RESUMO
We performed a comparative in vitro study of the involvement of NF-κB, PI3K, cAMP, ERK1/2, p38, JAKs, STAT3, JNK, and p53-dependent intracellular signaling in the functioning of neural stem cells (NSC) under the influence of basic fibroblast growth factor (FGF) and FGF receptor agonist, diterpene alkaloid songorine. The significant differences in FGFR-mediated intracellular signaling in NSC were revealed for these ligands. In both cases, stimulation of progenitor cell proliferation occurs with the participation of NF-κB, PI3K, ERK1/2, JAKs, and STAT3, while JNK and p53, on the contrary, inhibit cell cycle progression. However, under the influence of songorin, cAMP- and p38-mediated cascades are additionally involved in the transmission of the NSC division-activating signal. In addition, unlike FGF, the alkaloid stimulates progenitor cell differentiation by activating ERK1/2, p38, JNK, p53, and STAT3.
Assuntos
Diferenciação Celular , Proliferação de Células , Diterpenos , Células-Tronco Neurais , Receptores de Fatores de Crescimento de Fibroblastos , Fator de Transcrição STAT3 , Transdução de Sinais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Animais , Fator de Transcrição STAT3/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Diferenciação Celular/efeitos dos fármacos , NF-kappa B/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/agonistas , Fosfatidilinositol 3-Quinases/metabolismo , Alcaloides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , AMP Cíclico/metabolismo , Células Cultivadas , RatosRESUMO
Analysis of specific pharmacological activity evaluated high antinociceptive efficacy of the first synthesized compound 10-di(ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane (ethowurtzine) in models of somatogenic pain of different genesis (thermal, visceral pain, mechanical compression of paw).The new molecule from the class of hexaazaisowurtzitane effectively blocks nociceptive reactions at the supraspinal and peripheral levels of pain sensitivity organization. The effect of ethowurtzine was comparable or exceeded the effect of tramadol. The obtained results prove the possibility of creating new pharmacologically active molecules based on the high-energy substance hexaazaisowurtzitane.
Assuntos
Dor , Tramadol , Humanos , Medição da Dor/métodos , Dor/tratamento farmacológico , Tramadol/farmacologia , Tramadol/uso terapêutico , Limiar da Dor , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos Opioides/farmacologiaRESUMO
Using rat and mouse models of neurogenic, ethanol-induced, and indometacin-induced damage to the gastric mucosa we demonstrated that course preventive treatment with flavonoid complex from aerial parts of Lychnis chalcedonica L. increased the resistance of gastric mucosa to ulcerogenic factors of different etiology. The gastroprotective effect of the phytocomplex in a dose range of 16-1600 µg/kg was comparable with that of the reference drug plantaglucide and was superior to that of the reference drugs eleutherococcus extract and methyluracil in the therapeutic doses. The antiulcerogenic activity of Lychnis chalcedonica flavonoid complex considerably exceeded activity of Lychnis chalcedonica L. extract demonstrated in our previous experiments.
Assuntos
Antiulcerosos/uso terapêutico , Extratos Vegetais/uso terapêutico , Úlcera Gástrica/tratamento farmacológico , Animais , Animais não Endogâmicos , Antiulcerosos/isolamento & purificação , Antiulcerosos/farmacologia , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Etanol , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Indometacina , Lychnis/química , Masculino , Camundongos , Inflamação Neurogênica/tratamento farmacológico , Inflamação Neurogênica/patologia , Fitoterapia , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Silene , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
Possible involvement of µ1- and κ-opioid receptors and cannabinoid type 1 receptors (CB1) into the mechanism of analgesic activity of the experimental drug product "Thiowurtzine, (capsule 120 mg)" synthesized on the basis of active pharmaceutical substance 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo [5,5,0,03,11,05,9]dodecane was studied in vivo using the hot plate test and acetic acid writhing test. The involvement of κ-opioid receptors and noninvolvement of µ1-receptors and CB1 receptors in the mechanism of thiowurtzine analgesia were demonstrated. The mechanism of interaction of the test analgesic with opioid receptors differs from that of the reference drug tramadol. The interaction of thiowurtzine with serotonergic, GABAergic, and muscarinic cholinergic neurotransmitter systems was studied in vivo using pharmacological analyzers. The absence of muscarinic cholinolytic effect of thiowurtzine was demonstrated in the model of arecoline-induced tremor. The central serotonin-blocking activity of the analgesic was revealed in the model of 5-hydroxytryptophan hyperkinesis in mice. Anticonvulsant activity was demonstrated in the corazol convulsions test, which attested to the presence of a GABAergic component. The mechanism of central analgesia caused by the drug product "Thiowurtzine, capsule 120 mg" appeared to be polymodal. The antinociceptive activity of the analgesic was comparable to that of tramadol.
