RESUMO
Riboflavin, also known as vitamin B2, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.
RESUMO
AIM: To evaluate the anticancer efficacy of CKD-516, a novel vascular-disrupting agent, alone and in combination with doxorubicin in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In mice bearing luciferized HCC cells, therapeutic efficacy was assessed for seven days after single administration of CKD-516, doxorubicin, or combination of CKD-516 and doxorubicin. RESULTS: Bioluminescence-imaging (BLI) signals in the CKD-516 group abruptly decreased initially, but recovered at seven days after treatment. BLI signals in the doxorubicin group gradually decreased over the 7-day period. In the combination group, BLI signals were abruptly reduced and remained suppressed for the 7-day period. On histopathological examination, CKD-516-treated tumors showed extensive central necrosis, whereas the peripheral layers remained viable. Doxorubicin-treated tumors showed mild and scattered necrosis. Tumors from the combination group showed more extensive central and peripheral necrosis, with smaller viable peripheral layers than the CKD-516 group. CONCLUSION: Combination therapy can have additive effects for treatment of HCC compared with CKD-516 or doxorubicin monotherapy.
Assuntos
Benzofenonas/farmacologia , Carcinoma Hepatocelular/patologia , Doxorrubicina/farmacologia , Neoplasias Hepáticas/patologia , Valina/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Benzofenonas/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Necrose , Neovascularização Patológica/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Valina/administração & dosagem , Valina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We examined the effect of the subcutaneous (s.c.) pretreatment of formalin into both hind paws of mice on the antinociception induced by the intracerebroventricularly (i.c.v.) or intrathecally (i.t.) administration of beta-endorphin using the tail-flick test. Pretreatment with formalin (5%) for 5 h had no affect on the i.c.v. administered beta-endorphin-induced tail-flick response. However, pretreatment with formalin for 40 h attenuated the tail-flick inhibition induced by i.c.v. administered beta-endorphin. This antinociceptive tolerance to i.c.v. beta-endorphin continued up to 1 week, but to a lesser extent. Pretreatment with formalin for 5 and 40 h significantly reduced the i.t. beta-endorphin-induced inhibition of the tail-flick response, which continued up to 1 week. The s.c. formalin treatment increased the hypothalamic pro-opiomelanocortin (POMC) mRNA level at 2 h, but this returned to the basal level after 40 h. Our results suggest that the increase in the POMC mRNA level in the hypothalamus appears to be involved in the supraspinal or spinal beta-endorphin-induced antinociceptive tolerance in formalin-induced inflammatory pain.
Assuntos
Formaldeído , Medição da Dor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , beta-Endorfina/antagonistas & inibidores , beta-Endorfina/farmacologia , Animais , Northern Blotting , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Pró-Opiomelanocortina/biossíntese , Pró-Opiomelanocortina/fisiologia , RNA Mensageiro/biossíntese , beta-Endorfina/administração & dosagemRESUMO
Platycodin D (PD), one of several triterpene saponins, was isolated from roots of Platycodon grandiflorum. We previously reported that intracerebroventricular (i.c.v.) administration of PD showed an antinociceptive effect as measured by the tail-flick assay. However, its exact role in the regulation of antinociception in the various types of pain models has not yet been characterized. Thus, we attempted to find antinociceptive profiles of PD in various pain models. PD administered intraperitoneally (i.p.), i.c.v. or intrathecally (i.t.) showed antinociceptive effects in dose-dependent manners as measured by the tail-flick, writhing and formalin tests. In the tail-flick test, PD at the low doses reached the peak after 15 minutes and returned to the control level after 60 minutes. However, higher doses of PD showed a strong antinociception at least for 1 hour. PD administered i.t. showed stronger antinociception than that induced by i.c.v. administration PD in both tail-flick and writhing tests. In the formalin test, PD administered i.p., i.c.v. or i.t. showed antinociceptive effects during both the first (direct nociceptive stimulation) and second (late inflammatory) phases. Pretreatment with naltrexone i.p., i.c.v. or i.t. did not affect PD-induced inhibition of the tail-flick response. Our results suggest that PD shows a strong antinociceptive effect on the tail-flick, writhing and formalin tests, acting on central nervous system. However, PD-induced antinociception may not be mediated by the opioid receptors.
Assuntos
Dor/tratamento farmacológico , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Campanulaceae/química , Ventrículos Cerebrais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos ICR , Medição da Dor , Saponinas/administração & dosagem , Cauda/fisiologia , Triterpenos/administração & dosagemRESUMO
To characterize the antinociceptive profiles of Angelica gigas NAKAI (ANG; Korean angelica), methanol extract from the dried roots of ANG was made and mice were administered orally at the various doses (from 0.25 to 3 g/kg). ANG produced the increased latencies of the tail-flick and hot-plate paw-licking responses in a dose-dependent manner. In acetic acid-induced writhing test, ANG dose-dependently decreased writhing numbers. Moreover, the cumulative response time of nociceptive behaviors induced by intraplantar formalin injection was reduced during both the 1st and the 2nd phases in a dose-dependent manner in ANG-treated mice. Furthermore, oral administration of ANG did not cause licking, scratching and biting responses induced by TNF-alpha (100 pg), IFN-gamma (100 pg) or IL-1beta (100 pg) injected intrathecally (i.t.), especially at higher dose (3 g/kg). Additionally, in ANG treated mice, the cumulative nociceptive response time for i.t. administration of substance P or capsaicin was dose-dependently diminished. Finally, nociceptive responses elicited by i.t. injection of glutamate (20 microg), N-methyl-D-aspartic acid (60 ng), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (13 ng) or kainic acid (12 ng) were decreased by oral administration of ANG. Our results suggest that ANG produces antinociception via acting on the central nervous system and shows antinociceptive profiles in various pain models, especially inflammatory pain.
