RESUMEN
BACKGROUND: Our recent studies showed that prolonged administration of novel atypical antipsychotics affected the expression and activity of cytochrome P450 (CYP), as demonstrated in vitro on human hepatocytes and in vivo on the rat liver. The aim of the present work was to study the effect of repeated treatment with asenapine, iloperidone, and lurasidone on the expression of transcription factors regulating CYP drug-metabolizing enzymes in rat liver. METHODS: The hepatic mRNA (qRT-PCR) and protein levels (Western blotting) of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPARγ) were measured in male Wistar rats after 2 week-treatment with asenapine, iloperidone or lurasidone. RESULTS: The 2-week treatment with asenapine significantly diminished the AhR and PXR expression (mRNA, protein level), and CAR mRNA level in rat liver. Iloperidone lowered the AhR and CAR expression and PXR protein level. Lurasidone did not affect the expression of AhR and CAR, but increased PXR expression. The antipsychotics did not affect PPARγ. CONCLUSIONS: Prolonged treatment with asenapine, iloperidone, or lurasidone affects the expression of transcription factors regulating the CYP drug-metabolizing enzymes. The changes in the expression of AhR, CAR, and PXR mostly correlate with alterations in the expression and activity of respective CYP enzymes found in our previous studies. Since these transcription factors are also engaged in the expression of phase II drug metabolism and drug transporters, changes in their expression may affect the metabolism of endogenous substrates and pharmacokinetics of concomitantly used drugs.
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Antipsicóticos , Sistema Enzimático del Citocromo P-450 , Compuestos Heterocíclicos de 4 o más Anillos , Isoxazoles , Hígado , Clorhidrato de Lurasidona , Receptor X de Pregnano , Ratas Wistar , Receptores Citoplasmáticos y Nucleares , Animales , Antipsicóticos/farmacología , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/enzimología , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptor X de Pregnano/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Clorhidrato de Lurasidona/farmacología , Isoxazoles/farmacología , Piperidinas/farmacología , Receptor de Androstano Constitutivo/metabolismo , Dibenzocicloheptenos/farmacología , Receptores de Esteroides/metabolismo , PPAR gamma/metabolismo , Factores de Transcripción/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
PURPOSE: The aim of this study was to compare the efficacy and safety profile of lurasidone combined with either lithium or valproate, in the short-term treatment of patients with bipolar depression. METHODS: Data were pooled from two 6-week, double-blind, placebo-controlled trials of patients with bipolar depression on stable doses of lithium or valproate randomized to lurasidone (20-120 mg/d) or placebo. Efficacy measures included the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impressions Bipolar Scale, and the Quick Inventory of Depressive Symptomatology via self-assessment and were analyzed using a mixed model for repeated measures approach. RESULTS: Notably larger week 6 effect sizes were observed when lurasidone was added to lithium, compared with when lurasidone was added to valproate, on 2 of the 3 depression outcome measures, Montgomery-Åsberg Depression Rating Scale total score (d = 0.45 vs 0.22) and Quick Inventory of Depressive Symptomatology via self-assessment (d = 0.63 vs 0.29); the efficacy advantage was smaller on the Clinical Global Impressions Bipolar Scale depression score (d = 0.34 vs 0.29). Similar adverse event profiles were observed for lurasidone treatment in combination with either lithium or valproate. The most frequently reported events (≥5%) in both groups were nausea, parkinsonism, somnolence, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone combined with either lithium or valproate. CONCLUSIONS: Lurasidone added to either lithium or valproate was found to be an effective treatment for bipolar depression, with a larger antidepressant effect observed when lurasidone was combined with lithium. There were no clinically meaningful differences in the safety or tolerability of lurasidone when used adjunctively with lithium or valproate.
