Olanzapine-induced endoplasmic reticulum stress and inflammation in the hypothalamus were inhibited by an ER stress inhibitor 4-phenylbutyrate.

08:00 EDT 21st March 2019 | BioPortfolio

Summary of "Olanzapine-induced endoplasmic reticulum stress and inflammation in the hypothalamus were inhibited by an ER stress inhibitor 4-phenylbutyrate."

Antipsychotics are the most important treatment for schizophrenia. However, antipsychotics, particularly olanzapine and clozapine, are associated with severe weight gain/obesity side-effects. Although numerous studies have been carried out to identify the exact mechanisms of antipsychotic-induced weight gain, it is still important to consider other pathways. Endoplasmic reticulum (ER) stress signaling and its associated inflammation pathway is one of the most important pathways involved in regulation of energy balance. In the present study, we examined the role of hypothalamic protein kinase R like endoplasmic reticulum kinase- eukaryotic initiation factor 2α (PERK-eIF2α) signaling and the inflammatory IkappaB kinase β- nuclear factor kappa B (IKKβ-NFκB) signaling pathway in olanzapine-induced weight gain in female rats. In this study, we found that olanzapine significantly activated PERK-eIF2α and IKKβ-NFκB signaling in SH-SY5Y cells in a dose-dependent manner. Olanzapine treatment for 8 days in rats was associated with activated PERK-eIF2α signaling and IKKβ-NFκB signaling in the hypothalamus, accompanied by increased food intake and weight gain. Co-treatment with an ER stress inhibitor, 4-phenylbutyrate (4-PBA), decreased olanzapine-induced food intake and weight gain in a dose- and time-dependent manner. Moreover, 4-PBA dose-dependently inhibited olanzapine-induced activated PERK-eIF2α and IKKβ-NFκB signaling in the hypothalamus. These results suggested that hypothalamic ER stress may play an important role in antipsychotic-induced weight gain.


Journal Details

This article was published in the following journal.

Name: Psychoneuroendocrinology
ISSN: 1873-3360
Pages: 286-299


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A system of cisternae in the CYTOPLASM of many cells. In places the endoplasmic reticulum is continuous with the plasma membrane (CELL MEMBRANE) or outer membrane of the nuclear envelope. If the outer surfaces of the endoplasmic reticulum membranes are coated with ribosomes, the endoplasmic reticulum is said to be rough-surfaced (ENDOPLASMIC RETICULUM, ROUGH); otherwise it is said to be smooth-surfaced (ENDOPLASMIC RETICULUM, SMOOTH). (King & Stansfield, A Dictionary of Genetics, 4th ed)

Various physiological or molecular disturbances that impair ENDOPLASMIC RETICULUM function. It triggers many responses, including UNFOLDED PROTEIN RESPONSE, which may lead to APOPTOSIS; and AUTOPHAGY.

A type of endoplasmic reticulum lacking associated ribosomes on the membrane surface. It exhibits a wide range of specialized metabolic functions including supplying enzymes for steroid synthesis, detoxification, and glycogen breakdown. In muscle cells, smooth endoplasmic reticulum is called SARCOPLASMIC RETICULUM.

One of the BASIC-LEUCINE ZIPPER TRANSCRIPTION FACTORS that is synthesized as a membrane-bound protein in the ENDOPLASMIC RETICULUM. In response to endoplasmic reticulum stress it translocates to the GOLGI APPARATUS. It is activated by PROTEASES and then moves to the CELL NUCLEUS to regulate GENETIC TRANSCRIPTION of GENES involved in the unfolded protein response.

Subcellular structures found in nerve cell bodies and DENDRITES. They consist of granular endoplasmic reticulum (ENDOPLASMIC RETICULUM, ROUGH) and RIBOSOMES.

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