RESUMEN
When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca2+ release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.
Asunto(s)
Maprotilina , Células Ganglionares de la Retina , Ratones , Animales , Células Ganglionares de la Retina/metabolismo , Maprotilina/metabolismo , Maprotilina/farmacología , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Modelos Animales de Enfermedad , Homeostasis , Receptores Histamínicos/metabolismoRESUMEN
Maprotiline is an antidepressant that has been found to cause hypoglycemia. However, the effect of maprotiline on diabetic nephropathy (DN) has not been investigated. Here, we explored the effect of maprotiline on human renal glomerular endothelial cells (HRGECs) in response to high glucose (HG) stimulation. We found that maprotiline attenuated HG-induced oxidative stress in HRGECs with decreased reactive oxygen species production and increased superoxide dismutase activity. Maprotiline repressed the HG-induced expression of cyclooxygenases 2 at both mRNA and protein levels in HRGECs. The increased thromboxane B2 level and decreased 6-keto-prostaglandin F1α level induced by HG were significantly attenuated by maprotiline treatment. Maprotiline also prevented the HG-induced increase in the permeability of HRGECs and the decrease in the zonula occludens-1 expression and downregulated HG-induced increase in the expression of protein kinase C-α (PKC-α) in HRGECs. This protective effect of maprotiline on HG-induced HRGECs dysfunction was abolished by overexpression of PKC-α. In conclusion, maprotiline displayed a protective effect on HG-challenged HRGECs, which was mediated by the regulation of PKC-α. These findings provide further evidence for the potential use of maprotiline for the treatment of DN.
Asunto(s)
Nefropatías Diabéticas , Células Endoteliales , Células Cultivadas , Nefropatías Diabéticas/metabolismo , Células Endoteliales/metabolismo , Glucosa/farmacología , Humanos , Glomérulos Renales/metabolismo , Maprotilina/metabolismo , Maprotilina/farmacología , Estrés Oxidativo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandina-Endoperóxido Sintasas/farmacología , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C-alfa/farmacología , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/farmacología , Tromboxano B2/metabolismo , Tromboxano B2/farmacologíaRESUMEN
Isoflurane-induced neurotoxicity has attracted much interest. Recent studies suggest that isoflurane causes microglial activation, resulting in an inflammatory response and microglial insult. Maprotiline is a novel drug that has been licensed as an antidepressant with considerable anti-inflammatory activity. However, it is still unknown whether maprotiline possesses a protective effect against isoflurane-induced microglial insult. Here, we found that maprotiline ameliorated isoflurane-caused reduction in BV2 microglial cell viability and lactate dehydrogenase (LDH) release. Maprotiline mitigated isoflurane-induced oxidative stress by inhibiting reactive oxygen species (ROS) production and increasing superoxide dismutase (SOD) activity. Isoflurane-induced expression and production of inflammatory markers including tumor necrosis factor (TNF-α), interleukin (IL)-1ß, cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) were decreased in maprotiline-treated cells. Maprotiline inhibited the mRNA and protein levels of Iba1, a marker of microglial activation, in isoflurane-induced BV2 cells. Maprotiline treatment restored isoflurane-induced reduction of TREM2 in BV2 microglial cells. In addition, the knockdown of TREM2 abolished the beneficial effects of maprotiline against isoflurane. Collectively, maprotiline exerted protective effects against isoflurane-caused oxidative stress, inflammatory response, and cell injury via regulating TREM2. These findings show that maprotiline prevented the isoflurane-induced microglial activation, indicating that maprotiline might be used as an optimal therapeutic agent for preventing the isoflurane-caused neurotoxicity.