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Antimaníacos , Trastorno Bipolar , Quimioterapia Combinada , Clorhidrato de Lurasidona , Ácido Valproico , Humanos , Clorhidrato de Lurasidona/administración & dosificación , Clorhidrato de Lurasidona/efectos adversos , Clorhidrato de Lurasidona/farmacología , Clorhidrato de Lurasidona/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversos , Ácido Valproico/farmacología , Ácido Valproico/uso terapéutico , Femenino , Masculino , Adulto , Método Doble Ciego , Antimaníacos/administración & dosificación , Antimaníacos/efectos adversos , Antimaníacos/farmacología , Persona de Mediana Edad , Resultado del Tratamiento , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Antipsicóticos/farmacología , Compuestos de Litio/administración & dosificación , Compuestos de Litio/efectos adversos , Compuestos de Litio/farmacología , Escalas de Valoración PsiquiátricaRESUMEN
The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible mechanistic targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of lumateperone fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of lumateperone. The original model suggests that a constellation of effects on different receptors is necessary, but refinements, including the present study, suggest that the inhibition of the serotonin reuptake at the first level, the 5HT-2A blockade at the second level, and the norepinephrine alpha-1 receptors blockade at a third level in combination with D1 blockade contribute to the antidepressant effect in acute bipolar depression. The D2 blockade acts as a protective mechanism and reduces the risk of switching to mania/hypomania.
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Antipsicóticos , Trastorno Bipolar , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Trastorno Bipolar/tratamiento farmacológico , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Clorhidrato de Lurasidona/farmacología , Clorhidrato de Lurasidona/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéuticoRESUMEN
Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.
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Antipsicóticos , Clorhidrato de Lurasidona , Humanos , Ratas , Masculino , Animales , Clorhidrato de Lurasidona/farmacología , Antipsicóticos/farmacología , Antipsicóticos/metabolismo , Perfilación de la Expresión Génica , Corteza Prefrontal/metabolismo , Anhedonia/fisiologíaRESUMEN
Lurasidone is a novel atypical antipsychotic drug acting on dopaminergic, serotonergic and noradrenergic receptors; it is applied for the long-term treatment of schizophrenia and depression in patients with bipolar disorders. We aimed at performing a comparative study on the influence of chronic treatment with lurasidone on the expression of cytochrome P450 enzymes in the liver and in peripheral blood lymphocytes, and to evaluate the relationship between changes in the expression of CYP enzymes in the two experimental models. The obtained results show a fairly similar expression pattern of the main CYP enzymes in the rat livers and lymphocytes, and they indicate that in the liver, lurasidone exerts an inhibitory effect on the activity, protein and mRNA levels of CYP2B1/2 (not CYP2B2 mRNA), CYP2C11 and CYP2E1, while in the case of CYP3A1 and CYP3A2, it causes enzyme induction. At the same time, lurasidone decreases the expression of CYP2B, CYP2C11 (CYP2C11 protein only) and CYP2E1 but increases that of CYP3A2 (not CYP3A1) in lymphocyte cells. In conclusion, chronic treatment with lurasidone simultaneously and in the same way influences the expression and activity of CYP2B, CYP2C11, CYP2E1 and CYP3A2 in the liver and peripheral blood lymphocytes of rats. Thus, the lymphocyte cytochrome P450 profile may be utilized as an indicator of the hepatic cytochrome P450 profile in further clinical studies with lurasidone, and lymphocytes may serve as easily available surrogates for examining the impact of new drugs and chronic in vivo treatments on CYP enzyme expression, as well as to estimate drug-drug interactions and toxicity risk.
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Antipsicóticos , Humanos , Ratas , Animales , Antipsicóticos/farmacología , Antipsicóticos/metabolismo , Clorhidrato de Lurasidona/farmacología , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/metabolismo , Microsomas Hepáticos/metabolismo , ARN Mensajero/genética , Citocromo P-450 CYP3A/metabolismoRESUMEN
Lurasidone is a second-generation antipsychotic drug used to treat schizophrenia, mania, and bipolar disorder. The drug is an antagonist of the 5-HT2A and D2 receptors. No effect of lurasidone on the voltage-gated K+ (Kv) channels has yet been identified. Here, we show that lurasidone inhibits the vascular Kv channels of rabbit coronary arterial smooth muscle cells in a dose-dependent manner with an IC50 of 1.88 ± 0.21 µM and a Hill coefficient of 0.98 ± 0.09. Although lurasidone (3 µM) did not affect the activation kinetics, the drug negatively shifted the inactivation curve, suggesting that the drug interacted with the voltage sensors of Kv channels. Application of 1 or 2 Hz train steps in the presence of lurasidone significantly increased Kv current inhibition. The recovery time after channel inactivation increased in the presence of lurasidone. These results suggest that the inhibitory action of lurasidone is use (state)-dependent. Pretreatment with a Kv 1.5 subtype inhibitor effectively reduced the inhibitory effect of lurasidone. However, the inhibitory effect on Kv channels did not markedly change after pretreatment with a Kv 2.1 or a Kv7 subtype inhibitor. In summary, lurasidone inhibits vascular Kv channels (primarily the Kv1.5 subtype) in a concentration- and use (state)-dependent manner by shifting the steady-state inactivation curve.
