RESUMEN
Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.
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Antipsicóticos , Diabetes Mellitus Tipo 2 , Humanos , Ratas , Animales , Olanzapina/farmacología , Olanzapina/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Benzodiazepinas/farmacología , Benzodiazepinas/metabolismo , Antipsicóticos/farmacología , Antipsicóticos/metabolismo , Hipotálamo/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.
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Antipsicóticos , Receptores Opioides mu , Ratas , Femenino , Animales , Olanzapina/farmacología , Olanzapina/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Antipsicóticos/farmacología , Hipotálamo/metabolismo , Receptores Opioides/metabolismo , Conducta Alimentaria , Aumento de Peso , ARN MensajeroRESUMEN
Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.
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Hígado Graso , Transducción de Señal , Masculino , Animales , Ratones , Olanzapina/metabolismo , Transducción de Señal/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Quinasas Activadas por AMP/metabolismo , Hígado/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/genética , Hígado Graso/prevención & control , Ratones Noqueados , Inflamación/metabolismo , Ácido Graso Sintasas/metabolismo , Aumento de Peso , Hipotálamo/metabolismo , Ratones Endogámicos C57BLRESUMEN
Detrimental dietary habits with high-fat food are common in the psychiatric population, leading to higher obesity rate. Olanzapine (OLZ), as one of the mainstream antipsychotic drugs, shows superior efficacy in treating schizophrenia but limited by adverse effects such as obesity, dyslipidemia and liver injury, which are risk factors for the development of nonalcoholic fatty liver disease (NAFLD). Progesterone receptor component 1 (PGRMC1) is a key regulator associated with antipsychotic drug-induced metabolic disorders. Our study aims to investigate whether high-fat supplementation worsens OLZ-induced NAFLD and to validate the potential role of PGRMC1 pathway. In vivo, eight-week OLZ treatment successfully induced hepatic steatosis in female C57BL/6 mice fed with either a high-fat or normal diet, which is independent of body weight gain. Likewise, in vitro, OLZ markedly led to hepatocyte steatosis along with enhanced oxidative stress, which was aggravated by free fatty acids. Moreover, in vivo and in vitro, high-fat supplementation aggravated OLZ-induced hepatic lipid accumulation and oxidative stress via inhibition of hepatic PGRMC1-AMPK-mTORC1/Nrf2 pathways. Inspiringly, PGRMC1 overexpression effectively reversed OLZ-induced hepatocyte steatosis in vitro. Hence, hepatic PGRMC1 is attributable to OLZ-induced NAFLD especially with high-fat supplementation and potentially serves as a novel therapeutic target.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Femenino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Olanzapina/metabolismo , Olanzapina/uso terapéutico , Ratones Endogámicos C57BL , Hígado/metabolismo , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo de los Lípidos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismoRESUMEN
Olanzapine is an antipsychotic agent with species-dependent pharmacokinetic profiles in both humans and animals. In the present study, the metabolic profiles of olanzapine in vitro and in vivo were compared in non-transplanted immunodeficient NOG-TKm30 mice and chimeric mice with humanized livers (hereafter humanized-liver mice). Hepatic microsomal fractions prepared from humanized-liver mice and humans mediated olanzapine N10-glucuronidation, whereas fractions from cynomolgus monkeys, marmosets, minipigs, dogs, rabbits, guinea pigs, rats, CD1 mice, and NOG-TKm30 mice did not. The olanzapine N10-glucuronidation activity in liver microsomes from humanized-liver mice was inhibited by hecogenin, a human UDP-glucuronosyltransferase (UGT) 1A4 inhibitor. In addition, hepatocytes from humanized-liver mice suggest that olanzapine N10-glucuronidation was a major metabolic pathway in the livers of humanized-liver mice. After a single oral dose of olanzapine (10 mg/kg body weight) to humanized-liver mice and control NOG-TKm30 mice, olanzapine N10-glucuronide isomers and olanzapine N4'-glucuronide were detected only in the plasma of humanized-liver mice. In contrast, the area under the curve for N4'-demethylolanzapine, 2-hydroxymethylolanzapine, and 7-hydroxyolanzapine glucuronide was higher in NOG-TKm30 mice than that in humanized-liver mice. The cumulative excreted amounts of olanzapine N10-glucuronide isomers were high in the urine and feces from humanized-liver mice, whereas the cumulative excreted amounts of 2-hydroxymethylolanzapine were higher in NOG-TKm30 mice than in humanized-liver mice. Thus, production of human-specific olanzapine N10-glucuronide was observed in humanized-liver mice, which was consistent with the in vitro glucuronidation data. These results suggest that humanized-liver mice are useful for studying drug oxidation and conjugation of olanzapine in humans. SIGNIFICANCE STATEMENT: Human-specific olanzapine N10-glucuronide isomers were generated in chimeric NOG-TKm30 mice with humanized livers (humanized-liver mice), and high UGT1A4-dependent N10-glucuronidation was observed in the liver microsomes from humanized-liver mice. Hence, humanized-liver mice may be a suitable model for studying UGT1A4-dependent biotransformation of drugs in humans.
