RESUMEN
Psilocybe cubensis is a species of psilocybin mushroom (magic mushroom) of moderate potency whose principal active compounds are psilocybin and psilocin. Recent studies have shown the significant procognitive and mood-enhancer effects of Psilocybe cubensis. However, evidence is so limited, especially in preclinical studies. We aimed to investigate the effect of Psilocybe cubensis extract on posttraumatic stress disorder (PTSD)-like behavior, pain perception, locomotor activity, and anxiety in a rat model of PTSD. Male rats were exposed to three consecutive shocks (0.8 mA, 3 s interval) paired with three sounds broadcasted 3 s before delivering shocks (75 dB, 3 s). After 1, 3, or 21 days, freezing rate was measured in the fear-conditioning apparatus. Open filed test and hot plate were used to assess locomotor activity and anxiety, and pain subthreshold, respectively. Psilocybe cubensis was injected intraperitoneal at the dose of 25 mg/kg (single administration) before (pretrain) or after (posttrain) shocks, or before the test (pretest). Results showed psilocybin potently alleviated PTSD symptom is short- but not long-term after the induction of PTSD. Psilocybe cubensis decreased locomotor activity only in a short period after administration. Psilocybe cubensis also increased pain subthreshold and decreased anxiety. In conclusion, Psilocybe cubensis effects on PTSD-like behavior and locomotor activity seem to be remained in short-term, while Psilocybe cubensis effects on pain subthreshold and anxiety remained long-term. This is the first study evaluating the effect of Psilocybe cubensis on PTSD-like behavior in rats in three different time protocols (1, 3, and 21 days after fear conditioning). (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Asunto(s)
Modelos Animales de Enfermedad , Miedo , Trastornos por Estrés Postraumático , Animales , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/fisiopatología , Masculino , Miedo/efectos de los fármacos , Ratas , Psilocibina/farmacología , Recuerdo Mental/efectos de los fármacos , Recuerdo Mental/fisiología , Ansiedad/tratamiento farmacológico , Ratas WistarRESUMEN
Natural psychedelic compounds are emerging as potential novel therapeutics in psychiatry. This review will discuss how natural psychedelics exert their neurobiological therapeutic effects, and how different neurotransmission systems mediate the effects of these compounds. Further, current therapeutic strategies for depression, and novel mechanism of action of natural psychedelics in the treatment of depression will be discussed. In this review, our focus will be on N, N-dimethyltryptamine (DMT), reversible type A monoamine oxidase inhibitors, mescaline-containing cacti, psilocybin/psilocin-containing mushrooms, ibogaine, muscimol extracted from Amanita spp. mushrooms and ibotenic acid.
Asunto(s)
Alucinógenos , Alucinógenos/farmacología , Alucinógenos/uso terapéutico , Depresión/tratamiento farmacológico , Estructura Molecular , N,N-Dimetiltriptamina/farmacología , NeurotransmisoresRESUMEN
Almost half of the treatments with common antidepressants are failed or result in a relapse of symptoms after cessation. Moreover, the antidepressants side effects rationalize the use of complementary medicine as an adjunctive therapy. This study aimed to evaluate the efficacy and safety of propolis in complementary therapy of depressive disorder. Chromatography technics were used to detect propolis components. A double-blind, randomized, placebo-controlled trial was designed, and 54 participants were randomly assigned to receive either propolis or Placebo for 6 weeks. Treatment was defined as a decrease in 17-item Hamilton Depression Scale (HAMD-17) and Beck depression inventory (BDI). On D42, there was a significant reduction in HAMD score in the propolis group compared with the placebo group (p < .0001). HAMD score significantly decreased in the propolis group from 20.92 ± 3.77 on D0 to 10.03 ± 5.55 on D42, and BDI score was improved from 29.25 ± 3.06 on D0 to 14.17 ± 4.86 on D42. Our findings confirmed that complementary treatment of propolis with SSRIs could safely attenuate symptoms of moderate-severe MDD. These antidepressant effects might result from the rich phenolic acids and flavonoids content of Azerbaijan propolis.