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Antipsicóticos , Canales de Potasio con Entrada de Voltaje , Animales , Conejos , Clorhidrato de Lurasidona/farmacología , Antipsicóticos/farmacología , Vasos Coronarios , Miocitos del Músculo LisoRESUMEN
Cognitive deficits are associated with schizophrenia and show a progressive worsening, often being unresponsive to treatment. New antipsychotic molecules acting as antagonist at the serotoninergic 5-hydroxytryptamine receptor 7 (e.g. lurasidone) or partial agonists at dopamine D3 receptor (e.g. cariprazine) could have an impact on cognition in this patient group. The aim of the systematic review is to explore the efficacy of lurasidone and cariprazine in improving cognition in both animal models and human studies. The following terms: (lurasidone AND cognit*) OR (cariprazine AND cognit*) were searched in Web of Science from inception to December 2021. We included all studies that assessed changes in cognitive function after treatment with cariprazine or lurasidone. Of 201 selected articles, 36 were included. Twenty-four articles used animal models (rats, mice and marmosets), five evaluating the effects of cariprazine and 19 the effects of lurasidone. Twelve articles were clinical studies (cariprazine n = 2; lurasidone n = 10). In both animal and human studies lurasidone showed a greater efficacy on cognitive performance compared to placebo, quetiapine, ziprasidone or treatmentas- usual. Cariprazine was superior to other antipsychotics in improving cognitive functions in both animal and human studies. The cognitive effect of lurasidone could be explained by its potent antagonism at the 5-HT7 receptors combined with partial agonism at 5-HT1A receptors. The pro-cognitive effect of cariprazine is probably explained by its very high affinity for D3 receptors. Head-to-head studies comparing lurasidone and cariprazine are needed to establish the "first-choice" treatment for cognitive dysfunction associated with schizophrenia.
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Antipsicóticos , Esquizofrenia , Humanos , Ratas , Ratones , Animales , Clorhidrato de Lurasidona/farmacología , Clorhidrato de Lurasidona/uso terapéutico , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , CogniciónRESUMEN
RATIONALE: Stress represents a major contributor to the development of mental illness. Accordingly, exposure of adult rats to chronic stress represents a valuable tool to investigate the ability of a pharmacological intervention to counteract the adverse effects produced by stress exposure. OBJECTIVES: The aim of this study was to perform a time course analysis of the treatment with the antipsychotic drug lurasidone in normalizing the anhedonic phenotype in the chronic mild stress (CMS) model in order to identify early mechanisms that may contribute to its therapeutic activity. METHODS: Male Wistar rats were exposed to CMS or left undisturbed for 7 weeks. After two weeks of stress, both controls and CMS rats were randomly divided into two subgroups that received vehicle or lurasidone for five weeks. Weekly measures of sucrose intake were recorded to evaluate anhedonic behavior, and animals were sacrificed at different weeks of treatment for molecular analyses. RESULTS: We found that CMS-induced anhedonia was progressively improved by lurasidone treatment. Interestingly, after two weeks of lurasidone treatment, 50% of the animals showed a full recovery of the phenotype, which was associated with increased activation of the prefrontal and recruitment of parvalbumin-positive cells that may lead to a restoration of excitatory/inhibitory balance. CONCLUSION: These results suggest that the capacity of lurasidone to normalize anhedonia at an early stage of treatment may depend on its ability to modulate the function of the prefrontal cortex.