Asunto(s)
Isoflurano/farmacología , Maprotilina/farmacología , Glicoproteínas de Membrana/metabolismo , Microglía/efectos de los fármacos , Células Mieloides/efectos de los fármacos , Receptores Inmunológicos/metabolismo , Animales , Biomarcadores/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Inflamación/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Ratones , Microglía/metabolismo , Células Mieloides/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
Nav1.7 channels are mainly distributed in the peripheral nervous system. Blockade of Nav1.7 channels with small-molecule inhibitors in humans might provide pain relief without affecting the central nervous system. Based on the facts that many reported Nav1.7-selective inhibitors contain aryl sulfonamide fragments, as well as a tricyclic antidepressant, maprotiline, has been found to inhibit Nav1.7 channels, we designed and synthesized a series of compounds with ethanoanthracene and aryl sulfonamide moieties. Their inhibitory activity on sodium channels were detected with electrophysiological techniques. We found that compound 10o potently inhibited Nav1.7 channels stably expressed in HEK293 cells (IC50 = 0.64 ± 0.30 nmol/L) and displayed a high Nav1.7/Nav1.5 selectivity. In mouse small-sized dorsal root ganglion neurons, compound 10o (10, 100 nmol/L) dose-dependently decreased the sodium currents and dramatically suppressed depolarizing current-elicited neuronal discharge. Preliminary in vivo experiments showed that compound 10o possessed good analgesic activity: in a mouse visceral pain model, administration of compound 10o (30-100 mg/kg, i.p.) effectively and dose-dependently suppressed acetic acid-induced writhing.
Asunto(s)
Analgésicos/farmacología , Descubrimiento de Drogas , Maprotilina/farmacología , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Sulfonamidas/farmacología , Ácido Acético , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Inyecciones Intraperitoneales , Masculino , Maprotilina/administración & dosificación , Maprotilina/química , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Dolor/inducido químicamente , Dimensión del Dolor , Bloqueadores de los Canales de Sodio/administración & dosificación , Bloqueadores de los Canales de Sodio/química , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/químicaRESUMEN
Single injection of muscarinic cholinoceptor blocker atropine (1 mg/kg) to outbred male rats reduced ß-adrenergic responsiveness of erythrocytes (by 2.2 times) and the content of epinephrine granules on erythrocytes (by 1.5 times), significantly increased HR and rigidity of the heart rhythm, and manifold decreased the power of all spectral components of heart rhythm variability. Stimulation of the central neurotransmitter systems increased ß-adrenergic responsiveness of erythrocytes (by 15-26%), decreased the number of epinephrine granules on erythrocytes (by 25-40%), and increased HR and cardiac rhythm intensity. These changes were most pronounced after stimulation of the serotoninergic system. Administration of atropine against the background of activation of central neurotransmitter systems did not decrease ß-adrenergic responsiveness of erythrocytes (this parameter remained at a stably high level and even increased during stimulation of the dopaminergic system), but decreased the number of epinephrine granules on erythrocytes, increased HR, and dramatically decreased the power of all components of heart rhythm variability spectrum. The response to atropine was maximum against the background of noradrenergic system activation and less pronounced during stimulation of the serotoninergic system. Thus, substances that are complementary to cholinergic receptors modulated adrenergic effect on the properties of red blood cells, which, in turn, can modulate the adrenergic influences on the heart rhythm via the humoral channel of regulation. Stimulation of central neurotransmitter systems that potentiates the growth of visceral adrenergic responsiveness weakens the cholinergic modulation of the adrenergic influences, especially with respect to erythrocyte responsiveness. Hence, changes in the neurotransmitter metabolism in the body can lead to coupled modulation of reception and reactivity to adrenergic- and choline-like regulatory factors at the level of erythrocyte membranes, which can be important for regulation of heart rhythm.
Asunto(s)
Atropina/farmacología , Eritrocitos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Corazón/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Receptores Muscarínicos/metabolismo , Acetilcolina/farmacología , Inhibidores de Captación Adrenérgica/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Animales , Animales no Consanguíneos , Cardiotónicos/farmacología , Agonistas Colinérgicos/farmacología , Dopamina/farmacología , Epinefrina/farmacología , Eritrocitos/metabolismo , Corazón/fisiología , Frecuencia Cardíaca/fisiología , Maprotilina/farmacología , Norepinefrina/farmacología , RatasRESUMEN
Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases.
