Involvement of the Nrf2-Keap1 signaling pathway in protection against thallium-induced oxidative stress and mitochondrial dysfunction in primary hippocampal neurons.

Author(s) Lin, G.; Sun, Y.; Long, J.; Sui, X.; Yang, J.; Wang, Q.; Wang, S.; He, H.; Luo, Y.; Qiu, Z.; Wang, Y.
Journal Toxicol Lett
Date Published 2020 Feb 01

Thallium ion (Tl) and its neurotoxic products are widely known to cause severe neurological complications. However, the exact mechanism of action remains unknown, with limited therapeutic options available. This study aims to examine the toxic effects of Thallium (I) Nitrate (TlNO) on primary hippocampal neurons of E17-E18 Wistar rat embryos, and the potential neuroprotective role of Nrf2- Keap1 signaling pathway against thallium-induced oxidative stress and mitochondrial dysfunction. TlNO induces a significant increase in reactive oxygen species levels and mitochondrial dysfunction in primary hippocampal neurons. Furthermore, the Nrf2-Keap1 signaling pathway played a protective role against TlNO-induced hippocampal neuronal cytotoxicity. Moreover, mitochondrial fusion protein Mitofusin 2 (Mfn2) levels significantly decreased in hippocampal neurons when exposed to TlNO, indicating that Mfn2 protein levels are linked to TlNO-induced neurotoxicity. t-BHQ, a Nrf2 and phase II detoxification enzyme inducer, counteracted the oxidative damage in hippocampal neurons by activating the Nrf2-Keap1 signaling pathway after TlNO exposure; the activated Nrf2-Keap1 pathway could then maintain Mfn2 function by regulating Mfn2 protein expression. Thus, Nrf2-Keap1 pathway activation plays a protective role in Tl-induced brain damage, and specific agonists have been identified to have great potential for treating thallium poisoning.

DOI 10.1016/j.toxlet.2019.11.008
Keywords Animals; Brain Diseases; Female; Hippocampus; Kelch-Like ECH-Associated Protein 1; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Primary Cell Culture; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction; Thallium
ISSN 1879-3169
Citation Toxicol Lett. 2020;319:6673.