Role of Nrf2/ARE Signalling in Cadmium induced Alterations inNMDA ReceptorMediatedPostsynaptic Signalling inRat Hippocampus: Attenuation by Quercetin

Abstract Exposure tocadmium, a heavy metal distributed in the environment is a cause of concerndue to associated health effects in population world over. Continuing with the leadsdemonstrating alterations in brain cholinergic signalling in cadmium induced cognitive deficits;the study is focussed to understand involvement of N-Methyl-D-aspartate receptor (NMDA-R) and its post-synaptic signalling and Nrf2-ARE pathway in hippocampus. Also, the protective potential of quercetin, a polyphenolicbioflavonoid, was assessed in cadmium induced alterations. Cadmium treatment (5 mg/kg, body weight, p.o., 28 days)decreased mRNA expression and protein levels of NMDA receptor subunits (NR1, NR2A) in rat hippocampus, compared to controls. These rats also exhibited decrease in levels of NMDA-Rassociated downstream signalling proteins (CaMKIIα, PSD-95, TrkB, BDNF, PI3K, AKT, Erk1/2, GSK3β, and CREB) and increase in levels of SynGap, a negative regulator of Ras-MAPK in hippocampus. Alterations in protein levels of selected targets associated with AREsignalling (Nrf2, HO-1 and Keap1) and degeneration of pyramidal neurons were also evident in hippocampus of cadmium treated rats.Simultaneous treatment with quercetin (25 mg/kg body weight p.o., 28 days) was found to attenuate cadmium induced changes in hippocampus. No significantchange in any targetwas observed in hippocampus of ratstreated with quercetin alone.The results suggest that impairment in ARE signalling on exposure to cadmium may disrupt NMDA-R and its post-synaptic signaling in hippocampus and contribute in cadmium induced cognitive deficits in rats. Further, quercetin has the potential to protect cadmium induced changes in hippocampus possibly by modulating ARE signalling.