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Sneathia amnii is a poorly characterized emerging pathogen that has been implicated in amnionitis and urethritis. We found that S. amnii damages fetal membranes, and we identified and purified a cytotoxic exotoxin that lyses human red blood cells and damages cells from fetal membranes. The gene appears to be cotranscribed with a second gene that encodes a protein with identity to two-partner system transporters, suggesting that it is the "A," or secreted component of a type Vb system. The toxin is 1,881 amino acids with a molecular weight of approximately 200 kDa. It binds to red blood cell membranes and forms pores with a diameter of 2.0 to 3.0 nm, resulting in osmolysis. Because it appears to be the "A" or passenger component of a two-partner system, we propose to name this novel cytotoxin/hemolysin CptA for cytopathogenic toxin component A.IMPORTANCESneathia amnii is a very poorly characterized emerging pathogen that can affect pregnancy outcome and cause urethritis and other infections. To date, nothing is known about its virulence factors or pathogenesis. We have identified and isolated a cytotoxin, named CptA for cytopathogenic toxin, component A, that is produced by S. amnii CptA is capable of permeabilizing chorionic trophoblasts and lysing human red blood cells and, thus, may play a role in virulence. Except for small domains conserved among two-partner secretion system passenger proteins, the cytotoxin exhibits little amino acid sequence homology to known toxins. In this study, we demonstrate the pore-forming activity of this novel toxin.
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Toxinas Bacterianas/química , Toxinas Bacterianas/metabolismo , Fusobacterias/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/genética , Toxinas Bacterianas/toxicidad , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Fusobacterias/química , Fusobacterias/genética , Infecciones por Bacterias Gramnegativas/microbiología , Hemólisis/efectos de los fármacos , Humanos , Peso MolecularRESUMEN
The peculiar biotechnological applications of Oleispira spp. in the natural cleansing of oil-polluted marine systems stimulated the study of the phenotypic characteristics of the Oleispira antarctica RB-8(T) strain and modifications of these characteristics in relation to different growth conditions. Bacterial abundance, cell size and morphology variations (by image analysis) and hydrocarbon degradation (by gas chromatography with flame ionization detection, GC-FID) were analysed in different cultures of O. antarctica RB-8(T). The effects of six different hydrocarbon mixtures (diesel, engine oil, naval oil waste, bilge water, jet fuel and oil) used as a single carbon source combined with two different growth temperatures (4° and 15 °C) were analysed (for 22 days). The data obtained showed that the mean cell volume decreased with increasing experimental temperature. Three morphological bacterial shapes were identified: spirals, rods and cocci. Morphological transition from spiral to rod and coccoid shapes in relation to the different substrates (oil mixtures) and/or growth temperatures was observed, except for one experimental condition (naval oil waste) in which spiral bacteria were mostly dominant. Phenotypic traits and physiological status of hydrocarbon-degrading bacteria showed important modifications in relation to culture conditions. These findings suggest interesting potential for strain RB-8(T) for ecological and applicative purposes.
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Oceanospirillaceae , Bacterias/genética , Biodegradación Ambiental , Variación Biológica PoblacionalRESUMEN
The therapeutic landscape for early breast cancer (eBC) has expanded by introducing novel anticancer agents into clinical practice. During their reproductive years, women with eBC should be informed of the potential risk of premature ovarian insufficiency (POI) and infertility with the proposed systemic therapy. Although the topic of female fertility is becoming increasingly relevant in patients with cancer, limited information is available on the gonadotoxicity of new agents available for eBC treatment. Analyses from clinical trials and prospective data on ovarian function biomarkers are lacking. The purpose of this systematic review is to report the available preclinical and clinical data on female fertility risk with the use of the new agents that are part of clinical practice use or under development for eBC management. This review highlights the clear need to perform additional research efforts to improve our understanding on the gonoadtoxicity of new anticancer agents.
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Neoplasias de la Mama , Femenino , Humanos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Fertilidad/efectos de los fármacos , Infertilidad Femenina/inducido químicamente , Infertilidad Femenina/etiología , Insuficiencia Ovárica Primaria/inducido químicamente , Medición de RiesgoRESUMEN
OBJECTIVE: Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. METHODS: The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. RESULTS: A total of 61 participants completed the questionnaire (47 out of 180 MITO centers; compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. CONCLUSION: Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO. Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.
