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

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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.

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Acknowledgments

The study has been carried out as a part of the INDEPTH programme of the Council of Scientific and Industrial Research (CSIR), New Delhi. Richa Gupta and Pranay Srivastava acknowledges the support of CSIR, New Delhi, for providing Research Fellowship. The authors thank the Director, CSIR–Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, for his interest in the present study and providing necessary support. Technical assistance provided by Mr. B.S. Pandey is also acknowledged.

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  1. 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

    Richa Gupta, Rajendra K. Shukla, Lalit P. Chandravanshi, Pranay Srivastava, Yogesh K. Dhuriya, Jai Shanker, Aditya B. Pant & Vinay K. Khanna

  2. School of Pharmacy, Babu Banarsi Das University, Faizabad Road, Lucknow, 226 028, UP, India

    Richa Gupta & Manjul P. Singh

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  1. Richa Gupta
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Correspondence to Vinay K. Khanna.

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Gupta, R., Shukla, R.K., Chandravanshi, L.P. et al. Protective Role of Quercetin in Cadmium-Induced Cholinergic Dysfunctions in Rat Brain by Modulating Mitochondrial Integrity and MAP Kinase Signaling. Mol Neurobiol 54, 4560–4583 (2017). https://doi.org/10.1007/s12035-016-9950-y

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