Therapeutic Evaluation of Ellagic Acid against Cadmium Induced Neurotoxicity in Rats

Abstract

Cadmium (Cd) is categorized as the 4th major public health concern by the World Health Organization (WHO) by June 2020 and seventh most harmful substance to human health according to the Agency for Toxic Substances and Disease Registry. In the human body it holds a half-life of over 10-30 years which can lead to different toxicities including neurotoxicity. Many different types of metal toxicities caused by lead, mercury and arsenic had been studies, but no studies had been done against Cd induced metal toxicity and the therapeutic role of Ellagic Acid (EA). This study highlights the role of EA against Cd induced neurotoxicity and evaluate the gene expression levels of Synaptosomal-Associated Protein of 25 kDa (SNAP -25) through mRNA expression analysis in the hippocampus and cortex region of the rat’s brain. Four groups of 24 rats (each group contain 6 rats) were chosen in this study. Low and high dose of EA, 10mg/kg body weight (BW) and 50mg/kg BW respectively was given to the rats for 21 days with the Cd dose of 5mg/kg BW being given to neurotoxin and low and high dose treatment group. Biochemical analysis including Super Oxide Dismutase (SOD), Catalase (CAT) and Glutathione (GPx) were also carried out to measure the antioxidant enzyme activity. Moreover, histopathological analysis was also carried out using Hematoxylin and Eosin (H and E) staining in the hippocampus and cortex region of the brain. Also, pharmacological analysis was done to find the drug target disease network with the help of bioinformatics tools including string and cytoscape. The top target genes were undergone the molecular docking through pyrx and visualized through biovia discovery studio. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also developed which showed that the target genes play a critical role in the pathways of metal induced neurotoxicity. The result of our study highlights that there is a significant decrease in the cell count of the neurotoxin group as compared to the control group and the high dose treatment group showed recovered cell count in cortical layer 2 and 3 as well as Corno Ammonis (CA)1,2,3 and dentate gyrus region of the hippocampus. Additionally, gene expression levels SOD, GPx and CAT levels were also decreased in the neurotoxin group in contrast to the high dose treatment group. Molecular docking also showed greater binding affinities of the EA with the top 4 targeted genes. Altogether, these finding suggest that EA (50mg/kg) can serve as a good therapeutic option against Cd induced neurotoxicity. This study also led to a foundation in developing effective treatment against heavy metal induced neurological disorders.