Neuroscience. 2021 Feb 10;455:212-222. doi: 10.1016/j.neuroscience.2020.10.026. Epub 2020 Nov 13.

Rosiglitazone Prevents Autophagy by Regulating Nrf2-Antioxidant Response Element in a Rat Model of Lithium-pilocarpine-induced Status Epilepticus

Ying Peng  1 Li Chen  2 Youyang Qu  2 Di Wang  2 Yanmei Zhu  2 Yulan Zhu  3 Affiliations

Abstract

Status epilepticus (SE) leads to irreversible neuronal damage and consists of a complex pathogenesis that involves oxidative stress and subsequent autophagy. Rosiglitazone has recently been considered as a potential neuroprotective factor in epilepsy because of its antioxidative function. The aim of this study was to assess the effects of rosiglitazone in SE rat models and investigate whether its mechanisms of action involve autophagy via the antioxidant factor, nuclear factor erythroid 2-related factor 2 (Nrf2). The male Sprague-Dawley rats (200-220 g) were used to establish lithium-pilocarpine-induced SE model. We found that rosiglitazone markedly improved neuronal survival at 24-h post-SE as indicated via Hematoxylin-Eosin and Nissl staining. Furthermore, along with a reduction in reactive oxygen species, rosiglitazone pretreatment enhanced the antioxidative activity of superoxide dismutase and the expression level of Nrf2, as detected via chemical assay kits and Western blotting, respectively. In addition, the microtubule-associated protein light chain 3II (LC3II)/LC3I ratio was increased and peaked at 24 h after SE, whereas p62 mRNA levels were sharply elevated at 72 h after SE, both SE-induced increases of which were reversed via rosiglitazone pretreatment. To further test our hypothesis of the key role of Nrf2 in this process, small-interfering RNA for Nrf2 (siNrf2) was then transfected into SE rats to knockdown Nrf2 expression. We found that siNrf2 partially blocked the above effects of rosiglitazone on autophagy-related proteins in SE rats. Taken together, our findings suggest that rosiglitazone attenuates oxidative-stress-induced autophagy via increasing Nrf2 in SE rats and may be used as a promising therapeutic strategy for SE treatment.

Keywords: P62; microtubule-associated protein light chain 3; nuclear factor erythroid 2-related factor 2; oxidative stress; peroxisome proliferator-activated receptor gamma agonist.

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