Early Neurotoxic Effects of Inorganic Arsenic Modulate Cortical GSH Levels Associated With the Activation of the Nrf2 and NFκB Pathways, Expression of Amino Acid Transporters and NMDA Receptors and the Production of Hydrogen Sulfide

Abstract

Exposure to toxic metals and metalloids is an important cause of preventable diseases worldwide. Inorganic arsenic (iAs) affects several organs and tissues, causing neurobehavioral alterations in the central nervous system (CNS) that might lead to neurodegeneration. In this work, we wanted to explore the time-and dose-related changes on glutathione (GSH) levels in several regions of the CNS, such as the cortex, striatum, hippocampus, and cerebellum, to identify the initial cellular changes associated to GSH depletion due to iAs exposure. Mice received a single intraperitoneal injection containing 5 or 14 mg/kg sodium arsenite. Animals were killed at 2, 6, and 24 h. Significant depletion of GSH levels was observed in the cortex at 2 and 6 h, while on the striatum, hippocampus, or cerebellum regions, no significant changes were observed. GSH depletion in the cortex was associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NFκB) pathways, which led to the upregulation of xCT, excitatory amino acid carrier 1 (EAAC1), glutamate/aspartate transporter (GLAST), and glial glutamate transporter 1 (GLT-1), and the activation of the transsulfuration pathways, which led to the overproduction of H 2 S in the cortex and increased levels of GSH in the cortex and cerebellum at 24 h. In the cortex, the N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B were also altered at 24 h. These early effects were not homogeneous among different brain regions and indicate early neurotoxic alterations in the cortex and cerebellum.

Ursodeoxycholic Acid Protects Against Arsenic Induced Hepatotoxicity by the Nrf2 Signaling Pathway

“…Oxidative stress is currently the most widely accepted and studied mechanism of arsenic toxicity (Flora, 2011;Sharma et al, 2017;Okereafor et al, 2020). The abnormal increase of hepatocytes apoptosis is one of the important pathological mechanisms of arsenic-induced hepatotoxicity.…”

“…GSH is one of the effective antioxidants in cells (Silva-Adaya et al, 2020). As(III) also has a strongly binding ability of vicinal thiols or biological ligands containing cysteine residues in vitro and in vivo, while the elimination of ROS needs substances containing sulfur groups.…”

“…As(III) exposure stimulated excessive ROS generation, which seems to play a critical role in promotion the activity of p53 pathway (Sena and Chandel, 2012;Alamolhodaei et al, 2015). p53 is a tumor suppressor protein that promotes the apoptotic process (Jiang and Rusling, 2019;Silva-Adaya et al, 2020) and directly regulate the activity of the pro-apoptotic protein Bax, which further facilitates mitochondrial membrane permeabilization and apoptosis, A B FIGURE 9 | Schematic presentation probable protective mechanism of Ursodeoxycholic acid (UDCA) against As(III)-mediated hepatic injury by activating the Nrf2 pathway. (A) Protein-protein interaction (PPI) network between Nrf2-mediated oxidative stress pathway related proteins (SOD1, CAT, Gpx, HO-1, NQO-1, Keap1, Nrf2) and p53 mediated apoptosis pathway related proteins (Caspase-3, 9, Bax, Bcl-2, p53, CYCS) by STRING.…”

“…As(III) exposure stimulated excessive ROS generation, which seems to play a critical role in promotion the activity of p53 pathway ( Sena and Chandel, 2012 ; Alamolhodaei et al., 2015 ). p53 is a tumor suppressor protein that promotes the apoptotic process ( Jiang and Rusling, 2019 ; Silva-Adaya et al., 2020 ) and directly regulate the activity of the pro-apoptotic protein Bax, which further facilitates mitochondrial membrane permeabilization and apoptosis, especially the expression of several members of the Bcl-2 family ( Binju et al., 2019 ). The nuclear fraction of Nrf2 is able to bind to the Bcl-2 promoter and activate an anti-apoptotic program ( Gupta et al., 2019 ).…”

“…Arsenic compounds are common toxic materials which exposure is associated with numerous disease regime including diabetes mellitus, neurological disorders, and various forms of cancer cardiovascular and peripheral vascular diseases, (Flora, 2011;Sharma et al, 2017;Okereafor et al, 2020). In ancient times, the arsenic compounds were used to treat diseases.…”