Glutathione peroxidase‐1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin‐leucine‐arginine

Abstract

Although it has been well-recognized that microcystin-leucine-arginine (MCLR), the most common form of microcystins, induces neurotoxicity, little is currently known about the underlying mechanism for this neurotoxicity. Here, we found that MCLR (10 ng/μL/mouse, i.c.v.) induces significant neuronal loss in the hippocampus of mice. MCLR-induced neurotoxicity was accompanied by oxidative stress, as shown by a significant increase in the level of 4-hydroxynonenal, protein carbonyl, and reactive oxygen species (ROS). Superoxide dismutase-1 (SOD-1) activity was significantly increased, but glutathione peroxidase (GPx) level was significantly decreased following MCLR insult. In addition, MCLR significantly inhibited GSH/GSSG ratio, and significantly induced NFκB DNA binding activity. Because reduced activity of GPx appeared to be critical for the imbalance between activities of SODs and GPx, we utilized GPx-1 overexpressing transgenic mice to ascertain the role of GPx-1 in this neurotoxicity. Genetic overexpression of GPx-1 or NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly attenuated MCLR-induced hippocampal neuronal loss in mice. However, PDTC did not exert any additive effect on neuroprotection mediated by GPx-1 overexpression, indicating that NFκB is a neurotoxic target of MCLR. Combined, these results suggest that MCLR-induced neurotoxicity requires oxidative stress associated with failure in compensatory induction of GPx, possibly through activation of the transcription factor NFκB.

Neurotoxicity induced by microcystins and cylindrospermopsin: A review

“…However, important contributions have been made lately, confirming these mechanisms using mostly in vivo experimental models. In this sense, the studies carried out using different animal models (mice, fish) revealed an important effect on the neurotransmission induced by MC-LR (Wu et al, 2016;Qian et al, 2018;Shin et al, 2018;Wang et al, 2018), together with an enhancement in oxidative stress in mice (Shin et al, 2018;Wang et al, 2018), and cytoskeleton disruption in the case of rats (Zhang et al, 2018) (Fig. B).…”

“…All of the results obtained in this study suggest that memory impairments in mice exposed were due to oxidative stress in spite of by neuroinflammation process, which could be confirmed by the enhancement of nuclear factor erythroid-derived 2 (Nrf2) observed in both exposed groups. In addition, the reduced responses of GPx-1 Tg compared to non-Tg mice suggest a possible prevention of memory impairment by compounds implied in antioxidant activity (Shin et al, 2018).…”

“…Nowadays, several in vivo studies have been carried out focusing on the neurotoxic potential MCs can exert in terrestrial animals (Table 4). Many of them have been performed in nematodes (Li et al, 2009a, b;Ju et al, 2013Ju et al, , 2014Moore et al, 2014;Saul et al, 2014), mice (Shin et al, 2018;Wang et al, 2018) and rats (Li et al, 2012a, b;Wang et al, 2013;Li et al, 2014;Li et al, 2015b;Zhang et al, 2018) using pure MC congeners, mainly MC-LR. This is probably due to the fact that, although a total of 246 variants of MCs have been described so far (Meriluoto et al, 2017), MC-LR has demonstrated to be one of the most toxic structural variants, contributing on 46-99.8% of the total MCs in natural waters (Ufelmann et al, 2012).…”

Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer’s Disease

“…The antioxidant capacity of GPX1 may participate in the regulation of the inflammatory cascade reaction in the brain. Gpx1 −/− astrocytes reduce the H 2 O 2 clearance rate to cause cell death (Liddell et al, 2006;Shin et al, 2018). However, mice with ischemic brain diseases and GPX1 overexpression have significantly fewer overactivated astrocytes and microglia than corresponding mice without GPX1 overexpression (Ishibashi et al, 2002).…”

Effects of Antioxidant Gene Overexpression on Stress Resistance and Malignization In Vitro and In Vivo: A Review

“…The main aim of this review was to systemize and sum up the available studies covering the effects of antioxidant defense gene overexpression on cell resistance to oxidative stress. We analyzed 166 such works [ 20 , 51 , 56 , 58 , 62 , 65 , 66 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ,…”