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Supervivientes de Cáncer , Neoplasias de los Genitales Femeninos , Terapia de Reemplazo de Hormonas , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Supervivientes de Cáncer/estadística & datos numéricos , Genes BRCA1 , Genes BRCA2 , Neoplasias de los Genitales Femeninos/genética , Conocimientos, Actitudes y Práctica en Salud , Heterocigoto , Italia , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Salpingooforectomía , Encuestas y CuestionariosRESUMEN
No evidence exists as to whether body mass index (BMI) impairs clinical outcomes from ALK inhibitors (ALKi) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). Retrospective data of patients affected by metastatic ALK-rearranged NSCLC treated with ALKi were collected. We divided patients into "low- BMI" (≤25 kg/m2) and "high- BMI" (>25 kg/m2) categories and correlated them with overall survival (OS) and progression-free survival (PFS). We included 40 patients treated with ALKi. We observed a 3-year OS of 81.5% in high-BMI vs. 49.6% in low-BMI categories (p = 0.049); the 3-year first-line PFS was superior in high-BMI vs. low-BMI patients (47% vs. 19%, p = 0.019). As expected, patients treated with Alectinib had a 55.6% 3-year PFS vs. 7.1% for others treated with ALKi (p = 0.025). High-BMI was associated with a 100% 3-year PFS rate vs. 25.4% in low-BMI Alectinib patients (p = 0.03). BMI was independently correlated with first-line PFS and OS at multivariate analysis with PS (HR 0.39, CI 95% 0.16-0.96, p = 0.042; HR 0.18, CI 95% 0.05-0.61, p = 0.006). High-BMI was associated with higher efficacy in ALK-rearranged patients. These results are particularly exciting for Alectinib and could be correlated to mechanisms that should be investigated in subsequent prospective studies.
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OBJECTIVE: To evaluate the efficacy of preoperative low-residue diet on postoperative ileus in women undergoing elective cesarean section (CS). METHODS: This is a surgeon-blind, randomized controlled trial enrolling pregnant women at ≥39 weeks of gestation undergoing elective CS. Patients were preoperatively randomized to receive either low-residue diet (arm A) or free diet (arm B) starting from three days before surgery. The primary outcome was the postoperative ileus. The secondary outcomes were the postoperative pain (assessed through VAS scale), the quality of the surgical field (scored using a 5-point scale, from poor to excellent), postoperative complications, and the length of hospital stay. Perioperative data were collected and compared between groups. RESULTS: A total of 166 patients were enrolled and randomized in arm A (n = 83) and arm B (n = 83). Postoperative ileus over 24 h was significantly shorter in arm A, compared to arm B (19.3% vs 36.2%). The surgical evaluation of small intestine was scored ≥3 in 96.4% of arm A patients versus 80.7% in arm B, while evaluation of large intestine, respectively, in 97.7% and 81.9%. Postoperative pain after 12 h from CS was significantly lower in arm A (VAS, 3.4 ± 1.7) compared to arm B (VAS, 4.1 ± 1.8). There were no significant differences as regards postoperative pain at 24 and 48 h, nausea/vomit, surgical complications, and hospital stay. CONCLUSIONS: Implementation of a preoperative low-residue diet for women scheduled for elective CS would reduce postoperative ileus and pain. Further large-scale studies are required before translating these research findings into routine obstetrical practice.
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Ileus , Obstetricia , Humanos , Femenino , Embarazo , Cesárea/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Dolor Postoperatorio , Ileus/epidemiología , Ileus/etiología , Ileus/prevención & control , Tiempo de InternaciónRESUMEN
BACKGROUND: Inflammatory microenvironment is an essential component of all tumors, including thyroid cancer. Autoimmune thyroid diseases are often associated with thyroid cancer. CD25, expressed in Treg cells and B cells, has been found to be associated with autoimmune thyroid diseases and the NFkB pathway is critical to tumor formation, regulating immune-related genes, and pro-inflammatory cytokine. METHODS: Protein expression of CD25 and NFkB and its phosphorylated form was analyzed by immunohistochemistry in 80 patients with thyroid cancer (10 cases of cancers with Hashimoto's thyroiditis and 70 cases without). RESULTS: CD25 was mainly detected in the nucleus of the inflammatory cells such as in the thyrocytes and neoplastic cells. Protein staining was detected in the T-lymphocytes of the outermost zone of the lymphoid follicles. Moreover, in all cancer alterations, there were a higher level of p-NFkB than in the surrounding tissues. Again, p-NFkB staining was evident in neoplastic cells but not evident in inflammatory cells. CONCLUSIONS: Strong inflammatory infiltrate in the tumor microenvironment is correlated with an invasive phenotype. CD25 and p-NFkB levels were statistically significantly overexpressed in cancer cells.