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Glucurónidos , Microsomas Hepáticos , Porcinos , Humanos , Ratones , Ratas , Animales , Conejos , Perros , Cobayas , Olanzapina/metabolismo , Glucurónidos/metabolismo , Porcinos Enanos/metabolismo , Microsomas Hepáticos/metabolismo , Glucuronosiltransferasa/metabolismo , UDP Glucuronosiltransferasa 1A9 , Ratones Endogámicos , Hígado/metabolismoRESUMEN
Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.
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Antipsicóticos , Diabetes Mellitus Tipo 2 , Humanos , Antipsicóticos/efectos adversos , Olanzapina/farmacología , Olanzapina/metabolismo , Aripiprazol/farmacología , Aripiprazol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacología , Piperazinas/uso terapéutico , Adipocitos/metabolismoRESUMEN
Olanzapine (OLA) is a common drug used to treat schizophrenia and has recently come under increasing scrutiny as an emerging contaminant. However, its impact on lipid metabolism in fish and its mechanisms of action are not well understood. In this study, common carp were exposed to 0, 10, 100, and 250 µM OLA for 60 days. The results indicated that OLA exposure increased weight gain, total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) and decreased high-density lipoprotein (HDL). In addition, lipids accumulated in the liver of the common carp. To explore the underlying mechanisms of action, gut microbiota, short-chain fatty acids (SCFAs), liver transcripts, and genes related to lipid metabolism were measured. It was discovered that OLA exposure altered the common carp gut microbiota composition and increased the abundance of SCFA-producing bacteria. Correspondingly, this study showed that OLA exposure increased the levels of SCFAs, which are highly relevant to the development of lipid accumulation. Transcriptome sequencing results indicated that OLA exposure could change lipid metabolism signalling pathways, including steroid biosynthesis, the PPAR signalling pathway, asglycerophospholipid metabolism, glycerolipid metabolism, and fatty acid metabolic pathways of the common carp. Additionally, OLA exposure interrupted lipid metabolism by means of significant upregulation of lipid synthesis-related genes, including pparγ, srebp1, and fas. OLA exposure also resulted in significant lipolysis-related gene downregulation, including cpt, lpl, hsl, and pparα. The results of this study indicated that contamination of aquatic environments with OLA alters lipid metabolism in common carp. In addition, the underlying mechanism might be due in part to the modulation of the gut microbiota-SCFA-PPAR signalling pathway.
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Antipsicóticos , Carpas , Microbioma Gastrointestinal , Animales , Carpas/metabolismo , Metabolismo de los Lípidos , Olanzapina/metabolismo , Antipsicóticos/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Ácidos Grasos Volátiles/metabolismo , Hígado/metabolismoRESUMEN
BACKGROUND: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. METHODS: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPKα1 in mice were also analyzed. RESULTS: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i.p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. CONCLUSION: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.