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Antipsicóticos , Clorhidrato de Lurasidona , Ratas , Masculino , Animales , Clorhidrato de Lurasidona/farmacología , Anhedonia , Ratas Wistar , Antipsicóticos/farmacología , Corteza Prefrontal , Estrés Psicológico/tratamiento farmacológicoRESUMEN
BACKGROUND: Many psychoactive compounds have been developed to have more beneficial clinical efficacy than conventional drugs by adding agonistic action at 5-HT1A receptors. The aim of the present study was to evaluate several psychotropic drugs that had been reported to behave as an agonist at 5-HT1A receptor (aripiprazole, brexpiprazole, asenapine, lurasidone, and vortioxetine) in both rat and postmortem human brain membranes. METHODS: The [35S]GTPγS binding assay for Gi/o proteins coupled with 5-HT1A receptors was performed in rat brain membranes and postmortem human brain membranes. RESULTS: The specific binding was stimulated by brexpiprazole in rat hippocampus, human hippocampus, and human prefrontal cortex. Aripiprazole also behaved as an agonist in the same brain regions. Interestingly, its potency was much higher in rat hippocampal membranes than in human brain membranes, indicating the possibility of species differences. Although vortioxetine was an efficacious stimulator at high concentrations, its potency was undeterminable because of a lack of saturability. In addition to 5-HT1A receptor agonism, involvement of other components, e.g., 5-HT1B receptor agonism, was speculated by the biphasic inhibitory effects of the selective 5-HT1A receptor neutral antagonist. Negligible stimulatory effects were obtained as to lurasidone and asenapine. CONCLUSIONS: Our previous studies have raised the concept of a psychoactive drug group with a common pharmacological mechanism of action, i.e., 5-HT1A receptor agonism, consisting of perospirone, aripiprazole, ziprasidone, clozapine, quetiapine, nemonapride, and trazodone. The present study demonstrates the data indicating that brexpiprazole and probably vortioxetine are included in this drug group. Lurasidone and asenapine are excluded from this group.
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Receptor de Serotonina 5-HT1A , Serotonina , Ratas , Humanos , Animales , Aripiprazol/farmacología , Serotonina/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Vortioxetina/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Clorhidrato de Lurasidona/farmacología , Agonistas de Receptores de Serotonina/farmacología , Encéfalo/metabolismo , Psicotrópicos/farmacologíaRESUMEN
The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats received lurasidone (1 mg/kg ip.) for two weeks. The activity of CYP2D was measured in brain and liver microsomes as the rate of bufuralol 1'-hydroxylation. The CYP2D protein level was determined in microsomes by Western blot analysis. The CYP2D gene expression was estimated in liver tissue by a qRT-PCR method. Lurasidone decreased the activity and protein level of CYP2D in the frontal cortex but increased them in the striatum, nucleus accumbens, brain stem, substantia nigra, and the remainder of the brain. The neuroleptic did not affect CYP2D in the hippocampus, hypothalamus, and cerebellum. In the liver, lurasidone did not affect the CYP2D activity and protein level, though it enhanced the mRNA of CYP2D1 without affecting that of CYP2D2, CYP2D3, CYP2D4, and CYP2D5. In conclusion, lurasidone regulates brain (but not liver) CYP2D activity/protein level in a region-dependent manner, which is similar to that of other atypical neuroleptics (iloperidone and asenapine) as concerns the frontal cortex (down-regulation) and nigrostriatal pathway (up-regulation) and may be of pharmacological significance. However, further molecular studies with selective receptor agonists are necessary to find out which individual monoaminergic receptors/signaling pathways are involved in the regulation of the rat CYP2D4 and human CYP2D6 enzyme in particular brain structures.