Asunto(s)
Depresión , Própolis , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Método Doble Ciego , Humanos , Própolis/uso terapéutico , Escalas de Valoración Psiquiátrica , Resultado del TratamientoRESUMEN
Adolescence is a pivotal period of brain development during lifespan, which is sensitive to stress exposure. Early social isolation stress (SIS) is known to provoke a variety of psychiatric comorbidities as well as seizure risk. Psychiatric comorbidities present challenging dilemmas for treatment and management in people with seizure disorders. In this study, we aimed to investigate whether gabapentin (GBP) as an anti-epileptic drug is able to alleviate the seizure activity as well as comorbid behavioral abnormalities in socially isolated mice. Results showed that early SIS induced proconvulsant effects along with depressive, aggressive and anxiety-like behaviors. Whereas the administration of both acute and chronic GBP at sub-effective doses produced no alterations in the behavioral profile of socially conditioned counterparts the same treatments effectively reversed the seizure susceptibility to pentylenetetrazole and behavioral deficits in isolated mice. Results of the study indicate that 1) Early SIS could be considered as an animal model of psychosocial stress to investigate the psychiatric comorbidities in seizure disorders, 2) Chronic administration of low dose GBP prevented the shaping of behavioral abnormalities in adulthood, 3) Chronic administration of low dose GBP produced no negative behavioral effects in socially conditioned mice suggesting the safety of the drug, 4) Gabapentin at low doses may be considered as an agent for management of epilepsy in individuals with psychiatric comorbidities.
Asunto(s)
Aminas/farmacología , Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Ácidos Ciclohexanocarboxílicos/farmacología , Convulsiones/complicaciones , Convulsiones/prevención & control , Convulsiones/psicología , Aislamiento Social/psicología , Ácido gamma-Aminobutírico/farmacología , Agresión/efectos de los fármacos , Animales , Ansiedad/complicaciones , Comorbilidad , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta a Droga , Gabapentina , Vivienda , Locomoción/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Convulsiones/fisiopatología , Estrés Psicológico/complicacionesRESUMEN
In this study, we tested whether acute administration of lithium mitigates the deleterious effect of adolescent social isolation stress (SIS) on seizure susceptibility. In comparison with socially conditioned (SC) mice, isolated conditioned (IC) mice exhibited an increase in seizure susceptibility to pentylenetetrazole. Acute administration of lithium (10mg/kg) reversed the proconvulsant effect of SIS in IC mice, but this effect was not observed in SC mice. Coadministration of subthreshold doses of lithium (3mg/kg) with nitric oxide synthase (NOS) inhibitors reversed the effect of SIS on seizure susceptibility and decreased hippocampal nitrite levels in IC animals. In addition, a subthreshold dose of a nitric oxide precursor reduced the protective effect of lithium on seizure susceptibility and increased nitrite levels in the hippocampus of IC mice. These results suggest that lithium exerts a protective influence against the proconvulsant effect of adolescent SIS via a nitrergic system that includes activation of neuronal NOS in the hippocampus.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Cloruro de Litio/uso terapéutico , Óxido Nítrico/fisiología , Convulsiones/prevención & control , Aislamiento Social/psicología , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicología , Animales , Convulsivantes , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Hipocampo/metabolismo , Cloruro de Litio/antagonistas & inhibidores , Masculino , Ratones , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico Sintasa de Tipo I/metabolismo , Pentilenotetrazol , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Natación/psicologíaRESUMEN