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Proteínas Quinasas Activadas por AMP , Hipotálamo , Masculino , Ratones , Animales , Olanzapina/metabolismo , Olanzapina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Fosforilación , Hipotálamo/metabolismo , Termogénesis/fisiología , Peso Corporal , Metabolismo Energético , Aumento de Peso , Tejido Adiposo Pardo/metabolismoRESUMEN
Hypothalamic detection of elevated circulating glucose triggers suppression of endogenous glucose production (EGP) to maintain glucose homeostasis. Antipsychotics alleviate symptoms associated with schizophrenia but also increase the risk for impaired glucose metabolism. In the current study, we examined whether two acutely administered antipsychotics from different drug classes, haloperidol (first generation antipsychotic) and olanzapine (second generation antipsychotic), affect the ability of intracerebroventricular (ICV) glucose infusion approximating postprandial levels to suppress EGP. The experimental protocol consisted of a pancreatic euglycemic clamp, followed by kinomic and RNA-seq analyses of hypothalamic samples to determine changes in serine/threonine kinase activity and gene expression, respectively. Both antipsychotics inhibited ICV glucose-mediated increases in glucose infusion rate during the clamp, a measure of whole-body glucose metabolism. Similarly, olanzapine and haloperidol blocked central glucose-induced suppression of EGP. ICV glucose stimulated the vascular endothelial growth factor (VEGF) pathway, phosphatidylinositol 3-kinase (PI3K) pathway, and kinases capable of activating KATP channels in the hypothalamus. These effects were inhibited by both antipsychotics. In conclusion, olanzapine and haloperidol impair central glucose sensing. Although results of hypothalamic analyses in our study do not prove causality, they are novel and provide the basis for a multitude of future studies.
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Antipsicóticos , Antipsicóticos/farmacología , Glucosa/metabolismo , Fosfatidilinositol 3-Quinasas , Factor A de Crecimiento Endotelial Vascular , Olanzapina/farmacología , Olanzapina/metabolismo , Benzodiazepinas/farmacologíaRESUMEN
OBJECTIVES: Olanzapine (OZP) is a safe and effective atypical antipsychotic drug used in treating schizophrenia and bipolar disorders. The dosage forms currently on the market for OZP are administered via oral or intramuscular routes. However, there are many problems associated with oral and intramuscular routes of drug administration. Thus, our aim was to develop a drug-in-adhesive transdermal delivery system (TDS) that can deliver OZP for 3 days. METHODS: We determined passive permeation, effect of oleic acid as chemical enhancer, and delivery of OZP across different skin types. Based on preliminary studies and saturation solubility of OZP in different pressure-sensitive adhesives (PSAs), we formulated and characterized solution-based TDS in acrylate PSA and suspension-based TDS in silicone and PIB PSA, with oleic acid as chemical enhancer. RESULTS: Acrylate solution-based TDS, silicone, and PIB suspension-based TDS delivered 58.97 ± 6.59 µg/sq.cm, 129.34 ± 16.59 µg/sq.cm, and 245.00 ± 2.51 µg/sq.cm, respectively, using in vitro permeation testing. PIB PSA suspension-based TDS met the 3 days desired target delivery. Skin irritation testing using In vitro EpiDermTM skin irritation test (EPI-200-SIT) kit found PIB TDS to be nonirritant. CONCLUSION: The PIB PSA suspension-based TDS could serve as a potentially effective transdermal delivery system for olanzapine.
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Adhesivos , Absorción Cutánea , Humanos , Masculino , Acrilatos/metabolismo , Acrilatos/farmacología , Adhesivos/química , Adhesivos/metabolismo , Adhesivos/farmacología , Administración Cutánea , Sistemas de Liberación de Medicamentos , Olanzapina/metabolismo , Olanzapina/farmacología , Ácido Oléico/metabolismo , Ácido Oléico/farmacología , Permeabilidad , Preparaciones Farmacéuticas/metabolismo , Antígeno Prostático Específico/metabolismo , Antígeno Prostático Específico/farmacología , Siliconas/química , Piel/metabolismo , Parche TransdérmicoRESUMEN
OBJECTIVES: Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD. METHODS: This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 µmol/L olanzapine (low-dose group), 50 µmol/L olanzapine (medium-dose group), and 100 µmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 µmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively. RESULTS: After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups (P>0.05). Olanzapine dose-dependently increased the plasma TG, ALT and AST levels, and reduced plasma ApoA5 levels (all P<0.05), whereas there was no significant difference in plasma cholesterol (HDL-C, LDL-C, and TC) levels among the 3 groups (all P>0.05). Olanzapine dose-dependently up-regulated ApoA5 protein levels in liver tissues (all P<0.05), but there was no significant change in ApoA5 mRNA expression among groups (P>0.05). In the control group, the structure of liver tissues was intact, the morphology of liver cells was regular, and only a few scattered lipid droplets were found in the cells. In the olanzapine-treated group, there was a large amount of lipid deposition in hepatocytes, and cells were balloon-like and filled with lipid droplet vacuoles. The nucleus located at the edge of cell, and the number of lipid droplets was increased significantly, especially in the high-dose group. Likewise, when HepG2 cells were treated with olanzapine for 24 h, the number and size of lipid droplets were significantly elevated in a dose-dependent manner. Moreover, olanzapine dose-dependently up-regulated ApoA5 protein levels in HepG2 cells (all P<0.05), but there was no significant difference in ApoA5 mRNA expression among groups (P>0.05). Compared with the HepG2 cells transfected with scrambled siRNA, the number and size of lipid droplets in HepG2 cells transfected with ApoA5 siRNA were significantly reduced. CONCLUSIONS: The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Apolipoproteína A-V/genética , Peso Corporal , Dimetilsulfóxido/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Olanzapina/metabolismo , ARN Mensajero/metabolismo , ARN Interferente Pequeño , TriglicéridosRESUMEN
Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].