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Antipsicóticos , Esquizofrenia , Animales , Masculino , Ratas , Humanos , Antipsicóticos/farmacología , Clorhidrato de Lurasidona/farmacología , Clorhidrato de Lurasidona/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Ratas Wistar , Microsomas Hepáticos/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Encéfalo/metabolismoRESUMEN
Influenza virus infections continue to be a significant and recurrent public health problem. Although vaccine efficacy varies, regular immunisation is the most effective method for suppressing the influenza virus. Antiviral drugs are available for influenza, although two of the four FDA-approved antiviral treatments have resulted in significant drug resistance. Therefore, new treatments are being sought to reduce the burden of flu-related illness. The time-consuming development of treatments for new and re-emerging diseases such as influenza and the high failure rate are increasing concerns. In this context, we used an in silico-based drug repurposing method to repurpose FDA-approved drugs as potential therapies against the H7N9 virus. To find potential inhibitors, a total of 2568 drugs were screened. Promacta, tucatinib, and lurasidone were identified as promising hits in the DrugBank database. According to the calculations of MM-GBSA, tucatinib (-54.11 kcal/mol) and Promacta (-56.20 kcal/mol) occupied the active site of neuraminidase with a higher binding affinity than the standard drug peramivir (-49.09 kcal/mol). Molecular dynamics (MD) simulation studies showed that the C-α atom backbones of the complexes of tucatinib and Promacta neuraminidase were stable throughout the simulation period. According to ADME analysis, the hit compounds have a high gastrointestinal absorption (GI) and do not exhibit properties that allow them to cross the blood-brain barrier (BBB). According to the in silico toxicity prediction, Promacta is not cardiotoxic, while lurasidone and tucatinib show only weak inhibition. Therefore, we propose to test these compounds experimentally against the influenza H7N9 virus. The investigation and validation of these potential H7N9 inhibitors would be beneficial in order to bring these compounds into clinical settings.
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Subtipo H7N9 del Virus de la Influenza A , Gripe Humana , Antivirales/química , Antivirales/farmacología , Antivirales/uso terapéutico , Benzoatos , Reposicionamiento de Medicamentos , Humanos , Hidrazinas , Gripe Humana/tratamiento farmacológico , Clorhidrato de Lurasidona/farmacología , Clorhidrato de Lurasidona/uso terapéutico , Neuraminidasa/química , PirazolesRESUMEN
Chronic stress represents a major contributor for the development of mental illness. This study aimed to investigate how animals exposed to chronic mild stress (CMS) responded to an acute stress (AS), as a vulnerability's challenge, and to establish the potential effects of the antipsychotic drug lurasidone on such mechanisms. Adult male Wistar rats were exposed or not (controls) to a CMS paradigm for 7 weeks. Starting from the end of week 2, animals were randomized to receive vehicle or lurasidone for 5 weeks. Sucrose intake was used to measure anhedonia. At the end, half of the animals were exposed to an acute stress before sacrifice. Exposure to CMS produced a significant reduction in sucrose consumption, whereas lurasidone progressively normalized such alteration. We found that exposure to AS produced an upregulation of Brain derived neurotrophic factor (Bdnf) in the prefrontal cortex of controls animals. This response was impaired in CMS rats and restored by lurasidone treatment. While in control animals, AS-induced increase of Bdnf mRNA levels was specific for Parvalbumin cells, CMS rats treated with lurasidone show a significant upregulation of Bdnf in pyramidal cells. Furthermore, when investigating the activation of different brain regions, CMS rats showed an impairment in the global response to the acute stressor, that was largely restored by lurasidone treatment. Our results suggest that lurasidone treatment in CMS rats may regulate specific circuits and mechanisms, which will ultimately contribute to boost resilience under stressful challenges.
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Factor Neurotrófico Derivado del Encéfalo , Clorhidrato de Lurasidona , Animales , Modelos Animales de Enfermedad , Clorhidrato de Lurasidona/farmacología , Masculino , Ratas , Ratas Wistar , Estrés Psicológico/tratamiento farmacológico , SacarosaRESUMEN
RATIONALE: Although the occurrence of stressful events is very common during life, their impact may be different depending on the experience severity and duration. Specifically, acute challenges may trigger adaptive responses and even improve the individual's performance. However, such a physiological positive coping can only take place if the underlying molecular mechanisms are properly functioning. Indeed, if these systems are compromised by genetic factors or previous adverse conditions, the response set in motion by an acute challenge may be maladaptive and even cause the insurgence or the relapse of stress-related psychiatric disorders. OBJECTIVES: On these bases, we evaluated in the rat brain the role of the antioxidant component of the redox machinery on the acute stress responsiveness and its modulation by potential detrimental or beneficial events. METHODS: The expression of several antioxidant enzymes was assessed in different brain areas of adult male rats exposed to acute stress 3 weeks after a chronic immobilization paradigm with or without a concomitant treatment with the antipsychotic lurasidone. RESULTS: The acute challenge was able to trigger a marked antioxidant response that, despite the washout period, was impaired by the previous adverse experience and restored by lurasidone in an anatomical-specific manner. CONCLUSIONS: We found that a working antioxidant machinery takes part in acute stress response and may be differentially affected by other experiences. Given the essential role of stress responsiveness in almost every life process, the identification of the underlying mechanisms and their potential pharmacological modulation add further translational value to our data.