Asunto(s)
Autofagia/inmunología , Autofagia/fisiología , Enfermedades del Sistema Inmune/inmunología , Infecciones/inmunología , Neoplasias/inmunología , Inmunidad Adaptativa/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Autofagia/efectos de los fármacos , Bencilisoquinolinas/farmacología , Colecalciferol/farmacología , Humanos , Inmunidad Innata/inmunología , Indoles , Isoquinolinas/farmacología , Lisosomas/metabolismo , Maprotilina/farmacología , Metformina/farmacología , Fenoles/farmacología , Pirroles/farmacología , Resveratrol , Sirolimus/farmacología , Espermidina/farmacología , Estilbenos/farmacología , Tetrahidroisoquinolinas/farmacología , Trehalosa/farmacologíaRESUMEN
The effects of intraperitoneal DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a noradrenergic neurotoxin) and maprotiline (an inhibitor of norepinephrine reuptake in synapses) on spectral components of heart rhythm variability were examined in outbred male and female rats treated with these agents in daily doses of 10 mg/kg for 3 days. At rest, DSP-4 elevated LF and VLF spectral components in male and female rats. Maprotiline elevated LF and VLF components in males at rest, increased HR and reduced all spectral components in resting females. Stress against the background of DSP-4 treatment sharply increased heart rate and reduced the powers of all spectral components (especially LF and VLF components). In maprotiline-treated rats, stress increased the powers of LF and VLF components. Thus, the central noradrenergic system participates in the formation of LF and VLF spectral components of heart rate variability at rest and especially during stressful stimulation, which can determine the phasic character of changes in the heart rate variability observed in stressed organism.
Asunto(s)
Bencilaminas/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Corazón/efectos de los fármacos , Maprotilina/farmacología , Neurotoxinas/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Neuronas Adrenérgicas/citología , Neuronas Adrenérgicas/efectos de los fármacos , Animales , Animales no Consanguíneos , Esquema de Medicación , Electrocardiografía , Femenino , Corazón/fisiopatología , Inyecciones Intraperitoneales , Masculino , Ratas , Descanso , Estrés FisiológicoRESUMEN
The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 µM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.
Asunto(s)
Analgésicos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Dolor/fisiopatología , Pregnenolona/toxicidad , Primidona/uso terapéutico , Canales Catiónicos TRPM/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Inhibidores de Captación Adrenérgica/uso terapéutico , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Calcio/metabolismo , Diclofenaco/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ganglios Espinales/citología , Células HEK293 , Humanos , Hiperalgesia/etiología , Masculino , Maprotilina/farmacología , Maprotilina/uso terapéutico , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Dolor/inducido químicamente , Umbral del Dolor/efectos de los fármacos , Técnicas de Placa-Clamp , Primidona/química , Primidona/farmacología , RatasRESUMEN
The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A2 (iPLA2) in antinociception induced by the norepinephrine reuptake inhibitor (NRI) and tetracyclic (tricyclic) antidepressant, maprotiline. Intraperitoneal injections of maprotiline increased iPLA2 mRNA and protein expression in the prefrontal cortex. This treatment also reduced grooming responses to von-Frey hair stimulation of the face after facial carrageenan injection, indicating decreased sensitivity to pain. The antinociceptive effect of maprotiline was abrogated by iPLA2 antisense oligonucleotide injection to the prefrontal cortex, indicating a role of this enzyme in antinociception. In contrast, injection of iPLA2 antisense oligonucleotide to the somatosensory cortex did not reduce the antinociceptive effect of maprotiline. Lipidomic analysis of the prefrontal cortex showed decrease in phosphatidylcholine species, but increase in lysophosphatidylcholine species, indicating increased PLA2 activity, and release of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after maprotiline treatment. Differences in sphingomyelin/ceramide were also detected. These changes were not observed in maprotiline-treated mice that received iPLA2 antisense oligonucleotide to the prefrontal cortex. Metabolites of DHA and EPA may help to strengthen a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate a role of prefrontal cortical iPLA2 and its enzymatic products in the antinociceptive effect of maprotiline.