Assuntos
Neurotransmissores/metabolismo , Receptores Opioides/metabolismo , Analgésicos , Animais , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Medição da Dor , Receptor CB1 de Canabinoide/metabolismo , Receptores Opioides kappa/metabolismoRESUMO
The use of lithium drugs in clinical practice requires constant monitoring of lithium plasma concentration, because toxicity is sometimes observed at therapeutic concentrations of lithium. This is often associated with fluctuations of plasma concentration of lithium ions after intake of individual doses. Therefore, the use of a porous carrier providing a stable blood level of the drug is extremely promising and important for clinical practice. We studied activity of a new lithium drug (lithium complex) consisting of aluminum-silicon base and lithium citrate immobilized on its surface. Lithium carbonate served as the reference drug. It was shown that lithium carbonate and lithium complex exhibited no anxiolytic activity in the conflict model, but produced an antidepressant effect and improved exploratory behavior of animals.
Assuntos
Lítio/farmacologia , Silicones/química , Óxido de Alumínio/química , Óxido de Alumínio/farmacologia , Animais , Ansiolíticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Carbonato de Lítio/química , Carbonato de Lítio/farmacologia , Masculino , CamundongosRESUMO
The article reflects the position held by the Institute of Economics and Industrial Engineering, Siberian Branch of the Russian Academy of Sciences regarding the problems and prospects of the socio-economic, scientific, and technological development of Siberia and the directions of strengthening its positions in the world and Russian space. The main development problems of Siberia and the Siberian Federal District are identified, taking into account modern challenges and threats. It is shown that the recovery of the Siberian economy as a whole and the regions of the Siberian Federal District, in particular, should be based on a significant increase in investment activity at all levels: macroregional, regional, and municipal. Proposals are made on a package of new Siberian investment projects with a focus on "embedding" Siberia in high-tech niches of the Russian and world economies, as well as on a system of priority measures that should be taken at the national, interregional, and regional levels.
RESUMO
Pronounced analgesic activity of the innovative compound 4-(3,4-dibromthiophencarbonyl)-2,6,8,12-tetraacethyl-2,4,6,8,10,12hexaazatetracyclo[5,5,0,03, 11,05, 9] dodecane (thiowurtzine) was observed in the thermal nociceptive hot plate test and in the acute visceral and somatic deep pain model (acetic acid writhing test). In these experimental models, naloxone-sensitive thiowurtzine-induced analgesia was revealed. The absence of tropism to peripheral opioid receptors in the acetic acid writhing test was demonstrated using naloxone methiodide. Course administration of low-toxic thiowurtzine in effective doses was not associated with ulcerogenic damage to the gastric mucosa in experimental animals.
Assuntos
Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Animais , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Masculino , Camundongos , Naloxona/uso terapêutico , Dor/fisiopatologia , Medição da Dor/métodosRESUMO
The study examined the effects of a novel neurotropic medication based on a lithium complex composed of lithium citrate, polymethylsiloxane, and aluminum oxide on electrophysiological parameters of the rat brain. In contrast to lithium carbonate (the reference drug), the novel preparation resulted in a wave-like dynamics of electrical activity in the visual cortex. Rhythmic photic stimulation of the rats treated with lithium carbonate resulted in appearance of the signs attesting to up-regulation of excitability of cerebral cortex in all examined ranges. In contrast, the complex lithium preparation diminished the delta power spectrum, which was the only affected frequency band. It is hypothesized that the complex lithium medication induces milder activation of the cerebral cortex in comparison with lithium carbonate. The novel medication composed of lithium citrate, aluminum oxide, and polymethylsiloxane, is characterized by greater efficacy and safety than the preparation based on inorganic lithium salt (lithium carbonate).
Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Lítio/farmacologia , Óxido de Alumínio/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citratos/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Lítio/química , Carbonato de Lítio/farmacologia , Masculino , Ratos , Silicones/farmacologiaRESUMO
Repeated administration of songorine to mice restored mnestic processes impaired by scopolamine treatment, which manifested in improvement of CPAR conditioning and normalization of behavioral activity throughtout the observation period. This thearpeutical effect surpassed that of pyracetam used as the reference drug.
Assuntos
Alcaloides/farmacologia , Diterpenos/farmacologia , Aconitum/química , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Escopolamina/farmacologiaRESUMO
Anti-inflammatory and analgesic activities of the complex of flavonoids from Lychnis chalcedonica L. were studied in the models of acute aseptic inflammation induced by carrageenan, histamine, and serotonin and acetic acid-induced painful chemical stimulation. It is demonstrated that course treatment with flavonoids derived from Lychnis chalcedonica L. produced a stable pharmacological effect comparable with that of the reference anti-inflammatory drug diclofenac.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Carragenina/toxicidade , Flavonoides/uso terapêutico , Inflamação/tratamento farmacológico , Lychnis/química , Ácido Acético/toxicidade , Animais , Diclofenaco/uso terapêutico , Feminino , Histamina/toxicidade , Inflamação/induzido quimicamente , Masculino , Camundongos , Serotonina/toxicidadeRESUMO
Psychopharmacological effects of JNK inhibitor were studied using a mouse model of posthypoxic encephalopathy. The preparation exhibited a pronounced cerebroprotective effect manifested in normalization of orientation and exploratory behavior and conditioned responses in posthypoxic mice. These effects were accompanied by marked elevation of neural stem cell content in the paraventricular region of the brain.
Assuntos
Encefalopatias/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Animais , Antracenos/farmacologia , Antracenos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encefalopatias/psicologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Medicina RegenerativaRESUMO
Psychopharmacological effects of atisine-type diterpene alkaloid Z77 were studied under conditions of experimental posthypoxic encephalopathy. The preparation had a pronounced cerebroprotective effect consisting in normalization of orientation and exploratory behavior and conditioned activity in experimental animals. These changes were accompanied by significant increase in the number of neural stem cells in the paraventricular region of the brain and markedly enhanced production of neurotrophic growth factors by neural tissue microenvironment cells.
Assuntos
Alcaloides/farmacologia , Alcaloides/uso terapêutico , Encefalopatias/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Medicina RegenerativaRESUMO
Injection of 5-fluorouracil to animals caused a pronounced toxic effect. Therapeutic and preventive treatment with Salix viminalis leaf extract significantly reduced the negative effects of the antitumor drug: promoted recovery of the bone marrow, peripheral blood, and visceral parameters and prevented ulceration. Combined use of the cytostatic and Salix viminalis extract increased the efficiency of antitumor therapy.
Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Fluoruracila/toxicidade , Fitoterapia , Extratos Vegetais/uso terapêutico , Salix/química , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Contagem de Células Sanguíneas , Medula Óssea/efeitos dos fármacos , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/secundário , Citostáticos/uso terapêutico , Citostáticos/toxicidade , Avaliação Pré-Clínica de Medicamentos , Etanol , Fluoruracila/uso terapêutico , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/prevenção & controle , Hematopoese/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Extratos Vegetais/farmacologia , Folhas de Planta/química , Solventes , Esplenomegalia/induzido quimicamente , Esplenomegalia/prevenção & controle , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Vísceras/efeitos dos fármacosRESUMO
The anxiolytic and antidepressant activities of complex preparations divaza and brizantin containing antibodies to brain-specific protein S100 were estimated using Vogel conflict test and Nomura forced swimming test. Course treatment (5 days) of brizantin in a dose of 2.5 ml/kg and divaza in a dose of 7.5 ml/kg significantly increased punished drinking in the Vogel conflict test in comparison with the control. Both drugs also improved general emotional behavior during training prior to the test procedure. Brizantin and divaza in a dose of 7.5 ml/kg increased the number of wheel revolutions in the Nomura forced swimming test in comparison with the control; the effect of divaza was more pronounced. High correlation coefficients between the number of wheel revolutions during the first and second 5-min sessions are also indicative of antidepressant action of divaza and brizantin.
Assuntos
Ansiolíticos/farmacologia , Anticorpos/farmacologia , Antidepressivos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Diazepam/farmacologia , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Estresse Psicológico/patologia , Natação/psicologiaRESUMO
Antianxiety action of diterpene alkaloid songorine was studied using Vogel conflict test. Songorine in a dose of 0.25 mg/kg demonstrated high anxiolytic activity comparable to that of phenazepam and produced no sedative effect.
