RESUMEN
Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine's ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine's effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine's pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine's moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine's cognitive effects, which are observed under chronic dosing conditions in patients with MDD.
Asunto(s)
Acetilcolina/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Espacio Extracelular/efectos de los fármacos , Hipocampo/patología , Piperazinas/farmacología , Escopolamina/farmacología , Sulfuros/farmacología , Animales , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Espacio Extracelular/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Masculino , Piperazinas/uso terapéutico , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Conducta Social , Sulfuros/uso terapéutico , Transmisión Sináptica/efectos de los fármacos , VortioxetinaRESUMEN
Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC.
Asunto(s)
Esclerosis Tuberosa , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Convulsiones/tratamiento farmacológico , Transducción de Señal , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/tratamiento farmacológicoRESUMEN
There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. The rat pharmacokinetic profile is favorable with high oral bioavailability, modest clearance (0.79 L/(h kg)), and good CNS permeability. In vivo mouse CNS microdialysis studies of lipopolysaccharide (LPS)-primed and 2'(3')-O-(benzoylbenzoyl)adenosine-5'-triphosphate (BzATP)-induced IL-1ß release demonstrate functional CNS target engagement. Importantly, Lu AF27139 was without effect in standard in vitro and in vivo toxicity studies. Based on these properties, we believe Lu AF27139 will be a valuable tool for probing the role of the P2X7 receptor in rodent models of CNS diseases.
Asunto(s)
Sistema Nervioso Central/metabolismo , Antagonistas del Receptor Purinérgico P2X/síntesis química , Receptores Purinérgicos P2X7/metabolismo , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Línea Celular , Sistema Nervioso Central/efectos de los fármacos , Perros , Femenino , Semivida , Humanos , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microsomas Hepáticos/metabolismo , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Antagonistas del Receptor Purinérgico P2X/metabolismo , Antagonistas del Receptor Purinérgico P2X/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2X7/químicaRESUMEN
Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in cancer and neurological disorders, including epilepsy. The rapamycin derivative ("rapalog") everolimus, which allosterically inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with spontaneous recurrent seizures (SRS) in individuals with tuberous sclerosis complex (TSC). In contrast to the efficacy in TSC, the efficacy of rapalogs on SRS in other types of epilepsy is equivocal. Furthermore, rapalogs only poorly penetrate into the brain and are associated with peripheral adverse effects, which may compromise their therapeutic efficacy. Here we compare the antiseizure efficacy of two novel, brain-permeable ATP-competitive and selective mTORC1/2 inhibitors, PQR620 and PQR626, and the selective dual pan-PI3K/mTORC1/2 inhibitor PQR530 in two mouse models of chronic epilepsy with SRS, the intrahippocampal kainate (IHK) mouse model of acquired temporal lobe epilepsy and Tsc1GFAP CKO mice, a well-characterized mouse model of epilepsy in TSC. During prolonged treatment of IHK mice with rapamycin, everolimus, PQR620, PQR626, or PQR530; only PQR620 exerted a transient antiseizure effect on SRS, at well tolerated doses whereas the other compounds were ineffective. In contrast, all of the examined compounds markedly suppressed SRS in Tsc1GFAP CKO mice during chronic treatment at well tolerated doses. Thus, against our expectation, no clear differences in antiseizure efficacy were found across the three classes of mTOR inhibitors examined in mouse models of genetic and acquired epilepsies. The main advantage of the novel 1,3,5-triazine derivatives is their excellent tolerability compared to rapalogs, which would favor their development as new therapies for TORopathies such as TSC.
Asunto(s)
Epilepsias Parciales/tratamiento farmacológico , Everolimus/uso terapéutico , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Sirolimus/uso terapéutico , Esclerosis Tuberosa/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Epilepsias Parciales/fisiopatología , Everolimus/farmacología , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Masculino , Ratones , Ratones Noqueados , Resultado del Tratamiento , Esclerosis Tuberosa/fisiopatologíaRESUMEN
The clinical significance and essential role of long non-coding RNA colorectal neoplasia differentially expressed (lncRNA CRNDE) have been well illuminated in various cancers. However, the function of CRNDE in intrahepatic cholangiocarcinoma (IHCC) has not been reported at present. The aim of the present study was to investigate the role of CRNDE in IHCC. Firstly, the relative expression of CRNDE was observed to be upregulated in IHCC cell lines and tissues. And high CRNDE expression was statistically associated with IHCC differentiation grade, lymph node metastasis, tumor-nodes-metastasis (TNM) stage and size. Survival analysis identified that high CRNDE expression is a predictor of worse overall survival (OS) and progression-free survival (PFS) in patients with IHCC. Moreover, high CRNDE expression was identified as an independent risk factor of IHCC poor OS and PFS. Further studies of in vitro assays suggested that CRNDE silencing could suppress the proliferation of HuCCT1 cells following CCK-8 and colony formation assays, while CRNDE ectopic expression in HCCC9810 cells promoted proliferation. Moreover, the migration and invasion of HuCCT1 cells were greatly repressed with CRNDE deficiency following Transwell and Matrigel assays. Accordingly, the motility of HCCC9810 cells was notably accelerated with CRNDE overexpression. Mechanistically, CRNDE was revealed to facilitate the epithelial-mesenchymal transition (EMT) of IHCC cells. In conclusion, these observations indicated that CRNDE could promote the clinical progression and metastasis of IHCC by facilitating EMT. CRNDE may be a novel prognostic marker and therapeutic target in IHCC.