Asunto(s)
Analgésicos/farmacología , Dolor Facial/tratamiento farmacológico , Fosfolipasas A2 Grupo VI/metabolismo , Maprotilina/farmacología , Corteza Prefrontal/efectos de los fármacos , Inhibidores de Captación Adrenérgica/farmacología , Animales , Antidepresivos de Segunda Generación/farmacología , Carragenina , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Dolor Facial/inmunología , Fosfolipasas A2 Grupo VI/antagonistas & inhibidores , Fosfolipasas A2 Grupo VI/genética , Masculino , Ratones Endogámicos C57BL , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Corteza Prefrontal/inmunología , ARN Mensajero/metabolismo , Corteza Somatosensorial/efectos de los fármacos , Corteza Somatosensorial/metabolismoRESUMEN
The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (5) and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (6) as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3) and (4) were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5), (6) and (3) showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively.
Asunto(s)
Antracenos/síntesis química , Ansiolíticos/síntesis química , Antidepresivos/síntesis química , Hidrocarburos Clorados/síntesis química , Animales , Antracenos/química , Antracenos/farmacología , Ansiolíticos/química , Ansiolíticos/farmacología , Antidepresivos/química , Antidepresivos/farmacología , Hidrocarburos Clorados/química , Hidrocarburos Clorados/farmacología , Pérdida de Tono Postural/efectos de los fármacos , Maprotilina/química , Maprotilina/farmacología , Ratones , Estructura Molecular , NataciónRESUMEN
Calcium-independent phospholipase A2 (iPLA2) is an 85-kDa enzyme that releases docosahexaenoic acid (DHA) from glycerophospholipids. DHA can be metabolized to resolvins and neuroprotectins that have anti-inflammatory properties and effects on neural plasticity. Recent studies show an important role of prefrontal cortical iPLA2 in hippocampo-prefrontal cortical LTP and antidepressant-like effect of the norepinephrine reuptake inhibitor (NRI) antidepressant, maprotiline. In this study, we elucidated the cellular mechanisms through which stimulation of adrenergic receptors could lead to increased iPLA2 expression. Treatment of SH-SY5Y neuroblastoma cells with maprotiline, another tricyclic antidepressant with noradrenaline reuptake inhibiting properties, nortriptyline, and the adrenergic receptor agonist, phenylephrine, resulted in increased iPLA2ß mRNA expression. This increase was blocked by inhibitors to alpha-1 adrenergic receptor, mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK) 1/2, and sterol regulatory element-binding protein (SREBP). Maprotiline and phenylephrine induced binding of SREBP-2 to sterol regulatory element (SRE) region on the iPLA2 promoter, as determined by electrophoretic mobility shift assay (EMSA). Together, results indicate that stimulation of adrenoreceptors causes increased iPLA2 expression via MAP kinase/ERK 1/2 and SREBP, and suggest a possible mechanism for effect of CNS noradrenaline on neural plasticity and crosstalk between sterol and glycerophospholipid mediators, that may play a role in physiological or pathophysiological processes in the brain and other organs.