Assuntos
Alcaloides/farmacologia , Ansiolíticos/farmacologia , Diterpenos/farmacologia , Estresse Psicológico/tratamento farmacológico , Aconitum/química , Alcaloides/isolamento & purificação , Animais , Ansiolíticos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/farmacologia , Conflito Psicológico , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos CBA , Estresse Psicológico/fisiopatologiaRESUMO
The role of cAMP- and IKK-2-dependent pathways in stimulation of the growth capacity of mesenchymal progenitor cells with alkaloid songorine was studied in vitro. Inhibitors of adenylate cyclase and IKK-2 were shown to abolish the increase in proliferative activity of progenitor cells. Moreover, blockade of the inhibitory kinase complex was accompanied by a decrease in the intensity of progenitor cell differentiation.
Assuntos
Adenilil Ciclases/genética , Alcaloides/farmacologia , AMP Cíclico/metabolismo , Quinase I-kappa B/genética , Células-Tronco Mesenquimais/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/antagonistas & inibidores , Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos CBA , Cultura Primária de Células , Transdução de Sinais , Células-Tronco , Tiofenos/farmacologiaRESUMO
Nootropic activity of water extract fractions from aerial parts of Filipendula vulgaris Moench was demonstrated on the models of hermetic volume hypoxia, conditioned passive avoidance response, open field test, and forced swimming with a load. The fractions stimulated hypoxic resistance, normalized orientation and exploratory behavior, improved conditioned response reproduction during testing after hypoxic injury, and increased exercise tolerance. Fractionation of the extract led to dissociation of the effect components, which suggests that individual constituents have specific characteristics. Ethylacetate fraction exhibited most pronounced nootropic activity and was superior to plant extract by some characteristics. The detected effects seemed to be caused by modulation of the hippocampus activity the under the effects of phenol and triterpene compounds.
Assuntos
Filipendula/química , Nootrópicos/farmacologia , Extratos Vegetais/química , Água/química , Animais , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Nootrópicos/química , Componentes Aéreos da Planta/químicaRESUMO
We studied the psychopharmacological effects of atisine-type diterpene alkaloid Z77 in a rat model of brain ischemia in the morning and at night. The type of developing locomotor disorders in animals was shown to depend on circadian rhythms. Administration of Z77 substantially corrected manifestations of psychoneurological symptoms. The parameters of orientation and exploratory behavior and conditioned reflex activity were normalized. The key role of receptors of neural stem cells to fibroblast growth factor in the realization of their growth potential under the influence of the alkaloid was demonstrated. Under in vitro conditions, antibodies to fibroblast growth factor receptor abolished the increase in the number of neural CFU caused by Z77 in the culture of intact cells from the paraventricular region of the brain.
Assuntos
Alcaloides/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Transtornos Neurológicos da Marcha/tratamento farmacológico , Alcaloides/farmacologia , Animais , Isquemia Encefálica/metabolismo , Transtornos Neurológicos da Marcha/metabolismo , Masculino , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Ratos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Medicina Regenerativa/métodosRESUMO
The effects of the extracts of the aboveground parts of Filipendula vulgaris Moench on the behavior and memory of mice after hypoxic injury and their physical performance in the open-field test were studied using the models of hypoxia in a sealed volume, conditioned passive avoidance response (CPAR), and forced swimming with a load. The extracts improved animal resistance to hypoxia, normalized orientation and exploration activities, promoted CPAR retention after hypoxic injury, and increased physical performance. Aqueous extract of meadowsweet had the most pronounced effect that corresponded to the effect of the reference drug piracetam. These effects were probably caused by modulation of hippocampal activity.
Assuntos
Filipendula/química , Nootrópicos/química , Nootrópicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Masculino , Camundongos , Piracetam/farmacologiaRESUMO
We studied the psychopharmacological effects of atisine-type diterpene alkaloid Z77 in a rat model of cerebral ischemia. Pronounced cerebroprotective effect was found consisting in normalization of the orienting and exploratory activity and conditioned behavior associated with significant correction of morphological changes in the brain. The direct stimulatory effect of Z77 on neural stem cells was shown in vitro.