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Antipsicóticos , Metformina , Animales , Antipsicóticos/metabolismo , Antipsicóticos/farmacología , Aripiprazol/metabolismo , Aripiprazol/farmacología , Femenino , Hipotálamo/metabolismo , Leptina/metabolismo , Metformina/metabolismo , Metformina/farmacología , Ratones , Neuronas/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Olanzapina/metabolismo , Olanzapina/farmacología , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Proopiomelanocortina/farmacologíaRESUMEN
AIMS/HYPOTHESIS: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. METHODS: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5-6.0 mg kg-1 day-1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. RESULTS: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. CONCLUSIONS/INTERPRETATION: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.
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Antipsicóticos , Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Animales , Antipsicóticos/efectos adversos , Aripiprazol/metabolismo , Aripiprazol/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Islotes Pancreáticos/metabolismo , Ratones , Olanzapina/efectos adversos , Olanzapina/metabolismoRESUMEN
Drug-induced toxicity has, in many cases, been linked to oxidative metabolism resulting in the formation of reactive metabolites and subsequent covalent binding to biomolecules. Two structurally related antipsychotic drugs, clozapine (CLZ) and olanzapine (OLZ), are known to form similar nitrenium ion reactive metabolites. CLZ-derived reactive metabolites have been linked to agranulocytosis and hepatotoxicity. We have studied the oxidative metabolism of CLZ and OLZ as well as two known metabolites of CLZ, desmethyl-CLZ (DCLZ), and CLZ-N-oxide (CLZ-NO), using in vitro rat liver microsomal (RLM) incubations with glutathione (GSH) trapping of reactive metabolites and liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS). Reactive metabolite binding to selected standard peptides and recombinant purified human proteins was also evaluated. Bottom-up proteomics was performed using two complementary proteases, prefractionation of peptides followed by LC-HRMS/MS for elucidating modifications of target proteins. Induced RLM was selected to form reactive metabolites enzymatically to assess the complex profile of reactive metabolite structures and their binding potential to standard human proteins. Multiple oxidative metabolites and several different GSH adducts were found for CLZ and OLZ. Modification sites were characterized on human glutathione S-transferase (hGST) alpha 1 (OLZ-modified at Cys112), hGST mu 2 (OLZ at Cys115), and hGST pi (CLZ, DCLZ, CLZ-NO and OLZ at Cys170), human microsomal GST 1 (hMGST1, CLZ and OLZ at Cys50), and human serum albumin (hSA, CLZ at Cys34). Furthermore, two modified rat proteins, microsomal GST 1 (CLZ and OLZ at Cys50) and one CYP (OLZ-modified, multiple possible isoforms), from RLM background were also characterized. In addition, direct effects of the reactive metabolite modifications on proteins were observed, including differences in protease cleavage specificity, chromatographic behavior, and charge-state distributions.