Asunto(s)
Glicerofosfolípidos/fisiología , Fosfolipasas A2 Grupo VI/biosíntesis , Receptor Cross-Talk/fisiología , Receptores Adrenérgicos/fisiología , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Agonistas Adrenérgicos/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antidepresivos/farmacología , Línea Celular Tumoral , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Maprotilina/farmacología , Receptor Cross-Talk/efectos de los fármacos , Esteroles/metabolismoRESUMEN
BACKGROUND: Although alterations in not only the pain sensitivity but also the analgesic effects of opioids have been reported under conditions of stress, the influence of unpredictable chronic mild stress (UCMS) on the antinociceptive effects of opioid analgesics remains to be fully investigated. The present study examined the influence of UCMS on the thermal pain sensitivity and antinociceptive effects of two opioid analgesics, morphine (an agonist of opioid receptors) and tramadol (an agonist of µ-opioid receptor and an inhibitor of both noradrenaline and serotonin transporters). We also examined the effects of pretreatment with maprotiline (a noradrenaline reuptake inhibitor) and escitalopram (a serotonin reuptake inhibitor) on the antinociceptive action of morphine in mice under an UCMS condition. RESULTS: Unpredictable chronic mild stress did not affect the basal thermal pain sensitivity in a mouse hot-plate test. Although morphine dose-dependently induced thermal antinociceptive effects under both the UCMS and non-stress conditions, the thermal antinociceptive effect of 3 mg/kg morphine under the UCMS condition was significantly lower than under the non-stressed condition. Unlike the case with morphine, we observed no significant difference in the thermal antinociceptive effect of tramadol between the UCMS and non-stress conditions. Furthermore, the reduced thermal antinociceptive effect of 3 mg/kg morphine under the UCMS condition was significantly ameliorated by pretreatment with 10 mg/kg maprotiline but not 3 mg/kg escitalopram. Pretreatment with neither maprotiline nor escitalopram alone was associated with an antinociceptive effect under either condition. CONCLUSIONS: We demonstrated that the antinociceptive effect of morphine but not tramadol was reduced in mice that had experienced UCMS. The reduced antinociceptive effect of morphine under the UCMS condition was ameliorated by pretreatment with maprotiline but not escitalopram. These results suggest that the reduced antinociceptive effects of morphine under conditions of chronic stress may be ameliorated by activation of the noradrenergic but not the serotonergic system.
Asunto(s)
Analgésicos/farmacología , Morfina/farmacología , Norepinefrina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estrés Fisiológico/efectos de los fármacos , Animales , Enfermedad Crónica , Citalopram/farmacología , Modelos Animales de Enfermedad , Masculino , Maprotilina/farmacología , Ratones Endogámicos BALB C , Temperatura , Tramadol/farmacologíaRESUMEN
Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.
Asunto(s)
Biopelículas/efectos de los fármacos , Francisella/efectos de los fármacos , Maprotilina/química , Maprotilina/farmacología , Proteínas Quinasas/metabolismo , Tularemia/tratamiento farmacológico , Animales , Biopelículas/crecimiento & desarrollo , Modelos Animales de Enfermedad , Femenino , Francisella/genética , Francisella/metabolismo , Francisella/patogenicidad , Regulación Bacteriana de la Expresión Génica , Islas Genómicas , Histidina Quinasa , Larva/microbiología , Maprotilina/aislamiento & purificación , Maprotilina/uso terapéutico , Ratones , Pruebas de Sensibilidad Microbiana , Mariposas Nocturnas/microbiología , Proteínas Quinasas/química , Tularemia/microbiología , Estados Unidos , United States Food and Drug Administration , Virulencia/efectos de los fármacos , Factores de Virulencia/genética , Factores de Virulencia/metabolismoRESUMEN
BACKGROUND: Methylphenidate (MPH), a psychostimulant drug used to treat attention-deficit/hyperactivity disorder, produces the effects of increasing alertness and improving attention. However, misuse of MPH has been associated with an increased risk of aggression and psychosis. We sought to determine the molecular mechanism underlying the complex actions of MPH. METHODS: Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex was measured. Behavioral changes induced by MPH were also examined in parallel. RESULTS: Administration of low-dose (.5 mg/kg) MPH selectively potentiated N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) via adrenergic receptor activation, whereas high-dose (10 mg/kg) MPH suppressed both NMDAR-mediated and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated EPSCs. The dual effects of MPH on EPSCs were associated with bidirectional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated prefrontal cortex-mediated temporal order recognition memory and attention. Animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of synaptosomal-associated protein 25, a key SNARE protein involved in NMDAR exocytosis, blocked the increase of NMDAR-mediated EPSCs by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and temporal order recognition memory via a mechanism dependent on synaptosomal-associated protein 25. CONCLUSIONS: These results provide a potential mechanism underlying the cognitive-enhancing effects of low-dose MPH as well as the psychosis-inducing effects of high-dose MPH.
