368, pp. 121785. Date of Electronic Publication: 2026 Apr 30. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Sequoia Country of Publication: Ireland NLM ID: 7903310 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7573 (Electronic) Linking ISSN: 03788741 NLM ISO Abbreviation: J Ethnopharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Limerick : Elsevier Sequoia Original Publication: Lausanne, Elsevier Sequoia. |
| Ιατρικοί όροι (MeSH): | Reperfusion Injury*/drug therapy , Reperfusion Injury*/metabolism , Reperfusion Injury*/pathology , Lactates*/pharmacology , Lactates*/therapeutic use , Brain Ischemia*/drug therapy , Neuroprotective Agents*/pharmacology, Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cell Survival/drug effects ; Brain/drug effects ; Brain/blood supply ; Cell Movement/drug effects ; Infarction, Middle Cerebral Artery/drug therapy ; Animals ; Rats, Sprague-Dawley ; Male ; Rats ; Cells, Cultured |
| Περίληψη: | Ethnopharmacological Relevance: Danshensu (DSS) is one of the water-soluble components extractable from the traditional Chinese medicine Salvia miltiorrhiza Bge., exhibiting pharmacological effects such as promoting blood circulation, dilating coronary arteries, and improving cerebral blood flow. The Danshensu derivative (OZD-1) obtained through the derivatization of DSS is a potential multi-target drug for the central nervous system, however, its mechanism of action against cerebral ischemia-reperfusion injury (CIRI) remains unclear. Aim of the Study: Systematically investigating the therapeutic potential and mechanisms of action of Danshensu derivative against cerebral ischemia-reperfusion injury. Materials and Methods: Rat brain microvascular endothelial cells (RBMVECs) were cultured in vitro to establish an oxygen-glucose deprivation/reoxygenation (OGD/R) injury model. Groups included a control group, an OGD/R model group, and OZD-1 low-dose (12.5 μmol/L), medium-dose (25 μmol/L), and high-dose (50 μmol/L) groups. Cell viability, migration capacity, and vascular lumen formation were assessed using the CCK-8 assay, cell scratch assay, and matrigel matrix gel assay, respectively. In vivo, a transient middle cerebral artery occlusion (tMCAO) model was established in rats. Animals were randomly divided into the sham, model, OZD-1 (35, 70, 140 mg/kg), Edaravone (Eda), and DSS groups. Daily oral administration was performed post-surgery for 14 consecutive days. Tissue pathology staining, behavioral tests, and regional cerebral blood flow imaging assessed brain tissue damage, cognitive function, and ischemic side cerebral blood flow recovery, respectively. Transcriptome sequencing analyzed differential gene expression and pathway enrichment patterns. Western blot detection measured expression levels of proteins related to the PI3K-AKT-CREB signaling pathway, phosphoproteins, downstream apoptosis-related proteins, and CD31, CD34, and VEGFA proteins. Results: In vitro experiments demonstrated that OZD-1 dose-dependently enhanced the viability of RBMVECs following OGD/R injury, significantly improving cell migration and luminal formation capabilities. In vivo studies revealed that compared to the model group, rats in all OZD-1 dosage groups exhibited markedly improved cognitive function, significantly restored cerebral blood flow in the ischemic hemisphere, and substantially reduced pathological brain tissue damage. Transcriptome sequencing results indicated significant enrichment of genes associated with the PI3K-AKT signaling pathway following OZD-1 intervention. Western blot experiments confirmed that OZD-1 significantly upregulates the phosphorylation levels of proteins related to the PI3K-AKT-CREB signaling pathway in OGD/R-injured cells and brain tissue from tMCAO rats, thereby promoting VEGFA-mediated angiogenesis and inhibiting apoptosis. To further verify pathway involvement, in vitro inhibition experiments were performed in RBMVECs using the PI3K inhibitor LY294002 and CREB inhibitor 666-15. These inhibitors abolished the OZD-1-induced upregulation of p-PI3K, p-AKT, and p-CREB, and reversed its protective effects on cell viability, migration, and tube formation. These results confirm that OZD-1 protects vascular endothelial cells directly via activating the PI3K-AKT-CREB pathway. Conclusion: OZD-1 exhibits significant neuroprotective effects against CIRI in rats, improving cognitive function, promoting vascular regeneration in ischemic areas, repairing damaged RBMVECs, and reducing apoptosis. Its mechanism of action is associated with the activation of the PI3K-AKT-CREB-VEGFA signaling pathway. (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that there are no conflicts of interest. |
| Contributed Indexing: | Keywords: Apoptosis; Cerebral ischemia-reperfusion injury; Danshensu derivative; Vascular regeneration |
| Substance Nomenclature: | EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 4GF33A5PAJ (3,4-dihydroxyphenyllactic acid) 0 (Lactates) EC 2.7.1.- (Phosphatidylinositol 3-Kinases) 0 (Cyclic AMP Response Element-Binding Protein) 0 (Neuroprotective Agents) 0 (Creb1 protein, rat) |
| Entry Date(s): | Date Created: 20260502 Date Completed: 20260716 Latest Revision: 20260716 |
| Update Code: | 20260716 |
| DOI: | 10.1016/j.jep.2026.121785 |
| PMID: | 42069160 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1872-7573 |
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| DOI: | 10.1016/j.jep.2026.121785 |