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[PMID]:25120105
[Au] Autor:Jindal A; Mahesh R; Bhatt S
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan, 333031, India, kumarjindal26@gmail.com.
[Ti] Título:Etazolate, a phosphodiesterase-4 enzyme inhibitor produces antidepressant-like effects by blocking the behavioral, biochemical, neurobiological deficits and histological abnormalities in hippocampus region caused by olfactory bulbectomy.
[So] Source:Psychopharmacology (Berl);232(3):623-37, 2015 Feb.
[Is] ISSN:1432-2072
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Olfactory bulbectomy (OBX) is a widely used model for antidepressant screening and known to induce neurodegeneration in several brain areas. Our earlier studies demonstrated that etazolate produced antidepressant-like effects in behavioral despair models of depression; however, the potential role of etazolate on behavior and morphological changes in the hippocampus region along with its underlying mechanism(s) following OBX has not been adequately addressed. OBJECTIVES: We evaluated if etazolate could protect against OBX-induced depression-like behavioral deficits and neurodegeneration. The possible underlying mechanism of etazolate in OBX model was also investigated. METHODS: The effects of etazolate were measured in a battery of behavioral paradigms, including the forced swim test (FST), sucrose consumption, open arm activity in elevated plus maze (EPM), and hyperemotionality tests. The underlying mechanisms were investigated by measuring serum corticosterone (CORT), cyclic adenosine monophosphate (cAMP), cAMP response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), and oxidative/nitrosative stress (lipid peroxidation and nitrite) levels and antioxidant enzymes, like reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels in the hippocampus. RESULT: OBX rats showed depression-like behavior anomalies in behavioral paradigms. OBX rats also showed high CORT and decreased cAMP, phosphorylated CREB (pCREB), and BDNF levels. Additionally, we found increased oxidative/nitrosative stress and reduced antioxidant enzyme levels in the hippocampus. Histopathological analysis showed morphological changes and neuronal loss in the hippocampus. Etazolate (0.5 and 1 mg/kg) attenuated the OBX-induced behavioral, biochemical, neurobiological, and histopathological alterations. CONCLUSION: The aforesaid results suggest that etazolate produces an antidepressant-like effect and neuroprotection in OBX, which is possibly mediated by modulating biochemical and neurobiological markers in the hippocampus.
[Mh] Termos MeSH primário: Antidepressivos/farmacologia
Comportamento Animal/efeitos dos fármacos
Depressão/tratamento farmacológico
Etazolato/farmacologia
Hipocampo/efeitos dos fármacos
Inibidores da Fosfodiesterase 4/farmacologia
[Mh] Termos MeSH secundário: Animais
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Phosphodiesterase 4 Inhibitors); I89Y79062L (Etazolate)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140815
[St] Status:MEDLINE
[do] DOI:10.1007/s00213-014-3705-0


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[PMID]:24705918
[Au] Autor:Wang C; Zhang J; Lu Y; Lin P; Pan T; Zhao X; Liu A; Wang Q; Zhou W; Zhang HT
[Ad] Endereço:Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China, wangchuang@nbu.edu.cn.
[Ti] Título:Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice.
[So] Source:Metab Brain Dis;29(3):673-82, 2014 Sep.
[Is] ISSN:1573-7365
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF.
[Mh] Termos MeSH primário: Antidepressivos/farmacologia
Comportamento Animal/efeitos dos fármacos
Etazolato/farmacologia
Inibidores de Fosfodiesterase/farmacologia
Piperazinas/farmacologia
Transdução de Sinais/efeitos dos fármacos
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antidepressivos/uso terapêutico
AMP Cíclico/metabolismo
GMP Cíclico/metabolismo
Depressão/tratamento farmacológico
Depressão/metabolismo
Etazolato/uso terapêutico
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Masculino
Camundongos
Inibidores de Fosfodiesterase/uso terapêutico
Piperazinas/uso terapêutico
Córtex Pré-Frontal/efeitos dos fármacos
Córtex Pré-Frontal/metabolismo
Purinas/farmacologia
Purinas/uso terapêutico
Citrato de Sildenafila
Sulfonamidas/uso terapêutico
Natação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Phosphodiesterase Inhibitors); 0 (Piperazines); 0 (Purines); 0 (Sulfonamides); BW9B0ZE037 (Sildenafil Citrate); E0399OZS9N (Cyclic AMP); H2D2X058MU (Cyclic GMP); I89Y79062L (Etazolate)
[Em] Mês de entrada:1510
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140408
[St] Status:MEDLINE
[do] DOI:10.1007/s11011-014-9533-4