Asunto(s)
Atención/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Receptores de Glutamato/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Inhibidores de Captación Adrenérgica/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Análisis de Varianza , Animales , Benzazepinas/farmacología , Biofisica , Discriminación en Psicología/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Masculino , Maprotilina/farmacología , Neuronas/efectos de los fármacos , Péptidos/farmacología , Piperazinas/farmacología , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Receptores de Glutamato/genética , Proteína 25 Asociada a Sinaptosomas/química , Proteína 25 Asociada a Sinaptosomas/metabolismo , Yohimbina/farmacologíaRESUMEN
RATIONALE: Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is upregulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI), reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. OBJECTIVES: We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BDNF by testing for region-specific changes in areas CA1, CA3, and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. METHODS: Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and Western blotting. RESULTS: LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. CONCLUSIONS: LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium influx.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Ciclohexanoles/farmacología , Fluoxetina/farmacología , Hipocampo/metabolismo , Imipramina/farmacología , Masculino , Maprotilina/farmacología , Norepinefrina/metabolismo , Serotonina/metabolismo , Clorhidrato de VenlafaxinaRESUMEN
The synthesis of a diverse library of compounds structurally related to maprotiline, a norepinephrine reuptake transporter (NET) selective antidepressant which has recently been identified as a novel in vitro antiproliferative agent against Burkitt's lymphoma (BL) cell lines is reported. A series of 9,10-dihydro-9,10-ethanoanthracenes were synthesised with modifications to the bridge of the dihydroethanoanthracene structure and with alterations to the basic side chain. A number of compounds were found to reduce cell viability to a greater extent than maprotiline in BL cell lines. In addition a related series of novel 9-substituted anthracene compounds were investigated as intermediates in the synthesis of 9,10-dihydro-9,10-ethanoanthracenes. These compounds proved the most active from the screen and were found to exert a potent caspase-dependant apoptotic effect in the BL cell lines, while having minimal effect on the viability of peripheral blood mononuclear cells (PBMCs). Compounds also displayed activity in multi-drug resistant (MDR) cells.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Antineoplásicos/farmacología , Linfoma de Burkitt/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Maprotilina/farmacología , Inhibidores de Captación Adrenérgica/síntesis química , Inhibidores de Captación Adrenérgica/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Maprotilina/análogos & derivados , Maprotilina/síntesis química , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Objective: Despite the recognized anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. Thus, we evaluated the anti-inflammatory effect of amitriptyline, clomipramine, and maprotiline and the possible modulating properties of these drugs on neutrophil migration and mast cell degranulation. Methods: The hind paw edema and air-pouch models of inflammation were used. Male Wistar rats were treated with saline, amitriptyline, clomipramine or maprotiline (10, 30, or 90 mg/kg, per os [p.o.]) 1 h before the injection of carrageenan (300 μg/0.1 mL/paw) or dextran (500 μg/0.1 mL/paw). Then, edema formation was measured hourly. Neutrophil migration to carrageenan (500 μg/pouch) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10-6 M/mL/pouch) was also investigated in 6-day-old air-pouch cavities. Compound 48/80-induced mast cell degranulation was assessed in the mesenteric tissues of antidepressant-treated rats. Results: All tested antidepressants prevented both carrageenan- and dextran-induced edema. The anti-inflammatory effect of these drugs partially depends on the modulation of neutrophil migration, since they significantly counteracted the chemotactic response of both carrageenan and fMLP (p < 0.01). Furthermore, amitriptyline, clomipramine and maprotiline inhibited compound 48/80-induced mast cell degranulation (p < 0.001). Conclusions: These results suggest an important anti-inflammatory role of heterocyclic antidepressants, which is dependent on the modulation of neutrophil migration and mast cell stabilization. .