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Clozapina/metabolismo , Glutatión Transferasa/metabolismo , Olanzapina/metabolismo , Péptidos/metabolismo , Albúmina Sérica Humana/metabolismo , Cromatografía Liquida , Clozapina/química , Glutatión Transferasa/química , Humanos , Estructura Molecular , Olanzapina/química , Péptidos/química , Unión Proteica , Proteómica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Albúmina Sérica Humana/química , Espectrometría de Masas en TándemRESUMEN
Purpose: Olanzapine (OLZ) is an atypical antipsychotic agent that is characterized by low brain porousness. The present work aimed to develop radiolabeled olanzapine (OLZ) without colloidal impurities and evaluate its biodistribution following intravenous (I.V.) and intranasal (I.N.) administration as a potential agent for brain diagnosis. Materials and methods: OLZ was radiolabeled with technetium-99m by using sodium dithionite as the reducing agent. Biodistribution of 99mTc-OLZ complex in mice following I.V. and I.N. administrations was examined. Furthermore, a molecular docking study was performed.Results: Sodium dithionite labeling procedure resulted in highest radiochemical yield (96.30 ± 0.09%) and in vitro stability in serum up to 8 h. Biodistribution study of 99mTc-OLZ complex showed high brain uptake following I.N. (6.2 ± 0.12% ID/g) and I.V. (5.5 ± 0.09% ID/g) at 0.5 and 1 h post administration (P.I.), respectively. Docking into two brain targets predicts higher affinity of 99mTc-OLZ than free OLZ. Additionally, docking to P-glycoproteins shows less affinity for the radiolabelled OLZ and hence it is expected to be associated with better brain exposure than free OLZ.Conclusion: These chemical and preliminary biological merits strongly suggest that the 99mTc-OLZ complex with new reducing agent could be used as a potential diagnostic agent for brain.
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Encéfalo/efectos de la radiación , Simulación por Computador , Olanzapina/química , Tecnecio/química , Animales , Encéfalo/metabolismo , Estabilidad de Medicamentos , Masculino , Ratones , Olanzapina/metabolismo , Olanzapina/farmacocinética , Radioquímica , Distribución TisularRESUMEN
Transient receptor potential vanilloid type 1 (TRPV1) channels are emerging therapeutic targets for metabolic disorders. Berberine, which is a modulator of TRPV1, has proven antiobesity and antidiabetic potentials. The present study was aimed to investigate the protective effects of berberine in olanzapine-induced alterations in hypothalamic appetite control, inflammation and metabolic aberrations in mice targeting TRPV1 channels. Female BALB/c mice (18-23 g) were treated with olanzapine (6 mg/kg, p.o.) for six weeks to induce metabolic alterations, while berberine (100 and 200 mg/kg, p.o.) and metformin (100 mg/kg, p.o) were used as test and standard interventions respectively. Weekly assessment of feed-water intake, body temperature and body weight was done, while locomotion was measured at the end of week 1 and 6. Serum glucose and lipid profile were assessed by biochemical methods, while other serum biomarkers were assessed by ELISA. qPCR was used to quantify the mRNA expression in the hypothalamus. Olanzapine treatment significantly increased the feed intake, weight gain, adiposity index, while reduced body temperature and locomotor activity which were reversed by berberine treatment. Berberine treatment reduced serum ghrelin and leptin levels as well decrease in hypothalamic mRNA expression of orexigenic neuropeptides, inflammatory markers and ghrelin receptor in olanzapine-treated mice. Olanzapine treatment increased expression of TRPV1/TRPV3 in the hypothalamus which was significantly decreased by berberine treatment. Our results suggest that berberine, by TRPV1/TRPV3 modulation, attenuated the olanzapine-induced metabolic alterations in mice. Hence berberine supplementation in psychiatric patients could be a preventive approach to reduce the metabolic adverse effects of antipsychotics.
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Antipsicóticos/uso terapéutico , Berberina/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Olanzapina/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Antipsicóticos/efectos adversos , Berberina/efectos adversos , Temperatura Corporal , Peso Corporal , Citocinas/metabolismo , Ingestión de Líquidos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ghrelina/sangre , Ghrelina/metabolismo , Hipotálamo/metabolismo , Leptina/sangre , Leptina/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Terapia Molecular Dirigida/métodos , Neuropéptidos/metabolismo , Obesidad , ARN Mensajero , Transducción de Señal , Canales Catiónicos TRPV/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Antipsychotic medications are the common treatment for schizophrenia. However, reliable biomarkers that can predict individual treatment response are still lacking. The present study aimed to examine whether baseline putamen activity can predict individual treatment response in schizophrenia. METHODS: Two independent samples of patients with drug-naive, first-episode schizophrenia (32 patients in sample 1 and 44 in sample 2) and matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. Patients were treated with olanzapine for 8â¯weeks; symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and week 8. Fractional amplitude of low frequency fluctuation (fALFF) and pattern classification techniques were used to analyze the data. FINDINGS: Univariate analysis shows an elevated pre-treatment fALFF in the left ventromedial putamen in both patient samples compared to healthy controls (p'sâ¯<â¯0.001). The support vector regression (SVR) analysis suggests a positive relationship between baseline pre-treatment fALFF in the left ventromedial putamen and improvement in positive symptom at week 8 in each patient group using a cross-validated method (râ¯=â¯0.452, pâ¯=â¯.002; râ¯=â¯0.511, pâ¯=â¯.003, respectively). INTERPRETATION: Our study suggests that elevated pre-treatment mean fALFF in the left ventromedial putamen may predict individual therapeutic response to olanzapine treatment in drug-naive, first-episode patients with schizophrenia. Future studies are needed to confirm whether this finding is generalizable to patients with schizophrenia treated with other antipsychotic medications. FUND: The National Key R&D Program of China and the National Natural Science Foundation of China.
