Involvement of PKA/DARPP-32/PP1α and ß- arrestin/Akt/GSK-3ß Signaling in Cadmium-Induced DA-D2 Receptor-Mediated Motor Dysfunctions: Protective Role of Quercetin.

Given increasing risk of cadmium-induced neurotoxicity, the study was conducted to delineate the molecular mechanisms associated with cadmium-induced motor dysfunctions and identify targets that govern dopaminergic signaling in the brain involving in vivo, in vitro, and in silico approaches. Selective decrease in dopamine (DA)-D2 receptors on cadmium exposure was evident which affected the post-synaptic PKA/DARPP-32/PP1α and ß-arrestin/Akt/GSK-3ß signaling concurrently in rat corpus striatum and PC12 cells. Pharmacological inhibition of PKA and Akt in vitro demonstrates that both pathways are independently modulated by DA-D2 receptors and associated with cadmium-induced motor deficits. Ultrastructural changes in the corpus striatum demonstrated neuronal degeneration and loss of synapse on cadmium exposure. Further, molecular docking provided interesting evidence that decrease in DA-D2 receptors may be due to direct binding of cadmium at the competitive site of dopamine on DA-D2 receptors. Treatment with quercetin resulted in the alleviation of cadmium-induced behavioral and neurochemical alterations. This is the first report demonstrating that cadmium-induced motor deficits are associated with alteration in postsynaptic dopaminergic signaling due to a decrease in DA-D2 receptors in the corpus striatum. The results further demonstrate that quercetin has the potential to alleviate cadmium-induced dopaminergic dysfunctions.

Protective Role of Quercetin in Cadmium-Induced Cholinergic Dysfunctions in Rat Brain by Modulating Mitochondrial Integrity and MAP Kinase Signaling.

With the increasing evidences of cadmium-induced cognitive deficits associated with brain cholinergic dysfunctions, the present study aimed to decipher molecular mechanisms involved in the neuroprotective efficacy of quercetin in rats. A decrease in the binding of cholinergic-muscarinic receptors and mRNA expression of cholinergic receptor genes (M1, M2, and M4) was observed in the frontal cortex and hippocampus on exposure of rats to cadmium (5.0 mg/kg body weight, p.o.) for 28 days compared to controls. Cadmium exposure resulted to decrease mRNA and protein expressions of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) and enhance reactive oxygen species (ROS) generation associated with mitochondrial dysfunctions, ultrastructural changes, and learning deficits. Enhanced apoptosis, as evidenced by alterations in key proteins involved in the pro- and anti-apoptotic pathway and mitogen-activated protein (MAP) kinase signaling, was evident on cadmium exposure. Simultaneous treatment with quercetin (25 mg/kg body weight, p.o.) resulted to protect cadmium-induced alterations in cholinergic-muscarinic receptors, mRNA expression of genes (M1, M2, and M4), and expression of ChAT and AChE. The protective effect on brain cholinergic targets was attributed to the antioxidant potential of quercetin, which reduced ROS generation and protected mitochondrial integrity by modulating proteins involved in apoptosis and MAP kinase signaling. The results exhibit that quercetin may modulate molecular targets involved in brain cholinergic signaling and attenuate cadmium neurotoxicity.

Mediation of partial resistance to rice blast through anaerobic induction of ethylene.

ABSTRACT The correlation between anaerobic soil conditions and increased resistance to rice blast disease has long been observed without benefit of an adequate explanation. We researched flood depth, dissolved oxygen (DO), and ethylene relative to expression of partial blast resistance in cvs. M-201, Newbonnet, LaGrue, Mars, and Cypress. Cultivar blast index (BI) and flood DO decreased with increasing flood depth. BIs were positively correlated with DO. Total leaf blast lesions were 3.4 and 3.2 times greater in cvs. M-201 and LaGrue growing in a 5.0-mul liter(-1) DO nutrient solution than when growing in a 0.1-mul liter(-1) DO solution. Treatment with 0.25 mM ethephon, which releases ethylene, lowered BIs of Newbonnet, LaGrue, and Cypress growing upland when applied drench, foliar, or foliar-drench. If flooded, BIs of ethephon-treated cultivars were decreased by drench and foliar-drench applications only. BIs of upland plants were unchanged, whereas BIs of analogous flooded plants increased following treatment with 0.31 mM aminoethoxyvinylglycine (AVG), an ethylene biosynthesis inhibitor. We hypothesize that varying anaerobic conditions mediate production of phytohormones, particularly ethylene, which modify expression of inherent partial blast resistance in these rice cultivars.