Asunto(s)
Animales , Masculino , Ratas , Amitriptilina/farmacología , Antiinflamatorios/farmacología , Degranulación de la Célula/efectos de los fármacos , Clomipramina/farmacología , Maprotilina/farmacología , Mastocitos/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Carragenina/efectos adversos , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Edema/inducido químicamente , Mastocitos/fisiología , Ratas WistarRESUMEN
OBJECTIVE: Despite the recognized anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. Thus, we evaluated the anti-inflammatory effect of amitriptyline, clomipramine, and maprotiline and the possible modulating properties of these drugs on neutrophil migration and mast cell degranulation. METHODS: The hind paw edema and air-pouch models of inflammation were used. Male Wistar rats were treated with saline, amitriptyline, clomipramine or maprotiline (10, 30, or 90 mg/kg, per os [p.o.]) 1 h before the injection of carrageenan (300 µg/0.1 mL/paw) or dextran (500 µg/0.1 mL/paw). Then, edema formation was measured hourly. Neutrophil migration to carrageenan (500 µg/pouch) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10-6 M/mL/pouch) was also investigated in 6-day-old air-pouch cavities. Compound 48/80-induced mast cell degranulation was assessed in the mesenteric tissues of antidepressant-treated rats. RESULTS: All tested antidepressants prevented both carrageenan- and dextran-induced edema. The anti-inflammatory effect of these drugs partially depends on the modulation of neutrophil migration, since they significantly counteracted the chemotactic response of both carrageenan and fMLP (p < 0.01). Furthermore, amitriptyline, clomipramine and maprotiline inhibited compound 48/80-induced mast cell degranulation (p < 0.001). CONCLUSIONS: These results suggest an important anti-inflammatory role of heterocyclic antidepressants, which is dependent on the modulation of neutrophil migration and mast cell stabilization.
Asunto(s)
Amitriptilina/farmacología , Antiinflamatorios/farmacología , Degranulación de la Célula/efectos de los fármacos , Clomipramina/farmacología , Maprotilina/farmacología , Mastocitos/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Animales , Carragenina/efectos adversos , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Edema/inducido químicamente , Masculino , Mastocitos/fisiología , Ratas , Ratas WistarRESUMEN
Antidepressants are generally used for treatment of various mood and anxiety disorders. Several studies have shown the anti-tumor and cytotoxic activities of some antidepressants, but the underlying mechanisms were unclear. Maprotiline is a tetracyclic antidepressant and possesses a highly selective norepinephrine reuptake ability. We found that maprotiline decreased cell viability in a concentration- and time-dependent manner in Neuro-2a cells. Maprotiline induced apoptosis and increased caspase-3 activation. The activation of caspase-3 by maprotiline appears to depend on the activation of JNK and the inactivation of ERK. Maprotiline also induced [Ca(2+)](i) increases which involved the mobilization of intracellular Ca(2+) stored in the endoplasmic reticulum. Pretreatment with BAPTA/AM, a Ca(2+) chelator, suppressed maprotiline-induced ERK phosphorylation, enhanced caspase-3 activation and increased maprotiline-induced apoptosis. In conclusion, maprotiline induced apoptosis in Neuro-2a cells through activation of JNK-associated caspase-3 pathways. Maprotiline also evoked an anti-apoptotic response that was both Ca(2+)- and ERK-dependent.