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Imagen por Resonancia Magnética , Putamen/diagnóstico por imagen , Putamen/fisiopatología , Esquizofrenia/diagnóstico , Adolescente , Adulto , Estudios de Casos y Controles , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Olanzapina/metabolismo , Pronóstico , Esquizofrenia/tratamiento farmacológico , Adulto JovenRESUMEN
INTRODUCTION: Second generation antipsychotic (AP)s remain the gold-standard treatment for schizophrenia and are widely used on- and off-label for other psychiatric illnesses. However, these agents cause serious metabolic side-effects. The hypothalamus is the primary brain region responsible for whole body energy regulation, and disruptions in energy sensing (e.g. insulin signaling) and inflammation in this brain region have been implicated in the development of insulin resistance and obesity. To elucidate mechanisms by which APs may be causing metabolic dysregulation, we explored whether these agents can directly impact energy sensing and inflammation in hypothalamic neurons. METHODS: The rat hypothalamic neuronal cell line, rHypoE-19, was treated with olanzapine (0.25-100 uM), clozapine (2.5-100 uM) or aripiprazole (5-20 uM). Western blots measured the energy sensing protein AMPK, components of the insulin signaling pathway (AKT, GSK3ß), and components of the MAPK pathway (ERK1/2, JNK, p38). Quantitative real-time PCR was performed to determine changes in the mRNA expression of interleukin (IL)-6, IL-10 and brain derived neurotrophic factor (BDNF). RESULTS: Olanzapine (100 uM) and clozapine (100, 20 uM) significantly increased pERK1/2 and pJNK protein expression, while aripiprazole (20 uM) only increased pJNK. Clozapine (100 uM) and aripiprazole (5 and 20 uM) significantly increased AMPK phosphorylation (an orexigenic energy sensor), and inhibited insulin-induced phosphorylation of AKT. Olanzapine (100 uM) treatment caused a significant increase in IL-6 while aripiprazole (20 uM) significantly decreased IL-10. Olanzapine (100 uM) and aripiprazole (20 uM) increased BDNF expression. CONCLUSIONS: We demonstrate that antipsychotics can directly regulate insulin, energy sensing, and inflammatory pathways in hypothalamic neurons. Increased MAPK activation by all antipsychotics, alongside olanzapine-associated increases in IL-6, and aripiprazole-associated decreases in IL-10, suggests induction of pro-inflammatory pathways. Clozapine and aripiprazole inhibition of insulin-stimulated pAKT and increases in AMPK phosphorylation (an orexigenic energy sensor) suggests impaired insulin action and energy sensing. Conversely, olanzapine and aripiprazole increased BDNF, which would be expected to be metabolically beneficial. Overall, our findings suggest differential effects of antipsychotics on hypothalamic neuroinflammation and energy sensing.
