Metformin attenuates valproic acid–induced developmental cardiotoxicity through activation of the AMPK/PGC-1α axis and restoration of mitochondrial and redox homeostasis in zebrafish embryos
Drug and Chemical Toxicology, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Basım Tarihi: 2026
- Doi Numarası: 10.1080/01480545.2026.2684476
- Dergi Adı: Drug and Chemical Toxicology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE, Environment Index, MEDLINE, Academic Search Ultimate (EBSCO), Biomedical Reference Collection: Corporate Edition (EBSCO), Sociology Source Ultimate (EBSCO)
- Anahtar Kelimeler: AMPK/PGC-1α axis, developmental cardiotoxicity, metformin, mitochondrial dysfunction, oxidative stress, Valproic acid, zebrafish embryo
- İstanbul Medipol Üniversitesi Adresli: Evet
Özet
Prenatal valproic acid (VPA) exposure is strongly linked to developmental cardiotoxicity, yet no targeted pharmacological countermeasure exists. Converging mechanistic evidence indicates that VPA cardiotoxicity centers on AMPK/PGC-1α suppression, positioning the AMPK activator metformin (MET) as a rational candidate for in vivo protection. We examined MET’s protective effects against VPA-induced developmental cardiotoxicity in zebrafish embryos. Embryos were randomly allocated to four groups (Control, VPA 0.1 mM, MET 10 mM, VPA + MET) immediately after fertilization and chronically exposed until 96 hpf. Oxidative stress biomarkers (MDA, NO, SOD, GSH) and the expression of cardiac (nkx2.5, vmhc, amhc), AMPK (prkaa2, acaca), and mitochondrial/energy-related genes (ppargc1a, cpt1b, pck1, atp5pb, mt-nd1) were quantified. Compared with controls, VPA reduced nkx2.5 (p < 0.01) and elevated amhc (p < 0.05), triggered pericardial edema (p < 0.0001), suppressed prkaa2, ppargc1a, and atp5pb (p < 0.05, p < 0.001, and p < 0.0001, respectively), upregulated acaca (p < 0.0001), increased MDA and NO (p < 0.0001), and lowered SOD and GSH (p < 0.0001 and p < 0.001, respectively). Relative to the VPA group, MET co-treatment restored nkx2.5 expression (p < 0.001), attenuated pericardial edema (p < 0.0001), increased prkaa2 (p < 0.05), ppargc1a (p < 0.01), and atp5pb (p < 0.0001), suppressed acaca (p < 0.0001), and normalized MDA (p < 0.05), NO (p < 0.0001), SOD, and GSH (both p < 0.0001). The restoration of prkaa2/ppargc1a, mitochondrial, and antioxidant capacity by MET suggests that the AMPK/PGC-1α axis may serve as a central target in VPA cardiotoxicity.