Berberine ameliorates seizure activity and cardiac dysfunction in pentylenetetrazol-kindling seizures in rats: Modulation of sigma1 receptor, Akt/eNOS signaling, and ferroptosis

Seizures can lead to cardiac dysfunction. Multiple pathways contribute to this phenomenon, of which the chaperone sigma-1 receptor (S1R) signaling represents a promising nexus between the abnormalities seen in both epilepsy and ensuing cardiac complications. The study explored the potential of Berberine (BER), a promising S1R agonist, in treating epilepsy and associated cardiac abnormalities in a pentylenetetrazol (PTZ) kindling rat model of epilepsy. Male Wistar albino rats received PTZ (35 mg/kg) every other day alone, with BER, with phenytoin (PHT), with both BER and PHT and with both BER and an S1R blocker (NE-100) over 27 days. BER decreased seizure severity and improved hemodynamic parameters. Histopathological abnormalities were more pronounced in the PTZ, and blocker group than in other groups, in heart tissue. In cardiac tissue, BER enhanced the AKT/eNOS signaling pathway and mitigated ferroptosis by boosting the cystine/glutamate transporter/Glutathione/Glutathione Peroxidase 4 (XCT/GSH/GPX4) system and ferritin heavy chain-1 (FTH-1) expression, while reducing iron and Transferrin receptor protein 1 (TFR1) levels. Such effects were largely negated by NE-100 pretreatment. In conclusion, BER shows protective effects on cardiac dysfunction induced by the PTZ kindling model by acting as an S1R agonist and influencing the AKT/eNOS signaling pathway and ferroptosis. ROS; reactive oxygen species; S1R; Sigma1 receptor; NO; Nitric oxide; BNP; B-type natriuretic peptide; P53; Tumor suppressor protein; AKT; Serine/threonine protein kinase; TGF-β; Transforming growth factor-β; αSMA; Alpha smooth muscle actin; FTH1; Ferritin heavy chain 1; XCT; cystine-glutamate antiporter; MMP9; Matrix metalloproteinase9; GPX4; Glutathione peroxidase 4; GSH; Glutathione; eNOS; endothelial nitric oxide synthase; HO-1; heme oxygenase-1TFR1; transferrin receptor-1. [Display omitted] •Berberine acts as a sigma-1 receptor agonist.•Berberine treats epilepsy and arrhythmias by reducing ferroptosis.•Berberine induces AKT/eNOS signaling, which causes its cardioprotective effects.