Differential alterations in the expression of AMPA receptor and its trafficking proteins in the hippocampus is associated with recognition memory impairment the rotenone-Parkinson's disease mouse model: neuroprotective role of Bacopa monneiri extract CDRI 08

Abstract

Abstract Parkinson's disease (PD), one of the age-associated neurodegenerative disorders, is associated with motor abnormalities. In addition, the PD leads to gradual deterioration of cognitive decline with advancing age. Apart from the hallmark accumulation of α-Synuclein (α-Syn) in the substantia nigra pars compacta (SNPc) dopaminergic neurons leading to their loss, the precise molecular basis of the PD-induced cognitive decline and the therapeutic intervention is not yet understood. In the current study, our Western blotting and qRT-PCR data from the rotenone-induced PD mouse model reveal that the PD-induced recognition memory loss is associated with significant upregulation of the GluR1 subunit and downregulation of Glur2 subunit of the AMPA receptor in the hippocampus of rotenone-treated mice as compared to the vehicle control mice. Our data also reveal that its trafficking proteins are significantly upregulated in hippocampus (DG, CA3, and CA1 regions) of PD mice compared to the vehicle control. Bacopa monnieri extract (BME) called CDRI-08 at the dose of 200mg/Kg BW has shown its abilities to reverse the expression of AMPA receptor subunit and its trafficking protein in differential manner depending on whether the BME treatment was given prior to or after the rotenone treatment to mice. Our data clearly suggest that the pre treatment given to mice reverses the expression of the memory associated genes compared to the treatment after rotenone administration. Our study further suggests that the above changes in the gene expression in PD affected hippocampus are associated with modulation of their transcriptional machinery by BDNF and CREB. Expression of both are significantly lowered in the hippocampus the rotenone-treated mice in comparison to their levels in the control mice. The mice treated first with CDRI-08 significantly upregulated their expression compared to rotenone-treated mice, and when compared with mice treated after the rotenone treatment. Our results provide the evidence for the underlying molecular basis of cognitive decline in PD in rotenone-PD model and the possible mechanisms for the neuroprotective role of Bacopa monnieri extract CDRI-08 which shows its therapeutic potential for the PD-induced cognitive impairment.