Mother-infant interactions are known to be associated with the psychological well-being of an individual in adulthood. It is well accepted that emotional stress in early life, such as maternal separation (MS), leads to alterations in the neurotransmission systems of various brain regions, especially the mesolimbic dopaminergic system, and subsequently can increase the risk for development of psychiatric disorders including depression in adulthood. Selegiline is an irreversible monoamine oxidase (MAO) type B inhibitor which increases striatal dopamine levels and exerts an antidepressant effect. In this study, 180min of MS stress was applied to mice at postnatal day (PND) 2-14 followed by behavioral tests for determining depressive-like behaviors, such as forced swimming test (FST), splash test and sucrose preference test (SPT) in adult mice (PND 50). The open field test (OFT) also was applied to validate FST results. We used SCH23390 (D1 antagonist) and sulpiride (D2 antagonist) in order to determine the role of D1 and D2 dopamine receptors in antidepressant-like effects of selegiline. Our results revealed that MS provoked depressive-like behaviors in adult male mice, and the administration of selegiline attenuated depressive-like behaviors in MS mice. Our findings showed that D1 dopamine receptors facilitate the positive effects of selegiline on the passive behavior in the FST. Furthermore, antidepressant effects of selegiline on hedonic difficulties are mediated via D2 receptor in the SPT. The results of the splash test revealed that both D1 and D2 receptors mediate the protective effect of selegiline against motivational and self-care problems. Based on our results, we conclude that both D1 and D2 dopamine receptors are involved in mediating the antidepressant-like effect of selegiline. We found that D1 receptors mediate an effect on despair behavior, D2 receptors mediate an effect on anhedonia, and both D1 and D2 receptors contribute to the protective effects of selegiline on motivational complications.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Privación Materna , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Selegilina/uso terapéutico , Análisis de Varianza , Animales , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Preferencias Alimentarias/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Masculino , Ratones , Motivación/efectos de los fármacos , Selegilina/farmacología , Natación/psicologíaRESUMEN
CONTEXT: Myrtus communis L. (Myrtaceae), myrtle, is an evergreen shrub with strong antibacterial, anti-inflammatory, antihyperglycemic and antioxidant activities. Also, it is used as a sedative-hypnotic plant in Iranian traditional medicine. OBJECTIVE: This study evaluates the effect of 80% ethanolic extract of M. communis leaves on sleep and anxiety in mice and rats. MATERIALS AND METHODS: Male NMRI mice were subjected to open field, righting reflex, grip strength and pentylentetrazole-induced seizure tests. Male Wistar rats were used to evaluate the alterations in rapid eye movement (REM) and non-REM (NREM) sleep. They were treated with 25-400 mg/kg doses of the extract intraperitoneally. RESULTS: The applied doses (50-200 mg/kg) of M. communis extract increased vertical (ED50 = 40.2 ± 6.6 mg/kg) and vertical and horizontal activity (ED50 = 251 ± 55 mg/kg), while treatment with 200 and 400 mg/kg attenuated muscle tone significantly compared to vehicle treated animals (p < 0.001 for all) in a dose-independent manner. Also, a significant hypnotic and not anticonvulsant effect was observed when animals were treated with 200 mg/kg of the extract (p < 0.01). In this regard, electroencephalography results showed that REM sleep time was decreased (2.4 ± 0.5%), while total and NREM sleep times were increased significantly compared to the control group of mice (82.5 ± 7.6%). DISCUSSION AND CONCLUSION: The data show the anxiolytic and muscle relaxant effect of the extract without anticonvulsant activities. The anxiolytic, myorelaxant and hypnotic effects without effect on seizure threshold are in line with the effect of a alpha 2 GABA receptor agonist.