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Antipsicóticos/farmacología , Metabolismo Energético/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Antipsicóticos/metabolismo , Aripiprazol/metabolismo , Aripiprazol/farmacología , Línea Celular , Clozapina/metabolismo , Clozapina/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inflamación/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Olanzapina/metabolismo , Olanzapina/farmacología , Fosforilación/efectos de los fármacos , Ratas , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Potential risk of agranulocytosis is one of the drug-induced adverse effects of the second-generation antipsychotic agents. The present investigation aimed to formulate and investigate olanzapine (OLZ)-loaded nanostructured lipid carriers (OLZ-NLCs) via intranasal (i.n.) route. The NLC was prepared by melt emulsification method and optimized by Box-Behnken design. Mucoadhesive NLC was prepared by using 0.4% Carbopol 974P (OLZ-MNLC (C)) and the combination of 17% poloxamer 407 and 0.3% of HPMC K4M (OLZ-MNLC (P+H)). The particle size, zeta potential, and entrapment efficiency were found to be 88.95 nm ± 1.7 nm, - 22.62 mV ± 1.9 mV, and 88.94% ± 3.9%, respectively. Ex vivo permeation of OLZ-NLC, OLZ-MNLC (P+H), and OLZ-MNLC (C) was found to be 545.12 µg/cm2 ± 12.8 µg/cm2, 940.02 µg/cm2 ± 15.5 µg/cm2, and 820.10 µg/cm2 ± 11.3 µg/cm2, respectively, whereas the OLZ-MNLC (P+H) formulation showed rapid drug permeation than the OLZ-NLC and OLZ-MNLC (C) formulations. The OLZ-MNLC (P+H) formulation was shown to have 13.57- and 27.64-fold more Jss than the OLZ-MNLC (C) and OLZ-NLC formulations. The OLZ nanoformulations showed sustained release of up to 8 h. Finally, the brain Cmax of technetium-99m (99mTc)-OLZ-MNLC (i.n.) and 99mTc-OLZ-NLC (i.v.) was found to be 936 ng and 235 ng, respectively, whereas the Cmax of i.n. administration was increased 3.98-fold more than the Cmax of i.v. administration. The in vivo hematological study of OLZ-MNLC (P+H) confirmed that the i.n. formulation did not reflect any variation in leukocyte, RBC and platelet counts. Hence, it can be concluded that the nose-to-brain delivery of OLZ-MNLC (P+H) can be considered as an effective and safe delivery for CNS disorders.
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Agranulocitosis/prevención & control , Sistema Nervioso Central/efectos de los fármacos , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Nanoestructuras/administración & dosificación , Olanzapina/administración & dosificación , Administración Intranasal , Animales , Sistema Nervioso Central/metabolismo , Ingeniería Química/métodos , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Lípidos , Masculino , Ratones , Nanopartículas/química , Nanopartículas/metabolismo , Nanoestructuras/química , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Olanzapina/química , Olanzapina/metabolismo , Tamaño de la Partícula , Ratas , Ratas Wistar , OvinosRESUMEN
The use of antipsychotics is associated with severe disruptions in whole body glucose and lipid metabolism which may in part occur through the central nervous system and impaired insulin action at the brain. Here we investigated whether olanzapine treatment might also affect the ability of central insulin treatment to regulate food intake and fuel preference in the light and dark cycle. Male Sprague-Dawley rats were treated with olanzapine (or vehicle solution; 3 mg/kg, subcutaneous) and a simultaneous acute intracerebral ventricular (ICV) infusion of insulin (or vehicle; 3 µL at 10mU; ICV) at the beginning of the 12-h light and dark cycles. Olanzapine treatment reduced RER in the dark and light phases (most consistently in the 4-hours post-treatment), while ICV insulin reduced average RER predominantly in the dark phase, but also at the end of the light cycle. The RER lowering effect of ICV-insulin during the light cycle was absent in the group co-administered olanzapine. The reduction in RER during the dark phase was mirrored by decreased food intake with ICV insulin, but not olanzapine treated rats. The reduction in food intake by ICV-insulin was abolished in rats co-administered olanzapine suggesting rapid induction of central insulin resistance. A combination of ICV-insulin and olanzapine similarly reduced RER in the dark phase, independent of changes in food intake. Olanzapine treatment, alone or in combination with ICV-insulin, significantly reduced VCO2 at regular intervals in the dark phase (specifically 3 h post-treatment), while VO2 was not significantly altered by either treatment. Finally, heat production was increased by olanzapine treatment in the light phase, though this effect was not consistent. The findings confirm that acute olanzapine treatment directly reduces RER and suggest that treatment with this drug may also override central insulin-mediated reductions in food intake at the hypothalamus (while still independently favoring fatty acid oxidation). Acute central insulin similarly reduces RER, but in contrast to olanzapine, this may represent a physiologically appropriate response to reduction in food intake.