Alleviating effect of antioxidants on combined chromium and cadmium-induced neurotoxicity and apoptosis by activating the Nrf2-keap1 and associated pathway in Swiss albino mice.

Abstract

Chromium (Cr) and cadmium (Cd) are well-known cytotoxic and carcinogenic elements co-existing in the biosphere. Though their separate toxicities have been well researched, little is known about their combined effects, particularly with regard to the cellular stress response. The current study intends to explore the individual and combined toxic effects of Cr and Cd in the brain of Swiss albino mice in addition to examining the possible neuroprotective functions of coenzyme Q10 (CoQ10), biochanin-A (BCA), and phloretin (PHL), the naturally occurring flavonoids with antioxidant qualities. Mice were administered orally with Cr and Cd (75 ppm each) along with the i.p. dose of CoQ10 (10 mg/kg), BCA, and PHL (50 mg/kg each), respectively. After two weeks of treatment, an array of biochemical assays, histopathological examination, and gene expression analyses were carried out to evaluate the underlying mechanisms of the selected nutraceuticals. Our findings, which underscore the importance of this research, demonstrated that the administration of the nutraceuticals reduced oxidative stress and restored the antioxidant defense system by decreasing the levels of malondialdehyde (MDA) and protein carbonyl content (PCC) with concomitant increase in superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), and total thiol (TT) activity. A decrease in cholinesterase activity was also observed, along with the altered histo-architecture. The qRT-PCR analysis of mRNA expression revealed the upregulation of genes associated with antioxidant defense (SIRT1, Nrf2, HO-1, NQO1) along with the downregulation of the apoptotic markers caspase-8 and 3, respectively. The study highlights the neuroprotective effects of CoQ10, BCA, and PHL against Cr and Cd-induced oxidative stress via enhancing Nrf2-mediated exogenous antioxidant defenses and mitigating cellular damage and neural apoptosis. These results imply that these nutraceuticals may have therapeutic value in alleviating neurological disorders brought on by heavy metal exposure, with potential significant impact on future treatments.