Asunto(s)
Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Electroencefalografía , Etanol/química , Hipnóticos y Sedantes/farmacología , Fármacos Neuromusculares/farmacología , Extractos Vegetales/farmacología , Sueño/efectos de los fármacos , Solventes/química , Animales , Ansiolíticos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Electromiografía , Agonistas de Receptores de GABA-A/farmacología , Hipnóticos y Sedantes/aislamiento & purificación , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Fuerza Muscular/efectos de los fármacos , Myrtus/química , Fármacos Neuromusculares/aislamiento & purificación , Fitoterapia , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Plantas Medicinales , Ratas Wistar , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo , Factores de TiempoRESUMEN
OBJECTIVES: Cardiomyocyte hypertrophy is an important structural feature of diabetic cardiomyopathy. Calcineurin/nuclear factor of activated T-cell (NFAT) pathway plays a central role in the pathogenesis of cardiac hypertrophy. The purpose of this study was to investigate the effects of tropisetron, a novel calcineurin inhibitor, on high glucose (HG)-induced cardiomyocyte hypertrophy and its underlying mechanism. METHODS: H9c2 myocardial cells were treated with tropisetron or cyclosporine A 1 h before exposure to HG for 48 h. KEY FINDINGS: Exposure to HG resulted in enhanced cell size, protein content and atrial natriuretic peptide (ANP) protein expression. HG significantly increased Ca(2+) level, calcineurin expression and nuclear translocation of NFATc4. Both tropisetron and cyclosporine A markedly prevented the hypertrophic characteristic features, calcineurin overexpression and nuclear localization of NFATc4 while intracellular Ca(2+) was not affected. CONCLUSION: Our results showed that tropisetron may have protective effects against HG-induced cardiomyocyte hypertrophy. The mechanism responsible for this beneficial effect seems to be, at least in part, blockade of calcineurin/NFAT signalling pathway.
Asunto(s)
Inhibidores de la Calcineurina/farmacología , Calcineurina/metabolismo , Cardiomegalia/prevención & control , Cardiomiopatías Diabéticas/prevención & control , Glucosa/toxicidad , Indoles/farmacología , Miocitos Cardíacos/efectos de los fármacos , Factores de Transcripción NFATC/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transporte Activo de Núcleo Celular , Animales , Factor Natriurético Atrial/metabolismo , Calcio/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/patología , Línea Celular , Tamaño de la Célula/efectos de los fármacos , Citoprotección , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Transducción de Señal/efectos de los fármacos , TropisetrónRESUMEN
Lithium (Li), a glycogen synthase kinase-3ß (GSK-3ß) inhibitor, has used to attenuate the cannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this are unclear. Recent studies indicate the involvement of upstream extracellular signal kinase1/2 (ERK1/2) and downstream GSK-3ß pathways in the development of cannabinoid-induced dependence. This is mediated through cannabinoid receptor 1 (CB1) enriched in cerebellar granular neurons (CGNs). Accordingly, the present study aimed to investigate the mechanism of modulatory/neuroprotective effects of Li on a cannabinoid agonist (WIN 55,212-2 (WIN))-induced dependence, through quantitative analysis of some involved proteins such as ERK1/2, GSK-3ß and related signaling pathways including their phosphorylated forms; and cAMP level as the other molecular mechanisms leading to dependence, in CGNs model. The CGNs were prepared from 7-day-old Wistar rat pup in a 12-well plate, pretreated with Li (1mM) and an ERK1/2 inhibitor SL327 (SL, 10 µM). The WIN (1 µM) was added 30 minutes prior to treatment and AM251 (AM, 1 µM), as a cannabinoid antagonist was co-treated with WIN. The cAMP level, as an indicator of cannabinoid-induced dependence, was measured by ELISA following forskolin (FSK) stimulation. Western blot analyses determined the phosphorylated forms of ERK1/2 (p-ERK1/2), GSK-3ß (p-GSK-3ß) as well as their total expressions in various treatment times and doses in CGNs. WIN alone could down regulate the cAMP/p-ERK1/2 cascade compared to AM treatment. However, P-GSK-3ß was up-regulated with Li and WIN or with SL and Li pretreatment to AM-induced cellular response, which was the highest 60 minutes after CGNs exposure. Results further suggested the potential role of Li pretreatment to diminish the development of cannabinoid-induced dependence/neuronal injury through possible mechanisms of modulating the cAMP/p-ERK1/2 cascade independent of p-GSK-3ß signaling pathway in-vitro.
