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.
Over the last decade, there has been an increased concern about the health risks from exposure to arsenic at low doses, because of their neurotoxic effects on the developing brain. The exact mechanism underlying arsenic-induced neurotoxicity during sensitive periods of brain development remains unclear, although enhanced oxidative stresses, leading to mitochondrial dysfunctions might be involved. Here, we highlight the generation of reactive oxygen species (ROS) and oxidative stress which leads to mitochondrial dysfunctions and apoptosis in arsenic-induced developmental neurotoxicity. Here, the administration of sodium arsenite at doses of 2 or 4 mg/kg body weight in female rats from gestational to lactational (GD6-PD21) resulted to increased ROS, led to oxidative stress, and increased the apoptosis in the frontal cortex, hippocampus, and corpus striatum of developing rats on PD22, compared to controls. Enhanced levels of ROS were associated with decreased mitochondrial membrane potential and the activity of mitochondrial complexes, and hampered antioxidant levels. Further, neuronal apoptosis, as measured by changes in the expression of pro-apoptotic (Bax, Caspase-3), anti-apoptotic (Bcl2), and stress marker proteins (p-p38, pJNK) in arsenic-exposed rats, was discussed. The severities of changes were found to more persist in the corpus striatum than in other brain regions of arsenic-exposed rats even after the withdrawal of exposure on PD45 as compared to controls. Therefore, our results indicate that perinatal arsenic exposure leads to abrupt changes in ROS, oxidative stress, and mitochondrial functions and that apoptotic factor in different brain regions of rats might contribute to this arsenic-induced developmental neurotoxicity.
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