title: Protective Role of Quercetin in Cadmium-Induced Cholinergic Dysfunctions in Rat Brain by Modulating Mitochondrial Integrity and MAP Kinase Signaling.
abstract: 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.
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.|School of Pharmacy, Babu Banarsi Das University, Faizabad Road, Lucknow, 226 028, UP, India.
authors.forename: Richa
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Shukla
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.
authors.forename: Lalit P
authors.initials: LP
authors.lastname: Chandravanshi
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.
authors.forename: Pranay
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.
authors.forename: Yogesh K
authors.initials: YK
authors.lastname: Dhuriya
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.
authors.forename: Jai
authors.initials: J
authors.lastname: Shanker
authors.affiliation: School of Pharmacy, Babu Banarsi Das University, Faizabad Road, Lucknow, 226 028, UP, India.
authors.forename: Manjul P
authors.initials: MP
authors.lastname: Singh
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India.
authors.forename: Aditya B
authors.initials: AB
authors.lastname: Pant
authors.affiliation: Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226 001, UP, India. vkkhanna1@gmail.com.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Khanna
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology* / Q000648:ultrastructure; D002104:Cadmium / Q000633:toxicity*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology / Q000648:ultrastructure; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D064546:Protein Kinase C beta / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011976:Receptors, Muscarinic; D002104:Cadmium; D045304:Cytochromes c; D011794:Quercetin; D002795:Choline O-Acetyltransferase; D064546:Protein Kinase C beta; D000110:Acetylcholinesterase
keywords: Cadmium; MAP kinase signaling; Neuroprotection; Quercetin; Rat brain