RESUMEN
Recent studies have shown that calcineurin plays a central role in hypertrophy and extracellular matrix (ECM) accumulation in glomeruli at the early stages of diabetic nephropathy. Tropisetron is an effective antiemetic drug which also can potently inhibit calcineurin. The aim of this study was to investigate whether tropisetron can prevent glomerular hypertrophy and ECM expansion in early diabetic nephropathy. Streptozotocin (STZ)-induced diabetic rats were treated with tropisetron and cyclosporine A, a pharmacological calcineurin inhibitor, and the renal function and the expression of calcineurin and fibronectin were then assessed as well as nuclear localization of nuclear factor of activated T-cell c1 (NFATc1). 2 weeks after diabetes induction, all STZ-treated rats showed hyperglycemia, polyuria, body weight loss and renal dysfunction, as evidenced by increased glomerular filtration rate (GFR), along with a marked pathological changes in kidney. Calcineurin expression was increased in association with increased nuclear localization of the calcineurin substrate NFATc1 and fibronectin expression in glomeruli of diabetic rats. In parallel, the diabetic glomeruli became hypertrophic with an increase in kidney weight. Tropisetron, as potent as cyclosporine A, significantly ameliorated the early nephropathy symptoms, potentially through suppression of calcineurin expression, nuclear localization of NFATc1 and accumulation of fibronectin, and thereby reduced hypertrophy in glomeruli of diabetic rats. In conclusion, our results showed that tropisetron could ameliorate kidney injury in the early stage of diabetic nephropathy in rats. The renoprotective effects of tropisetron can be attributed, at least in part, to the suppression of diabetes-induced increases in calcineurin expression in kidney tissue.
Asunto(s)
Inhibidores de la Calcineurina/farmacología , Calcineurina/metabolismo , Nefropatías Diabéticas/prevención & control , Indoles/farmacología , Glomérulos Renales/efectos de los fármacos , Sustancias Protectoras/farmacología , Factores de Transcripción/antagonistas & inhibidores , Animales , Ciclosporina/farmacología , Diabetes Mellitus Experimental/inducido químicamente , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Hipertrofia/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Ratas , Estreptozocina , Factores de Transcripción/metabolismo , TropisetrónRESUMEN
Approximately more than 50% of patients with depression have the co-occurrence of anxiety, which complicates the treatment of disease. Recently, social isolation stress (SIS) paradigm has been suggested as an animal model to investigate the underlying mechanism involved in depression-anxiety co-occurrence. In this study, applying six weeks of SIS to adolescent mice, we tested whether nitrergic system plays a role in co-occurrence of depression and anxiety. In this study, comparisons between socially and isolated conditioned (SC and IC) animals showed that SIS induces behaviors relevant to depression and anxiety in IC mice and in addition, nitrergic system is involved in mediating the negative outcomes of SIS. Administration of subeffective doses of aminoguanidine (a specific inducible nitric oxide synthase inhibitor or iNOS, 50mg/kg) and L-NAME (non-specific inhibitor of NOS, 10mg/kg) significantly reversed the negative effects of SIS on behavioral profile as well as nitrite levels in the cortex of IC mice, Although administration of subeffective dose of 7-nitroindazole (a specific neuronal NOS inhibitor, 25mg/kg) decreased the nitrite levels in the hippocampus, but had no effect on depressant and anxiogenic effects of SIS. Results of this study confirmed that SIS is an appropriate animal model to investigate the potential mechanisms in depression-anxiety co-occurrence. We also showed that nitrergic system has contributed to co-occurrence of depression and anxiety in IC mice as an underlying mechanism.
