Potential of Quercetin to Protect Cadmium Induced Cognitive Deficits in Rats by Modulating NMDA-R Mediated Downstream Signaling and PI3K/AKT-Nrf2/ARE Signaling Pathways in Hippocampus.

Exposure to cadmium, a heavy metal distributed in the environment is a cause of concern due to associated health effects in population around the world. Continuing with the leads demonstrating alterations in brain cholinergic signalling in cadmium induced cognitive deficits by us; the study is focussed to understand involvement of N-Methyl-D-aspartate receptor (NMDA-R) and its postsynaptic signalling and Nrf2-ARE pathways in hippocampus. Also, the protective potential of quercetin, a polyphenolic bioflavonoid, 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. Cadmium treated rats also exhibited decrease in levels of NMDA-R associated downstream signalling proteins (CaMKIIα, PSD-95, TrkB, BDNF, PI3K, AKT, Erk1/2, GSK3ß, and CREB) and increase in levels of SynGap in hippocampus. Further, decrease in protein levels of Nrf2 and HO1 associated with increase in levels of Keap1 exhibits alterations in Nrf2/ARE signalling in hippocampus of cadmium treated rats. Degeneration of pyramidal neurons in hippocampus was also evident on cadmium treatment. Simultaneous treatment with quercetin (25 mg/kg body weight p.o., 28 days) was found to attenuate cadmium induced changes in hippocampus. The results provide novel evidence that cadmium exposure may disrupt integrity of NMDA receptors and its downstream signaling targets by affecting the Nrf2/ARE signaling pathway in hippocampus and these could contribute in cognitive deficits. It is further interesting that quercetin has the potential to protect cadmium induced changes by modulating Nrf2/ARE signaling which was effective to control NMDA-R and PI3K/AKT cell signaling pathways.

Lambda-cyhalothrin enhances inflammation in nigrostriatal region in rats: Regulatory role of NF-κß and JAK-STAT signaling.

The risk to develop neurobehavioural abnormalities in humans on exposure to lambda-cyhalothrin (LCT) - a type II synthetic pyrethroid has enhanced significantly due to its extensive uses in agriculture, homes, veterinary practices and public health programs. Earlier, we found that the brain dopaminergic system is vulnerable to LCT and affects motor functions in rats. In continuation to this, the present study is focused to unravel the role of neuroinflammation in LCT-induced neurotoxicity in substantia nigra and corpus striatum in rats. Increase in the mRNA expression of proinflammatory cytokines (TNF- α, IL-1ß, IL-6) and iNOS whereas decrease in anti-inflammatory cytokine (IL-10) was distinct both in substantia nigra and corpus striatum of rats treated with LCT (0.5, 1.0, 3.0 mg/kg body weight, p.o, for 45 days) as compared to control rats. Further, LCT-treated rats exhibited increased levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the glial marker proteins both in substantia nigra and corpus striatum as compared to controls. Exposure of rats to LCT also caused alterations in the levels of heat shock protein 60 (HSP60) and mRNA expression of toll-like receptors (TLR2 and TLR4) in the substantia nigra and corpus striatum. An increase in the phosphorylation of key proteins involved in NF-kß (P65, Iκß, IKKα, IKKß) and JAK/STAT (STAT1, STAT3) signaling and alteration in the protein levels of JAK1 and JAK2 was prominent in LCT-treated rats. Histological studies revealed damage of dopaminergic neurons and reactive gliosis as evidenced by the presence of darkly stained pyknotic neurons and decrease in Nissl substance and an increase in infiltration of immune cells both in substantia nigra and corpus striatum of LCT-treated rats. Presence of reactive microglia and astrocytes in LCT-treated rats was also distinct in ultrastructural studies. The results exhibit that LCT may damage dopaminergic neurons in the substantia nigra and corpus striatum by inducing inflammation as a result of stimulation of neuroglial cells involving activation of NF-κß and JAK/STAT signaling.