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Ethnopharmacological Relevance: Antipsychotics often induce hyperprolactinemia. The transforming growth factor (TGF)-beta1 signaling in the pituitary and hypothalamus inhibits prolactin synthesis and secretion, and its impairment is implicated in neuropsychiatric disorders. Longdan Xiegan Tang (LXT) alone or together with antipsychotics have been used to treat various neuropsychiatric diseases and hyperprolactinemia-associated disorders., Aim of the Study: To investigate the effect of LXT on hyperprolactinemia and involvement of the TGF-beta1 signaling., Materials and Methods: Male rats were co-administered with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) (p.o., × 8 weeks). Plasma concentrations of prolactin and TGF-beta1 were determined by ELISA. Protein expression was analyzed by Western blot., Results: Treatment of rats with LXT extract suppressed olanzapine-induced increase in plasma prolactin concentration and overexpression of pituitary and hypothalamic prolactin protein. Importantly, LXT restored olanzapine-induced decrease in protein expression of the key components of the TGF-beta1 signaling, TGF-beta1, type II TGF-beta receptor, type I TGF-beta receptor and phosphorylated SMAD3 in the pituitary and hypothalamus. Further, it antagonized downregulation of pituitary and hypothalamic dopamine D2 receptor (D2R) protein level, and inhibited pituitary estrogen receptor (ER) alpha and ERbeta protein expression., Conclusions: The present results suggest that LXT ameliorates antipsychotic-induced hyperprolactinemia in rats by repairing the pituitary and hypothalamic TGF-beta1 signaling possibly via D2R, ERs or/and other pathways. Our findings may also provide scientific elucidation for use of the ancient Chinese formula to treat the impaired TGF-beta1 signaling-associated neuropsychiatric disorders., Competing Interests: Declaration of competing interest The authors declare that there is no duality of interest associated with this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The modified Longdan Xiegan Tang (mLXT) has been used clinically for various neuropsychiatric disorders and liver diseases. The use of antipsychotics is associated with nonalcoholic fatty liver disease., Aim of the Study: To investigate the effect and underlying mechanisms of mLXT on antipsychotic-induced fatty liver., Materials and Methods: The representative active components in the formula were identified and quantified by a HPLC method. Fatty liver in male rats was induced by olanzapine (5 mg/kg) (p.o., × 8 weeks), and the rats were co-treated with mLXT extract (50 and 500 mg/kg). Blood and liver variables were determined enzymatically or histologically. Gene/protein expression was analyzed by real-time PCR and Western blot., Results: Treatment of rats with mLXT decreased olanzapine-induced increases in hepatic triglyceride content, cell vacuolar degeneration and Oil Red O-stained area, accompanied by suppression of olanzapine-stimulated hepatic mRNA and/or protein overexpression of sterol regulatory element-binding protein (SREBP)-1c, and its downstream lipogenic enzymes for de novo lipogenesis. Besides, mLXT also activated hepatic expression of peroxisome proliferator-activated receptor-alpha and its target genes associated with fatty acid beta-oxidation, phosphorylated Thr 172 in AMP-activated protein kinase (AMPK)-alpha (the upstream enzyme of SREBP-1c and PPAR-alpha), and its ratio to total AMPK-alpha., Conclusions: The present results suggest that chronic treatment with mLXT ameliorates olanzapine-induced fatty liver by regulating hepatic de novo lipogenesis- and fatty acid beta-oxidation-associated gene expression mediated by SREBP-1c and PPAR-alpha, respectively, through activation of AMPK-alpha. Our findings provide the evidence that supports clinical use of the formula for antipsychotic medication-induced fatty liver., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Chronic treatment with antipsychotics, especially most of atypical ones, leads to development of metabolic abnormalities. Olanzapine is an atypical antipsychotic widely used in the treatment of schizophrenia and bipolar disorder. The mechanisms underlying olanzapine-induced metabolic adverse effects in the liver, however, remain unclear. This study was designed to investigate olanzapine-induced insulin-desensitivity in the liver., Main Methods: Male rats were treated with olanzapine (5 mg/kg, by a gavage method, once daily for consecutive 8 weeks. Blood and liver variables were determined enzymatically or histologically. Gene/protein expression was analyzed by real-time PCR and Western blot., Key Findings: Olanzapine treatment significantly increased fasting plasma insulin concentration, the index of the homeostasis model assessment of insulin resistance (HOMA-IR), and hepatic triglyceride and fatty droplet accumulation in rats. Hepatic gene/protein expression profile revealed that olanzapine activated mRNA and protein expression of sterol regulatory element-binding protein-1c, and mRNA levels of its downstream lipogenic enzymes, acetyl-CoA carboxylase-1, fatty acid synthase and stearoyl-CoA desaturase-1. More importantly, phosphorylated protein level of both Ser 307 in insulin receptor substrate (IRS)-1 and Ser 731 in IRS-2 was increased. Furthermore, phosphorylation of Tyr 607 in phosphoinositide 3-kinase (PI3K) p85α, Ser 473 in Akt and Ser 2448 in mammalian target of rapamycin was also enhanced., Significance: Our results suggest that the IRS/PI3K/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats. Our findings may provide better understanding of the antipsychotic-induced metabolic adverse effects., (Copyright © 2018. Published by Elsevier Inc.)

Paeoniflorin, a prominent component in some Chinese formulas for hyperprolactinemia-associated disorders, has been found to inhibit prolactin secretion in prolactinoma cells. To examine the efficacy of paeoniflorin on hyperprolactinemia and the underlying mechanisms of action. Hyperprolactinemia in female rats was generated by administration of olanzapine (5 mg/kg, by a gavage method, once daily, × 13 weeks). The rats were co-treated with paeoniflorin (10 and 50 mg/kg). Prolactin and TGF-β1 concentrations were detected by ELISA. Protein expression was determined by Western blot. The effect in MMQ cells was also examined. Paeoniflorin inhibited olanzapine-induced increases in plasma prolactin concentration and prolactin protein overexpression in the pituitary and hypothalamus of rats. Further, paeoniflorin restored olanzapine-induced downregulation of pituitary and hypothalamic dopamine D2 receptor (D2R) protein expression. More importantly, paeoniflorin attenuated olanzapine-suppressed protein expression of transforming growth factor (TGF)-β1 and its downstream genes, type II TGF-β receptor, type I TGF-β receptor and phosphorylated SMAD3 in the tissues. However, paeoniflorin did not affect plasma TGF-β1 concentration and hepatic TGF-β1 protein expression. In accord, olanzapine-induced increase in prolactin concentration, upregulation of prolactin protein expression, and downregulation of protein expression of the D2R and TGF-β1 signals in MMQ cells were attenuated. This study demonstrates that paeoniflorin ameliorates olanzapine-induced hyperprolactinemia in rats by attenuating impairment of the D2R and TGF-β1 signaling pathways in the hypothalamus and pituitary. Our findings may provide evidence to support the use of paeoniflorin-contained Chinese herbs and formulas for hyperprolactinemia and its associated disorders. Image 1 [ABSTRACT FROM AUTHOR]