Asunto(s)
Trastornos de Ansiedad/etiología , Depresión/etiología , Hipocampo/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Óxidos de Nitrógeno/metabolismo , Aislamiento Social/psicología , Animales , Animales Recién Nacidos , Trastornos de Ansiedad/complicaciones , Depresión/complicaciones , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Masculino , Ratones , Autocuidado , Natación/psicologíaRESUMEN
Cannabis is one of the most banned drugs in the world. Cannabinoid-induced dependence or withdrawal signs are indicated by the result of complex molecular mechanisms including upstream protein kinases (PKs), such as an extracellular signal regulated kinase1/2 (ERK1/2) and downstream glycogen synthase kinase-3ß (GSK-3ß), which lead to neuronal plasticity. In this study, we examined the protective effect of lithium (Li) as a potent ERK1/2 and GSK-3ß modulator to prevent the development of dependence on cannabinoids. For this purpose, rats were treated twice daily with increasing doses of WIN 55,212-2 (WIN, 2-8 mg/kg, intraperitoneally (i.p.), for five consecutive days. AM251 (AM, 2 mg/kg), a cannabinoid antagonist, was injected i.p to induce manifestations of abstinence in rat dependency on WIN, and the subsequent withdrawal signs were recorded. To evaluate the preventive effect of Li, the rats were pre-treated with Li (10 mg/kg, i.p.) twice daily, 30 minutes before every injection of WIN. SL327, as an ERK1/2 inhibitor, was also injected (SL, 50 mg/kg, i.p.) 30 minutes before the last doses of WIN in separate groups. The p-ERK1/2, total ERK1/2, p-GSK-3ß and total GSK-3ß expressions were determined with Western blot method after 60 minutes, prior to the Li, WIN or AM injections. Li and SL pre-treatment attenuated the global withdrawal signs in regarding their modulation effect on the up-regulation of p-ERK1/2 cascade enhanced by AM injection. Furthermore, the p-GSK-3ß expression was up-regulated with SL and Li pre-treatment against AM injection, without alteration on the total contents of ERK1/2 and GSK-3ß level. Therefore, p-ERK1/2 and p-GSK-3ß pathways are involved in the cannabinoid-induced dependence. However, no crosstalk was indicated between these two pathways. In conclusion, Li neuroprotectionwith regard to cannabinoid abstinence may occur through the regulation of the p-ERK1/2 cascade inconsequent of p-GSK-3ß signaling pathways in rats.
Asunto(s)
Benzoxazinas/farmacología , Cannabinoides/farmacología , Glucógeno Sintasa Quinasa 3/metabolismo , Litio/farmacología , Morfolinas/farmacología , Naftalenos/farmacología , Animales , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta , Masculino , Fosforilación , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.
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Cisplatino/efectos adversos , Indoles/farmacología , Riñón/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Animales , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Tropisetrón , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
Neural Cell Adhesion Molecules (NCAMs) are known to influence memory by affecting neural cell-cell and cell-extracellular matrix junctions. This study investigated the possible role of cAMP pathway in the expression of hippocampal NCAM and its polysialylated derivative (PSA-NCAM). The following pharmacological tools were employed for manipulation of cAMP pathway: a) forskolin; the activator of adenylyl cyclase (AC), b) 8-Br-cAMP; a protein kinase A (PKA) agonist, c) 8-pCPT-2'-O-Me-cAMP; a selective enhancer of exchange protein activated by cAMP (Epac) and d) Rp-cAMP; a PKA inhibitor. Memory acquisition was tested by passive avoidance paradigm after injecting the above compounds for three consecutive days into the CA1 region of dorsal hippocampus of rats. Forskolin and 8-Br-cAMP enhanced memory retrieval while Rp-cAMP significantly reduced memory and NCAM levels. 8-pCPT-2'-O-Me-cAMP failed to alter memory performance or NCAM levels as compared to vehicle. We observed no significant changes in PSA-NCAM, however the expression of St8sia4 and St8sia2 (the polysialyltransferase isoforms) were altered. The mRNA levels of St8sia4 was down-regulated by 8-Br-cAMP, Rp-cAMP and 8-pCPT while forskolin led to almost 3 and 5 fold increase in mRNAs of St8sia2 and St8sia4, respectively. The current insight might endorse the predominant role of PKA as compared to Epac in cAMP pathway in expression of NCAM and memory function.
