Monoisoamyl DMSA reduced copper-induced neurotoxicity by lowering 8-OHdG level, amyloid beta and Tau protein expressions in Sprague-Dawley rats.

Abstract

copper dyshomeostasis has long been linked with several neurodegenerative disorders. The binding of Cu with amyloid beta and other neuronal proteins in the brain leads to the generation of oxidative stress, which eventually causes neurotoxicity. the present study was aimed at elucidating the efficacy of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA) and d-penicillamine (DPA) (0.3 mEq kg-1, oral administration for 2 weeks) against Cu(ii)-induced (20 mg kg-1, oral administration for 16 weeks) neurotoxicity in Sprague-Dawley (SD) rats. we observed that the MiADMSA treatment modulated the altered oxidative and nitrosative stress parameters, antioxidant enzymes, and acetylcholinesterase (AChE) activity. Significant improvements were noticed in the neurobehavioral parameters except for the memory parameter. We also observed moderate improvement of memory impairment in the rats treated with MiADMSA and DPA post Cu(ii) exposure, as assessed by a passive avoidance test. Disease progression involves multiple factors and results in the up-regulation of intra and extracellular proteins such as amyloid beta and tau proteins; the expressions of these proteins were significantly reduced by the treatment proposed in our study, and these results were confirmed by ELISA and qRT-PCR. The expression of caspase-3 was higher in Cu(ii)-exposed rats, whereas it was lower in the MiADMSA-treated group. The proposed treatment reduced the copper-induced histological changes in the cortex and hippocampus regions of the brain. it can be summarised from the present study that MiADMSA is effective in reducing Cu(ii)-induced oxido-nitrosative stress, antioxidant defense enzymes, neurobehavioral changes, neuronal markers, apoptotic markers, and their genetic expressions. We conclude that chelation therapy using MiADMSA might be a promising approach for the treatment of copper-induced neurotoxicity.