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Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.

ABSTRACT: The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both in vitro and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the protein expression of astrocyte markers including glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B), and activated TLR4 signaling in vitro. In rats, 8- and 36-day olanzapine treatment caused weight gain accompanied by increased GFAP and S100B protein expression and activated TLR4 signaling in the hypothalamus. These effects still existed in pair-fed rats, suggesting that these effects were not secondary effects of olanzapine-induced hyperphagia. Moreover, treatment with an endoplasmic reticulum (ER) stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic GFAP, S100B, and TLR4 signaling. The expression of GFAP, S100B, and TLR4 correlated with food intake and weight gain. These findings suggested that olanzapine-induced increase in hypothalamic astrocytes and activation of TLR4 signaling were related to ER stress, and these effects may be related to olanzapine-induced obesity.

SUBMITTER: He M

PROVIDER: S-EPMC7874166 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.

He Meng M Qian Kun K Zhang Ying Y Huang Xu-Feng XF Deng Chao C Zhang Baohua B Gao Guanbin G Li Jing J Xie Hao H Sun Taolei T

Frontiers in neuroscience 20210113

The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both <i>in vitro</i> and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the ...[more]

PMID: 33584172

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Project description:Ginkgolide B (GB), the diterpenoid lactone compound isolated from the extracts of Ginkgo biloba leaves, significantly improves cognitive impairment, but its potential pharmacological effect on astrocytes induced by β‑amyloid (Aβ)1‑42 remains to be elucidated. The present study aimed to investigate the protective effect and mechanism of GB on astrocytes with Aβ1‑42‑induced apoptosis in Alzheimer's disease (AD). Astrocytes obtained from Sprague Dawley rats were randomly divided into control, Aβ, GB and GB + compound C groups. Cell viability and apoptosis were analyzed using Cell Counting Kit‑8 and flow cytometry assays, respectively. Protein and mRNA expression levels were analyzed using western blotting and reverse transcription‑quantitative PCR, respectively. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH‑Px), reactive oxygen species (ROS) and ATP were determined using the corresponding commercial kits. The findings revealed that GB attenuated Aβ1‑42‑induced apoptosis and the 5' adenosine monophosphate‑ activated protein kinase (AMPK) inhibitor compound C reversed the protective effects of GB. In addition, GB reversed Aβ1‑42‑induced oxidative damage and energy metabolism disorders, including decreases in the levels of SOD, GSH‑Px and ATP and increased the levels of MDA and ROS in astrocytes, while compound C reversed the anti‑oxidative effect and the involvement of GB in maintaining energy metabolism in astrocytes. Finally, GB decreased the expression levels of the endoplasmic reticulum stress (ERS) proteins and the apoptotic protein CHOP and increased both mRNA and protein expression of the components of the energy metabolism‑related AMPK/peroxisome proliferator‑activated receptor γ coactivator 1α/peroxisome proliferator‑activated receptor α and anti‑oxidation‑related nuclear respiratory factor 2/heme oxygenase 1/NAD(P)H dehydrogenase (quinone 1) pathways and downregulated the expression of β‑secretase 1. However, compound C could antagonize these effects. In conclusion, the findings demonstrated that GB protected against Aβ1‑42‑induced apoptosis by inhibiting ERS, oxidative stress, energy metabolism disorders and Aβ1‑42 production probably by activating AMPK signaling pathways. The findings provided an innovative insight into the treatment using GB as a therapeutic in Aβ1‑42‑related AD.

Dataset Information

Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.

Publications

Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.

Similar Datasets

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