Daidzein Attenuates Cadmium‐Induced Neurotoxicity via Inhibiting Apoptosis and Mitophagy in the Cerebral Cortex of Sprague–Dawley Rats

ABSTRACT Cadmium (Cd), a prevalent environmental pollutant, is of significant concern owing to its neurotoxicity; thus, the identification of effective interventions for nerve injury caused by Cd is crucial. Mitochondrial signaling pathway‐mediated apoptosis and PTEN‐induced putative kinase protein 1 (PINK1)/E3 ubiquitin ligase (Parkin)‐mediated mitophagy are the primary mechanisms responsible for the neurotoxic effects of Cd. Daidzein (Dz), a naturally occurring isoflavone found in leguminous plants, exhibits a wide range of pharmacological effects in the brain. To investigate the short‐term protective effects of Dz against Cd‐induced neurotoxicity in the rat cerebral cortex, 24 male Sprague–Dawley rats were treated with Dz (100 mg/kg) and/or CdCl 2 (2 mg/kg) for 12 days. Histological changes in the cerebral cortex were assessed by Nissl staining. Apoptosis‐ and mitophagy‐related indices were detected using TUNEL staining, western blotting, and immunofluorescence assays. The administration of Dz attenuated Cd‐induced nerve injury. Additionally, Dz reduced cell apoptosis by 66%, and the expression of apoptosis‐related proteins Bax/Bcl‐2 ratio by 27%, cleaved caspase‐9 by 42%, and cleaved caspase‐3 by 42%. Dz also decreased the expression of the mitophagy‐related proteins LC3 by 35%, PINK1 by 37%, and Parkin by 29%, and increased that of COX IV by 36%. Furthermore, Dz abolished the Cd‐induced colocalization of PINK1 and Parkin in the cerebral cortex of rats. In summary, our results indicate that Dz exerts neuroprotective effects in the cerebral cortex of rats by inhibiting mitochondrial signaling pathway‐mediated apoptosis and PINK1/Parkin‐mediated mitophagy. Therefore, Dz is a promising novel neuroprotective agent. However, some challenges remain, such as efficacy, bioavailability, and potential side effects. Further studies are needed to assess its potential as a therapeutic agent for Cd‐induced neurotoxicity in humans.