RESUMEN
Vortioxetine is a novel multimodal antidepressant that acts as a serotonin (5-HT)3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B receptor partial agonist; 5-HT1A receptor agonist; and 5-HT transporter inhibitor in vitro. In preclinical and clinical studies vortioxetine demonstrates positive effects on cognitive dysfunction. Vortioxetine's effect on cognitive function likely involves the modulation of several neurotransmitter systems. Acute and chronic administration of vortioxetine resulted in changes in histamine concentrations in microdialysates collected from the rat prefrontal cortex and ventral hippocampus. Based on these results and a literature review of the current understanding of the interaction between the histaminergic and serotonergic systems and the role of histamine on cognitive function, we hypothesize that vortioxetine through an activation of the orexinergic system stimulates the tuberomammilary nucleus and enhances histaminergic neurotransmission, which contributes to vortioxetine's positive effects on cognitive function.
Asunto(s)
Cognición/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Histamina/metabolismo , Área Hipotalámica Lateral/efectos de los fármacos , Orexinas/efectos de los fármacos , Piperazinas/farmacología , Serotoninérgicos/farmacología , Sulfuros/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , VortioxetinaRESUMEN
BACKGROUND: The mechanisms underlying stress-induced inflammation that contribute to major depressive disorder are unknown. We examine the role of the adenosine triphosphate (ATP)/purinergic type 2X7 receptor (P2X7R) pathway and the NLRP3 (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) inflammasome in interleukin (IL)-1ß and depressive behavioral responses to stress. METHODS: The influence of acute restraint stress on extracellular ATP, glutamate, IL-1ß, and tumor necrosis factor alpha in hippocampus was determined by microdialysis, and the influence of acute restraint stress on the NLRP3 inflammasome was determined by western blot analysis. The influence of P2X7R antagonist administration on IL-1ß and tumor necrosis factor alpha and on anxiety and depressive behaviors was determined in the chronic unpredictable stress rodent model. The role of the NLRP3 inflammasome was determined by analysis of Nlrp3 null mice. RESULTS: Acute restraint stress rapidly increased extracellular ATP, an endogenous agonist of P2X7R; the inflammatory cytokine IL-1ß; and the active form of the NLRP3 inflammasome in the hippocampus. Administration of a P2X7R antagonist completely blocked the release of IL-1ß and tumor necrosis factor alpha, another stress-induced cytokine, and activated NLRP3. Moreover, P2X7R antagonist administration reversed the anhedonic and anxiety behaviors caused by chronic unpredictable stress exposure, and deletion of the Nlrp3 gene rendered mice resistant to development of depressive behaviors caused by chronic unpredictable stress. CONCLUSIONS: These findings demonstrate that psychological "stress" is sensed by the innate immune system in the brain via the ATP/P2X7R-NLRP3 inflammasome cascade, and they identify novel therapeutic targets for the treatment of stress-related mood disorders and comorbid illnesses.
Asunto(s)
Adenosina Trifosfato/metabolismo , Ansiedad/metabolismo , Conducta Animal/fisiología , Depresión/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Estrés Psicológico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Anhedonia/fisiología , Animales , Ansiedad/etiología , Ansiedad/inmunología , Depresión/etiología , Depresión/inmunología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Noqueados , Agonistas del Receptor Purinérgico P2Y/metabolismo , Antagonistas del Receptor Purinérgico P2Y/metabolismo , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/complicaciones , Estrés Psicológico/inmunologíaRESUMEN
MMI-166 is a third-generation selective matrix metalloproteinase (MMP) inhibitor that prevents tumor invasion and metastasis by downregulating the activity of MMP-2 and MMP-9. However, MMI-166's effect in pancreatic cancer cells has not been widely studied. Initially, we treated SW1990, human pancreatic cancer cells, with 0, 50 or 100 µg/ml of MMI-166 for 24 h. Apoptosis in the cells was then observed by inverted fluorescence microscope and flow cytometry; the apoptosis rate was dependent on MMI-166 concentration. We then injected nude mice with SW1990 cells. Volume of the resulting xenograft tumors in nude mice treated with MMI-166 was far less than that of the control group, whereas their apoptotic index was much greater. Expression of MMP-2, MMP-9, c-myc and survivin were markedly lower in tumors from the treated mice than in the control group. In cell experiments, MMP-2 and MMP-9 activities were downregulated by MMI-166 compared with controls, as were both mRNA and protein levels of MMP-2, MMP-9 and c-myc, although survivin expression did not differ. These results show that MMI-166 can induce apoptosis of pancreatic cancer cells in vitro and in vivo. The mechanism may be related to downregulation of c-myc by MMI-166.
Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Neoplasias Pancreáticas/patología , Sulfonamidas/farmacología , Animales , Biomarcadores de Tumor/metabolismo , Regulación hacia Abajo , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities.
Asunto(s)
Citalopram/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Serotonina/deficiencia , Sulfuros/uso terapéutico , Tiofenos/uso terapéutico , 5-Hidroxitriptófano/administración & dosificación , Animales , Carbidopa/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Clorhidrato de Duloxetina , Conducta Exploratoria/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Long-Evans , Reconocimiento en Psicología/efectos de los fármacos , VortioxetinaRESUMEN
LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal behavioral models. However, the blood-brain barrier penetration of this amino acid derivative has never been studied. We report studies on the central nervous system (CNS) disposition of LSP1-2111 using quantitative microdialysis in rat. Significant unbound concentrations of the drug relative to its in vitro binding affinity and functional potency were established in extracellular fluid (ECF). These findings support the use of LSP1-2111 to study the CNS pharmacology of mGlu4 receptor activation through orthosteric agonist mechanisms.
RESUMEN
AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of alpha7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective alpha7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178-1.78 mg/kg) and the compound effect was found to be absent in homozygous alpha7 KO animals. Together, these data indicate that selective interaction with alpha7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective alpha7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.