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Antipsicóticos , Clorhidrato de Lurasidona , Animales , Antioxidantes/farmacología , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Humanos , Clorhidrato de Lurasidona/farmacología , Masculino , RatasRESUMEN
A part of atypical antipsychotics exert mood-stabilising effects via modulation of various monoamine receptors and intracellular signalling. Recent pharmacodynamic studies suggested that tripartite-synaptic transmission can be involved in pathophysiology of mood-disorders, schizophrenia, their associated cognitive impairments, and several adverse-reactions to atypical antipsychotics. Therefore, to explore mechanisms underlying antidepressive mood-stabilising and antipsychotic effects of lurasidone, we determined concentration-dependent effects of acute and subchronic lurasidone administrations on astroglial L-glutamate release, and expression of connexin43, ERK, AKT, adenosine monophosphate activated protein kinase (AMPK), 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors in cultured astrocytes using ultra-high-pressure liquid-chromatography with mass-spectrometry and capillary-immunoblotting systems. Therapeutically-relevant lurasidone concentration suppressed astroglial L-glutamate release through activated connexin43-containing hemichannel by decreasing connexin43 expression in plasma-membrane. Subchronic lurasidone administration downregulated 5-HT1AR and 5-HT7R in astroglial plasma-membrane concentration-dependently. Subchronic lurasidone administration attenuated ERK and AMPK signallings concentration-dependently without affecting AKT signalling. These results suggest that effects of subchronic lurasidone administration on astroglial L-glutamate release, 5-HT receptor, and intracellular signalling are similar to vortioxetine and different from mood-stabilising atypical antipsychotics, clozapine. Therefore, inhibitory effects of subchronic lurasidone administration on astroglial L-glutamate release through activated connexin43-containing hemichannel probably contribute to pathophysiology of antidepressive mood-stabilising effects of lurasidone. Furthermore, inhibitory effects of subchronic lurasidone administration on ERK and AMPK activities (without affecting AKT activity) induced by downregulation of 5-HT7R could result in clinical advantages of lurasidone, lower risk of weight gain.
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Antipsicóticos/farmacología , Clorhidrato de Lurasidona/farmacología , Trastornos del Humor/tratamiento farmacológico , Receptores de Serotonina/metabolismo , Transmisión Sináptica/efectos de los fármacos , Aumento de Peso/efectos de los fármacos , Quinasas de la Proteína-Quinasa Activada por el AMP/metabolismo , Animales , Astrocitos/metabolismo , Conexina 43/metabolismo , Femenino , Ácido Glutámico/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Trastornos del Humor/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are key drugs in cancer treatment due to their minor adverse effects and outstanding anticancer effects. However, drugs for overcoming EGFR-TKI resistance are not in clinical use so far. Therefore, to overcome resistance, we focused on lurasidone, a new antipsychotic drug, due to its mild adverse effect profile from the viewpoint of drug repositioning. MATERIALS AND METHODS: We explored the effects of lurasidone alone or in combination with EGFR-TKI on the growth of osimertinib-resistant cancer cells the anti-apoptotic marker expression such as survivin, and autophagy levels by LC-3B expression. RESULTS: Within a non-toxic concentration range in normal cells, lurasidone and osimertinib combination therapy showed a growth-inhibitory effect in osimertinib-resistant cancer cells in vitro and in vivo. Furthermore, lurasidone decreased survivin expression and mildly induced autophagy. CONCLUSION: Lurasidone may increase the sensitivity to osimertinib in osimertinib-resistant cancer cells in drug repurposing.