RESUMEN
5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.
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Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Oxazoles/química , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
INTRODUCTION: Primary sarcoma of the vulva is an extremely rare entity, representing only 1%-3% of all vulvar malignant neoplasms. Among sarcomas, leiomyosarcoma (LMS) is the most prevalent histologic variant. Due to the rarity of LMS, guidelines are lacking and phase III trials have not been carried out, so clinical management is based on local clinical practice and physician experience. CASE PRESENTATION: Here, we described a case of primary LMS of the vulva and its successful management, with the adoption of neoadjuvant chemotherapy and surgery. We report a case of a 74-year-old woman with 12.5 cm vulvar LMS. The patient received three cycles of neoadjuvant chemotherapy with a partial response. Radical vulvectomy with vulvar reconstruction with V-F flap was carried out. Surgical margins were negative. Three additional cycles of adjuvant chemotherapy were delivered. RESULTS: One year after treatment, the patient was disease-free. CONCLUSION: There are no approved therapeutic protocols for this rare neoplasia. Surgery is the mainstay of treatment. However, it is not always feasible, so neoadjuvant chemotherapy was delivered for downstaging the vulvar lesion. We suppose that neoadjuvant chemotherapy has optimized the possibilities of radical surgery. Despite the anectodical nature of this case presentation, neoadjuvant chemotherapy seems a valid therapeutic option for managing patients with bulky vulvar sarcoma. Further large collaborative studies are warranted to identify the best therapeutic option for these patients.
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Leiomiosarcoma , Sarcoma , Neoplasias de la Vulva , Femenino , Humanos , Anciano , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/cirugía , Neoplasias de la Vulva/tratamiento farmacológico , Neoplasias de la Vulva/cirugía , Vulva/patología , Vulva/cirugía , Terapia Neoadyuvante , Sarcoma/patologíaRESUMEN
The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3ß inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.
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Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacología , Tiofenos/farmacología , Línea Celular , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3 beta , Humanos , Modelos Moleculares , Estructura Molecular , Permeabilidad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridonas/síntesis química , Piridonas/química , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D3 antagonists together with SAR and selectivity data.
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Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Benceno/química , Benceno/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.
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Antagonistas de los Receptores de Hormonas Antidiuréticas , Pirazinas/farmacología , Pirroles/farmacología , Pirazinas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
Examination of dopamine-D3 (D3) receptors with positron emission tomography (PET) have been hampered in the past by the lack of a PET ligand with sufficient selectivity for D3 over dopamine-D2 (D2) receptors. The two types co-localize in the brain, with D2 density significantly higher than D3, hence nonselective PET ligands inform on D2, rather than D3 status. [(11)C]-(+)-PHNO is a novel PET ligand with a preferential affinity for D3 over D2. We used the selective D3 antagonist, SB-277011 to dissect regional fractions of the [(11)C]-(+)-PHNO signal attributable to D3 and D2 in primate brain. The results were compared with quantitative autoradiography with (3)H-(+)-PHNO in wild-type, D2-knock-out, and D3-knock-out mice examined at baseline and following administration of SB-277011. Both sets of results converged to indicate a predominant D3-related component to (+)-PHNO binding in extra-striatal regions, with binding in the midbrain being entirely attributable to D3. The midbrain is thus an excellent target region to examine D3 receptor occupancy with [(11)C]-(+)-PHNO PET in vivo.
