RESUMEN
BACKGROUND: Postpartum depression has a high prevalence in the United States (~13 %) and often goes undertreated/untreated. We conducted a multicenter, open-label, proof-of-concept trial to assess the Nesos wearable, non-invasive, transcutaneous auricular vagus nerve stimulation (taVNS) system for the treatment of major depressive disorder with peripartum onset (PPD). METHODS: Women (n = 25), ages 18 to 45, within 9 months postpartum, and diagnosed with PPD were enrolled at 3 sites. The study included 6 weeks open-label therapy and 2 weeks observation. Efficacy outcomes included change from baseline (CFB) in Hamilton Rating Scale for Depression (HAMD17) total scores, HAM-D17 response and remission, and patient and clinician global impression of change (PGIC, CGIC) scores. Analysis included descriptive statistics and mixed-effects models for repeated measures. RESULTS: The most common AEs (≥5 %) were discomfort (n = 5), headache (n = 3), and dizziness (n = 2); all resolved without intervention. No serious AEs or deaths occurred. Baseline mean HAM-D17 score was 18.4. Week 6 least squares (LS) mean CFB in HAM-D17 score was -9.7; 74 % achieved response and 61 % achieved remission. At week 6, at least some improvement was reported by 21 of 22 (95 %) clinicians on CGIC and 22 of 23 (96 %) participants on PGIC. LIMITATIONS: This was a single-arm, open-label study, and enrollment was limited to participants with mild-to-moderate peripartum depression. CONCLUSION: Results from this proof-of-concept study suggest that the Nesos taVNS system is well tolerated and may be an effective non-invasive, non-pharmacological treatment for major depressive disorder with peripartum onset. Further evaluation in larger sham-controlled studies is needed. CLINICALTRIALS: govNCT03972995.
Asunto(s)
Trastorno Depresivo Mayor , Estimulación Eléctrica Transcutánea del Nervio , Estimulación del Nervio Vago , Adolescente , Adulto , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Periodo Periparto , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , Nervio Vago , Estimulación del Nervio Vago/métodos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Palmitoylethanolamide (PEA) acts via several targets, including cannabinoid CB1 and CB2 receptors, transient receptor potential vanilloid type-1 (TRPV1) ion channels, peroxisome proliferator-activated receptor alpha (PPAR α) and orphan G protein-coupled receptor 55 (GRR55), all involved in the control of intestinal inflammation. Here, we investigated the effect of PEA in a murine model of colitis. EXPERIMENTAL APPROACH: Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters and by histology; intestinal permeability by a fluorescent method; colonic cell proliferation by immunohistochemistry; PEA and endocannabinoid levels by liquid chromatography mass spectrometry; receptor and enzyme mRNA expression by quantitative RT-PCR. KEY RESULTS: DNBS administration caused inflammatory damage, increased colonic levels of PEA and endocannabinoids, down-regulation of mRNA for TRPV1 and GPR55 but no changes in mRNA for CB1 , CB2 and PPARα. Exogenous PEA (i.p. and/or p.o., 1 mg·kg(-1) ) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB1 receptor expression. The anti-inflammatory effect of PEA was attenuated or abolished by CB2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine. CONCLUSIONS AND IMPLICATIONS: PEA improves murine experimental colitis, the effect being mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels.
Asunto(s)
Antiinflamatorios/uso terapéutico , Colitis/tratamiento farmacológico , Etanolaminas/uso terapéutico , Ácidos Palmíticos/uso terapéutico , Administración Oral , Amidas , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Bencenosulfonatos , Capsaicina/análogos & derivados , Capsaicina/farmacología , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Modelos Animales de Enfermedad , Endocannabinoides/metabolismo , Etanolaminas/administración & dosificación , Etanolaminas/farmacocinética , Etanolaminas/farmacología , Absorción Intestinal/efectos de los fármacos , Masculino , Ratones Endogámicos ICR , Ácidos Oléicos/metabolismo , PPAR alfa/genética , Ácidos Palmíticos/administración & dosificación , Ácidos Palmíticos/farmacocinética , Ácidos Palmíticos/farmacología , Peroxidasa/metabolismo , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/genética , Receptores de Cannabinoides/genética , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/genéticaRESUMEN
Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid (CB), which interacts with specific targets involved in carcinogenesis. Specifically, CBG potently blocks transient receptor potential (TRP) M8 (TRPM8), activates TRPA1, TRPV1 and TRPV2 channels, blocks 5-hydroxytryptamine receptor 1A (5-HT1A) receptors and inhibits the reuptake of endocannabinoids. Here, we investigated whether CBG protects against colon tumourigenesis. Cell growth was evaluated in colorectal cancer (CRC) cells using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and 3-amino-7-dimethylamino-2-methylphenazine hydrochloride assays; apoptosis was examined by histology and by assessing caspase 3/7 activity; reactive oxygen species (ROS) production by a fluorescent probe; CB receptors, TRP and CCAAT/enhancer-binding protein homologous protein (CHOP) messenger RNA (mRNA) expression were quantified by reverse transcription-polymerase chain reaction; small hairpin RNA-vector silencing of TRPM8 was performed by electroporation. The in vivo antineoplastic effect of CBG was assessed using mouse models of colon cancer. CRC cells expressed TRPM8, CB1, CB2, 5-HT1A receptors, TRPA1, TRPV1 and TRPV2 mRNA. CBG promoted apoptosis, stimulated ROS production, upregulated CHOP mRNA and reduced cell growth in CRC cells. CBG effect on cell growth was independent from TRPA1, TRPV1 and TRPV2 channels activation, was further increased by a CB2 receptor antagonist, and mimicked by other TRPM8 channel blockers but not by a 5-HT1A antagonist. Furthermore, the effect of CBG on cell growth and on CHOP mRNA expression was reduced in TRPM8 silenced cells. In vivo, CBG inhibited the growth of xenograft tumours as well as chemically induced colon carcinogenesis. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of CRC cells, an effect shared by other TRPM8 antagonists. CBG should be considered translationally in CRC prevention and cure.
Asunto(s)
Apoptosis/efectos de los fármacos , Cannabinoides/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Canales Catiónicos TRPM/antagonistas & inhibidores , Animales , Azoximetano/toxicidad , Western Blotting , Cannabis/química , Carcinógenos/toxicidad , Células Cultivadas , Colon/citología , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Desnudos , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inflammatory bowel disease (IBD) is an incurable disease which affects millions of people in industrialized countries. Anecdotal and scientific evidence suggests that Cannabis use may have a positive impact in IBD patients. Here, we investigated the effect of cannabigerol (CBG), a non-psychotropic Cannabis-derived cannabinoid, in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulphonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters (colon weight/colon length ratio and myeloperoxidase activity), by histological analysis and immunohistochemistry; interleukin-1ß, interleukin-10 and interferon-γ levels by ELISA, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blot and RT-PCR; CuZn-superoxide dismutase (SOD) activity by a colorimetric assay. Murine macrophages and intestinal epithelial cells were used to evaluate the effect of CBG on nitric oxide production and oxidative stress, respectively. CBG reduced colon weight/colon length ratio, myeloperoxidase activity, and iNOS expression, increased SOD activity and normalized interleukin-1ß, interleukin-10 and interferon-γ changes associated to DNBS administration. In macrophages, CBG reduced nitric oxide production and iNOS protein (but not mRNA) expression. Rimonabant (a CB1 receptor antagonist) did not change the effect of CBG on nitric oxide production, while SR144528 (a CB2 receptor antagonist) further increased the inhibitory effect of CBG on nitric oxide production. In conclusion, CBG attenuated murine colitis, reduced nitric oxide production in macrophages (effect being modulated by the CB2 receptor) and reduced ROS formation in intestinal epithelial cells. CBG could be considered for clinical experimentation in IBD patients.
Asunto(s)
Antiinflamatorios/farmacología , Cannabinoides/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Cannabinoides/uso terapéutico , Línea Celular , Colitis/tratamiento farmacológico , Colitis/patología , Colon/efectos de los fármacos , Colon/patología , Ciclooxigenasa 2/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Enfermedades Inflamatorias del Intestino/patología , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Antígeno Ki-67/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Óxido Nítrico Sintasa de Tipo II/metabolismo , Permeabilidad , Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
We describe the clinicopathological and morphological features of an unusual breast carcinoma classifiable as a lipid-rich variant of ductal invasive carcinoma, with a basal-type immunohistochemical profile. Basal-type breast cancers show no hormonal receptor expression, rarely over-express HER-2 but exhibit molecular high weight cytokeratins, EGFR and c-kit positivity. Special stains and histochemistry tests were used to elucidate the nature of vescicles in the neoplastic cells. Sudan IV was performed on formalin-fixed tissue. Commercially available antibodies tested were: ER, PgR, EGFR, HER2, c-kit, high molecular weight cytokeratins. Cytoplasmic lipids were highlighted as red-orange droplets on Sudan IV staining. As for immunohistochemistry, the tumor showed no reactivity to ER, PgR and HER2 (triple negative), and diffuse and strong positivity to high weight cytokeratins, EGFR and c-kit, such as a basal-type breast carcinoma. A basaloid phenotype in a lipid-rich carcinoma has not been previously reported.