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Acrilamidas/administración & dosificación , Compuestos de Anilina/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Clorhidrato de Lurasidona/administración & dosificación , Survivin/metabolismo , Células A549 , Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Animales , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Clorhidrato de Lurasidona/farmacología , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The identification and quantification of mitochondrial effects of novel antipsychotics (brexpiprazole, cariprazine, loxapine, and lurasidone) were studied in vitro in pig brain mitochondria. Selected parameters of mitochondrial metabolism, electron transport chain (ETC) complexes, citrate synthase (CS), malate dehydrogenase (MDH), monoamine oxidase (MAO), mitochondrial respiration, and total ATP and reactive oxygen species (ROS) production were evaluated and associated with possible adverse effects of drugs. All tested antipsychotics decreased the ETC activities (except for complex IV, which increased in activity after brexpiprazole and loxapine addition). Both complex I- and complex II-linked respiration were dose-dependently inhibited, and significant correlations were found between complex I-linked respiration and both complex I activity (positive correlation) and complex IV activity (negative correlation). All drugs significantly decreased mitochondrial ATP production at higher concentrations. Hydrogen peroxide production was significantly increased at 10 µM brexpiprazole and lurasidone and at 100 µM cariprazine and loxapine. All antipsychotics acted as partial inhibitors of MAO-A, brexpiprazole and loxapine partially inhibited MAO-B. Based on our results, novel antipsychotics probably lacked oxygen uncoupling properties. The mitochondrial effects of novel antipsychotics might contribute on their adverse effects, which are mostly related to decreased ATP production and increased ROS production, while MAO-A inhibition might contribute to their antidepressant effect, and brexpiprazole- and loxapine-induced MAO-B inhibition might likely promote neuroplasticity and neuroprotection. The assessment of drug-induced mitochondrial dysfunctions is important in development of new drugs as well as in the understanding of molecular mechanism of adverse or side drug effects.
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Antipsicóticos/farmacología , Mitocondrias/efectos de los fármacos , Adenosina Trifosfato/biosíntesis , Animales , Antipsicóticos/clasificación , Proteínas del Complejo de Cadena de Transporte de Electrón/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Loxapina/farmacología , Clorhidrato de Lurasidona/farmacología , Mitocondrias/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Consumo de Oxígeno/efectos de los fármacos , Piperazinas/farmacología , Quinolonas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Neurotransmisores/efectos de los fármacos , Porcinos , Tiofenos/farmacologíaRESUMEN
Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45ß, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45ß and Gilz gene expression and lurasidone normalized the Gadd45ß modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45ß gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45ß expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.
Asunto(s)
Epigénesis Genética , Regulación de la Expresión Génica/efectos de los fármacos , Glucocorticoides/metabolismo , Clorhidrato de Lurasidona/farmacología , Corteza Prefrontal/metabolismo , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico , Animales , Antipsicóticos/farmacología , Modelos Animales de Enfermedad , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , ARN Mensajero , Ratas , Ratas Wistar , Receptores de Glucocorticoides/genéticaRESUMEN
The current emergency of the novel coronavirus SARS-CoV2 urged the need for broad-spectrum antiviral drugs as the first line of treatment. Coronaviruses are a large family of viruses that already challenged humanity in at least two other previous outbreaks and are likely to be a constant threat for the future. In this work we developed a pipeline based on in silico docking of known drugs on SARS-CoV1/2 RNA-dependent RNA polymerase combined with in vitro antiviral assays on both SARS-CoV2 and the common cold human coronavirus HCoV-OC43. Results showed that certain drugs displayed activity for both viruses at a similar inhibitory concentration, while others were specific. In particular, the antipsychotic drug lurasidone and the antiviral drug elbasvir showed promising activity in the low micromolar range against both viruses with good selectivity index.
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Antivirales/farmacología , Benzofuranos/farmacología , Coronavirus Humano OC43/efectos de los fármacos , Reposicionamiento de Medicamentos , Imidazoles/farmacología , Clorhidrato de Lurasidona/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Línea Celular Tumoral , Chlorocebus aethiops , Simulación por Computador , Fibroblastos , Humanos , Células Vero , Replicación Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.