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Encéfalo/metabolismo , Agonistas de Dopamina/metabolismo , Dopamina/metabolismo , Oxazinas/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Encéfalo/anatomía & histología , Encéfalo/diagnóstico por imagen , Antagonistas de Dopamina/metabolismo , Mesencéfalo/anatomía & histología , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/metabolismo , Ratones , Ratones Noqueados , Nitrilos/metabolismo , Papio anubis , Tomografía de Emisión de Positrones , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/efectos de los fármacos , Receptores de Dopamina D3/genética , Tetrahidroisoquinolinas/metabolismoRESUMEN
The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
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Imidazolidinas/química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Química Orgánica/métodos , Química Farmacéutica/métodos , Antagonistas de los Receptores de Dopamina D2 , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Tomografía de Emisión de Positrones , Ratas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Relación Estructura-Actividad , PorcinosRESUMEN
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported.
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Imidazolidinas/química , Tomografía de Emisión de Positrones , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Gatos , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/farmacología , Ligandos , Receptores de Dopamina D3/metabolismo , Relación Estructura-ActividadRESUMEN
Compound 1 is a potent and selective antagonist of the dopamine D(3) receptor. With the aim of developing a carbon-11 labeled ligand for the dopamine D(3) receptor, 1 was selected as a potential PET probe. [(11)C]1 was obtained by palladium catalyzed cross coupling using [(11)C]cyanide and 4 with a specific activity of 55.5+/-25.9GBq/micromol (1.5+/-0.7Ci/micromol). [(11)C]1 was tested in porcine and non-human primate models to assess its potential as a radioligand for PET imaging of the dopamine D(3) receptor. We conclude that in both species and despite appropriate in vitro properties, [(11)C]1 does not show any specific signal for the dopamine D(3) receptor.
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Imidazolidinas/síntesis química , Piperidinas/síntesis química , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Radioisótopos de Carbono/química , Haplorrinos , Humanos , Imidazolidinas/química , Ligandos , Piperidinas/química , Radiofármacos/química , Ratas , Receptores de Dopamina D3/metabolismo , PorcinosRESUMEN
The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
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Benzazepinas/síntesis química , Benzazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzazepinas/química , Técnicas Químicas Combinatorias , Antagonistas de Dopamina/química , Diseño de Fármacos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
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Benzazepinas/síntesis química , Benzazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D3/antagonistas & inhibidores , Animales , Benzazepinas/química , Técnicas Químicas Combinatorias , Antagonistas de Dopamina/química , Diseño de Fármacos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
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Benzazepinas/síntesis química , Receptores de Dopamina D3/antagonistas & inhibidores , Triazoles/síntesis química , Acetilcolina/metabolismo , Administración Oral , Consumo de Bebidas Alcohólicas/prevención & control , Animales , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D3/agonistas , Receptores Histamínicos H1/metabolismo , Relación Estructura-Actividad , Tabaquismo/prevención & control , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
Glycogen synthase kinase (GSK3) is a constitutively active serine-threonine kinase associated to neurological and psychiatric disorders. GSK3 inhibition is considered a mediator of the efficacy of the mood-stabiliser lithium. This study aimed at comparing the central nervous system effect of lithium with the selective GSK3 inhibitors AZ1080 and compound A in biochemical, cellular, and behavioural tests. Collapsin response mediator protein 2 is a neuron-specific GSK3 substrate. Lithium, AZ1080, and compound A inhibited its phosphorylation in rat primary neurons with different pIC50. After systemic treatments with lithium or GSK3 inhibitors to assess specific functional responses, phosphorylation was unchanged in adult rat brain, while it was strongly inhibited by GSK3 inhibitors in pups, differently from lithium. Lithium may exert neurotrophic effect by increasing brain-derived neurotrophic factor (BDNF) levels: in the present experimental conditions, lithium exerted opposite effects on plasma BDNF levels compared to GSK3 inhibitors, suggesting this effect might not be necessarily mediated by GSK3 inhibition alone. While plasma thyroid-stimulating hormone and luteinising hormone were not affected by lithium, they were decreased by selective inhibitors. GH and prolactin displayed similar responses towards reduction. Follicle-stimulating hormone levels were not altered by treatments, whereas melatonin was specifically increased by AZ1080. Lithium impaired mouse spontaneous locomotion and decreased amphetamine-induced hyper-locomotion. AZ1080 had no effects on locomotion, while compound A reduced spontaneous locomotor activity without effects on amphetamine-induced hyper-locomotion. The present results indicate that a broad correlation between the effects of lithium and selective GSK3 inhibitors could not be devised, suggesting alternative mechanisms, whereas overlapping results could be obtained in specific assays.