Assuntos
Analgésicos/farmacologia , Angelica/química , Medição da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Animais , Capsaicina/farmacologia , Citocinas/farmacologia , Aminoácidos Excitatórios/farmacologia , Formaldeído , Temperatura Alta , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamente , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Equilíbrio Postural/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Substância P/farmacologiaRESUMO
Effects of ginsenosides on nitric oxide (NO) production induced by lipopolysaccharide plus TNF-alpha (LNT) were examined in C6 rat glioma cells. Among several ginsenosides, ginsenoside Rd showed a complete inhibition against LNT-induced NO production. Ginsenoside Rd attenuated LNT-induced increased phosphorylation of ERK. Among several immediate early gene products, only Jun B and Fra-1 protein levels were increased by LNT, and ginsenoside Rd attenuated Jun B and Fra-1 protein levels induced by LNT. Furthermore, LNT increased AP-1 DNA binding activities, which were partially inhibited by ginsenoside Rd. Our results suggest that ginsenoside Rd exerts an inhibitory action against NO production via blocking phosphorylation of ERK, in turn, suppressing immediate early gene products such as Jun B and Fra-1 in C6 glioma cells.
Assuntos
Ginsenosídeos/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Inibidores da Síntese de Proteínas/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Western Blotting , Linhagem Celular Tumoral , Regulação Enzimológica da Expressão Gênica , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Panax , Fosforilação , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/biossíntese , Ratos , Fator de Transcrição AP-1/metabolismoRESUMO
In the present study, we examined the effects of ginsenoside Rd (G-Rd) and decursinol (DC) on various neurotoxic responses induced by kainic acid (KA) administered intracerebroventricularly ( i. c. v.) in ICR mice. Ginseng total saponin (GTS) inhibited the KA (0.5 microg)-induced lethal toxicity in a dose-dependent manner. Furthermore, G-Rd, a component of GTS, also attenuated the KA-induced lethal toxicity as well as DC pretreated orally for 30 min. In ICR mouse, neurotoxic damage induced by KA (0.1 microg) in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. G-Rd and DC did not affect the pyramidal cell death in CA3 hippocampal region. In an immunohistochemical study, KA dramatically increased phospho-ERK and decreased phospho-CREB in the hippocampal area. G-Rd and DC attenuated, in part, the increased phospho-ERK and the decreased phospho-CREB protein levels. However, DC potentiated the increased c-Fos and c-Jun protein levels in the hippocampus induced by KA. Thus, our results suggest that the phosphorylation of ERK or the dephosphorylation of CREB protein may play a major role in the regulation of lethal toxicity induced by KA, whereas cell death in the hippocampal CA3 region induced by KA administered i. c. v. may not be directly mediated by ERK phosphorylation and CREB phosphorylation in the mouse.
Assuntos
Angelica , Benzopiranos/farmacologia , Butiratos/farmacologia , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Panax , Fitoterapia , Animais , Imuno-Histoquímica , Ácido Caínico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Preparações de Plantas/farmacologiaRESUMO
We have examined the effects of several ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1 and Rg3) administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the nociceptive behavior induced by substance P (0.7 microg) injected i.t. Among the several ginsenosides studied, Rb2, Rc, Rd, and Re, but not Rb1, Rf, Rg1 and Rg3, treated i.c.v. (50 microg) attenuated the nociceptive behavior induced by substance P injected i.t. On the other hand, we found that i.t. treatment with 50 microg of Rb1, Rb2, Rd, or Rf effectively attenuated the nociceptive behavior induced by i.t. injected substance P. However, the i.t. treatment with the same doses of Rc, Re, Rg1 or Rg3 was not effective for antagonizing i.t. injected substance P-induced nociceptive behavior. Our results show that ginsenosides Rb2, Rc, Rd, or R2 injected supraspinally exert a antinociceptive effect in the substance P-induced pain model. Furthermore, Rb1, Rb2, Rd, or Rf treated spinally produce antinociception in the substance P-induced pain model.
Assuntos
Analgésicos/farmacologia , Ginsenosídeos/farmacologia , Dor/prevenção & controle , Panax , Fitoterapia , Extratos Vegetais/farmacologia , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Ginsenosídeos/administração & dosagem , Ginsenosídeos/uso terapêutico , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Substância PRESUMO
Platycodin D administered intracerebroventricularly (i.c.v.) showed an antinociceptive effect in a dose-dependent manner as measured by the tail-flick assay. The antinociception induced by platycodin D was maintained at least 1 h. MK-801 [(+/-)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine maleate], a competitive N-methyl- D-aspartic acid (NMDA) receptor antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a non-NMDA receptor antagonist, muscimol (a GABA(A) receptor agonist), or baclofen (a GABA(B) receptor antagonist), or sulfated cholecystokinin (CCK-8 s; CCK A receptor agonist), injected i.c.v. significantly reduced the inhibition of the tail-flick response induced by platycodin D administered i.c.v. Additionally, intrathecal (i.t.) pretreatment with yohimbine (an alpha 2 -adrenergic receptor antagonist) or methysergide (a serotonin receptor antagonist) dose-dependently attenuated inhibition of the tail-flick response induced by i.c.v. administered platycodin D. However, naloxone (an opioid receptor antagonist) did not affect the inhibition of the tail-flick response induced by platycodin D. Our results suggest that platycodin D has an antinociceptive effect when it is administered supraspinally, and supraspinal GABA(A), GABA(B), NMDA and non-NMDA receptors are involved in platycodin D-induced antinociception. Furthermore, platycodin D administered supraspinally produces antinociception by stimulating descending noradrenergic and serotonergic, but not opioidergic, pathways.