Asunto(s)
Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Memoria/efectos de los fármacos , Moléculas de Adhesión de Célula Nerviosa/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Colforsina/farmacología , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacología , Immunoblotting , Masculino , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Ácidos Siálicos/metabolismo , Tionucleótidos/farmacologíaRESUMEN
Chalcone (1,3-diarylprop-2-en-1-one) derivatives have been introduced as selective cyclooxygenase-2 inhibitors. In the present study, anti-nociceptive and anti-inflammatory effects of eight novel compounds were evaluated in male mice and Wistar rats by using the writhing and formalin-induced paw edema tests respectively. The activities of the compounds were compared with celecoxib as a reference drug. Then, novel compounds were divided into two regioisomeric groups based on the position of the methylsulfonyl substitution. Compounds with substituents such as: 1) H, 2) Me, 3) F and 4) Cl at para position of the phenyl ring of (E)-3-(4-Methanesulfonylphenyl)-1-phenylprop-2 en-1-one were selected in the first group. The regioisomer compounds with 5) H, 6) Me, 7) F and 8) OMe substitutions at C-4 of phenyl ring of (E)-1-(4-Methanesulfonylphenyl)-3-phenylprop-2-en-1-one were chosen as second group. All compounds showed dose-dependent anti-nociceptive activity in writhing test. Interestingly, the potency of anti-nociceptive effect of compounds 1, 2, 5 and 6 were significantly higher than celecoxib. The regioisomeric compounds 1 and 5 with high anti-nociceptive effects, showed a significant dose-dependent anti inflammatory activity in the paw edema test as well. The results showed that compounds with no substituent or small size substituents at para position of the phenyl ring are the most potent compound in writhing test. Our results revealed that the introduction of a bulky group such as methoxy or chlorine at the vicinal aromatic chain of the derivatives decreases the anti-inflammatory/ anti-nociceptive effects. The comparison of estimated ED50 of each pair of the regioisomeric compounds indicates that the relative position of SO2Me to carbonyl moiety did not affect the potency.
RESUMEN
During embryonic life a group of cells become proliferated, migrated and differentiated to develop central nervous system. Migration has been suggested to be due to accumulation of polysialic acid (PSA), a negatively-charged glycoside, on the outer cell membrane. The same event happens to PSA in a tumor mass as well. Polysialylation is the product of polysialyl transfrase isozymes; STX (ST8SIA2), the embryonic active isoform, and PST (ST8SIA4), expressed in adults CNS. Additionally, cAMP concludes to activation of PKA and EPAC resulting to the initiation of gene expressions which are highly required during development. EPAC, the latter known target of cAMP in mammalian nervous system, has proliferative properties in the developing CNS. We propose for the proper action of EPAC, namely CNS development, the presence of STX and its elevation after EPAC activation is mandatory. This hypothesis is put forward after observing, in a preliminary experiment, a relationship between EPAC activation and STX mRNA expression levels in rat hippocampus. The interaction between EPAC and STX may be suggested to be through EPAC-induced gene expression of the latter. From the above assumptions one may suggest the use of EPAC activators as neurogenesis inducers and its inhibitors as tumor modulators.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/fisiología , Neurogénesis , Toxina Shiga/metabolismo , Humanos , Modelos TeóricosRESUMEN
Inflammatory bowel disease (IBD) is a group of inflammatory disorders mainly affecting the colon and small intestine. The main types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). UC is restricted to the large intestine whereas CD can affect any part of the gastrointestinal tract. Treating this disorder depends on the form and level of severity. Common treatment involves an anti-inflammatory drug, such as mesalazine, and an immunosuppressant, such as prednisone. Several signaling pathways, including nuclear factor (NF)-κB and nitric oxide (NO), and genetic and environmental factors are believed to play an important role in IBD. Amitriptyline is a commonly used antidepressant with known anti-inflammatory activities. Amitriptyline also acts on the NF-κB/NO pathway or cytokine production. Therefore, we hypothesize that antidepressants like amitriptyline can be pioneered and considered effective as an innovative and effective therapeutic in the treatment and attenuation of development of IBD in adjusted doses.