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.

Quercetin Declines Apoptosis, Ameliorates Mitochondrial Function and Improves Retinal Ganglion Cell Survival and Function in In Vivo Model of Glaucoma in Rat and Retinal Ganglion Cell Culture In Vitro

“…∆Ψm is a valuable indicator of mitochondrial functional status in living cells, and the lipophilic cation JC-1, a sensitive and non-invasive specific probe, is currently the gold standard for rapidly measuring ∆Ψm (Brooks et al, 2013 ). In this study, we found that Qcn treatment effectively recovered the ∆Ψm of RGC under hypoxia, indicating that Qcn has a protective role on mitochondrial function, which has been verified in several other types of cells and tissues, such as pancreatic β-cells (Carrasco-Pozo et al, 2016 ), the frontal cortex, hippocampus (Nichols et al, 2015 ; Gupta et al, 2017 ), mouse livers (Yu et al, 2016 ) and others. Mitochondria are the major sites of ROS production under physiologic conditions, and ROS generation is associated with mitochondrial dysfunction (Tezel, 2006 ).…”

Neuroprotective Polyphenols: A Modulatory Action on Neurotransmitter Pathways

“…In Aβ-treated neurons, EGCG increased cell viability, reduced number of apoptotic cells and decreased reactive oxygen species (ROS) generation [ 24 ]. The reduction in nAChR–mAChR receptors and expression of mRNA for the cholinergic receptor (M1, M2 and M4) was detected in the frontal cortex and hippocampus of rats exposed to cadmium, which is known to induce cognitive deficits associated with the cholinergic system [ 25 ].…”

“…action of quercetin is based on its antioxidative properties [ 25 ]. In clinical studies, quercetin prevented the inactivation of nAChR and mAChR receptors in AD brain tissue [ 26 ].…”

The In Vitro Anti-Proliferative Interaction of Flavonoid Quercetin and Toxic Metal Cadmium in the 1321N1 Human Astrocytoma Cell Line

“…Data have also been published regarding QE having a protective effect against Cd-induced alterations in brain cholinergic signaling and neurotoxicity in rats [28] and regarding the ability of QE to reverse the Cd-related cognitive impairment effect in female mice that were exposed to Cd during their lactating period [29]. QE protects experimental animals from memory impairment and from anxiogenic behavior induced by Cd by preventing alterations in the activities of enzymes present in rats' cerebral cortex, hippocampus, and hypothalamus [30][31][32].…”