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[PMID]:24434771
[Au] Autor:Guo J; Lin P; Zhao X; Zhang J; Wei X; Wang Q; Wang C
[Ad] Endereço:Ningbo University School of Medicine, Ningbo, Zhejiang 315211, PR China; Zhejiang Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang 315211, PR China.
[Ti] Título:Etazolate abrogates the lipopolysaccharide (LPS)-induced downregulation of the cAMP/pCREB/BDNF signaling, neuroinflammatory response and depressive-like behavior in mice.
[So] Source:Neuroscience;263:1-14, 2014 Mar 28.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Increasing evidence has indicated that immune challenge by bacterial lipopolysaccharide (LPS) induces depressive-like behavior, neuroinflammatory response and upregulates phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes cyclic adenosine monophosphate (cAMP). However, whether the potential PDE4 inhibitor etazolate prevents the LPS-induced depressive-like behavior remains unclear. Here using a model of depression induced by the repeated administration of LPS during 16days, and then investigated the influence of LPS on the expression of PDE4, interleukin-1ß (IL-1ß) and antidepressant action of etazolate in mice through forced swimming, novelty suppressed feeding, sucrose preference and open-field tests. Our results showed that etazolate pretreatment facilitated the recovery from weight loss and prevented the depressive-like behavior induced by repeated LPS administration. Moreover, the antidepressant action of etazolate was paralleled by significantly reducing the expression levels of PDE4A, PDE4B, PDE4D and IL-1ß and up-regulating the cAMP/phosphorylated cAMP response-element binding protein (pCREB)/brain-derived neurotrophic factor (BDNF) signaling in the hippocampus and prefrontal cortex of mice. These results indicate that the effects of etazolate on the depressive-like behavior induced by repeated LPS treatment may partially depend on the inhibition of PDE4 subtypes, the activation of the cAMP/pCREB/BDNF signaling and the anti-inflammatory responses in the hippocampus and prefrontal cortex.
[Mh] Termos MeSH primário: Antidepressivos/uso terapêutico
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo
Depressão/tratamento farmacológico
Depressão/enzimologia
Etazolato/uso terapêutico
Inibidores de Fosfodiesterase/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Fator Neurotrófico Derivado do Encéfalo/metabolismo
AMP Cíclico/metabolismo
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
Depressão/induzido quimicamente
Modelos Animais de Doenças
Regulação para Baixo
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Mediadores da Inflamação/metabolismo
Lipopolissacarídeos
Masculino
Camundongos
Camundongos Endogâmicos ICR
Córtex Pré-Frontal/efeitos dos fármacos
Córtex Pré-Frontal/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Brain-Derived Neurotrophic Factor); 0 (Cyclic AMP Response Element-Binding Protein); 0 (Inflammation Mediators); 0 (Lipopolysaccharides); 0 (Phosphodiesterase Inhibitors); E0399OZS9N (Cyclic AMP); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4); I89Y79062L (Etazolate)
[Em] Mês de entrada:1410
[Cu] Atualização por classe:140303
[Lr] Data última revisão:
140303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140118
[St] Status:MEDLINE


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[PMID]:23974048
[Au] Autor:Jindal A; Mahesh R; Bhatt S
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India. Electronic address: kumarjindal26@gmail.com.
[Ti] Título:Etazolate rescues behavioral deficits in chronic unpredictable mild stress model: modulation of hypothalamic-pituitary-adrenal axis activity and brain-derived neurotrophic factor level.
[So] Source:Neurochem Int;63(5):465-75, 2013 Nov.
[Is] ISSN:1872-9754
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Preliminary study in our laboratory showed that etazolate produced antidepressant- and anxiolytic-like effects in rodent models, however, the ability of etazolate to produce antidepressant- and anxiolytic-like effects and underlying mechanism(s) in chronic unpredictable mild stress (CUMS) model have not been adequately addressed. This study was aimed to investigate the beneficial effects of etazolate on CUMS-induced behavioral deficits (depression- and anxiety-like behaviors). In addition, the possible underlying mechanism(s) of etazolate in CUMS model was also investigated by measuring serum corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels. Mice were subjected to a battery of stressors for 28 days. Etazolate (0.5 and 1 mg/kg, p.o.) and fluoxetine (20mg/kg, p.o.) were administered during the last 21 days (8-28th) of the CUMS paradigm. The results showed that 4-weeks CUMS produces significant depression-like behavior in tail suspension test (TST) and partial anxiety-like behavior in elevated plus maze (EPM) and open field test (OFT). Stressed mice have also shown a significant high serum CORT and low BDNF level. Chronic treatment with etazolate (0.5 and 1mg/kg., p.o.) and fluoxetine (20mg/kg., p.o.) produced significant antidepressant-like behavior in TST (decreased duration of immobility), whereas, partial anxiolytic-like behavior in EPM (increased percentage of open arm entries) and OFT (increased % central ambulation score, total ambulation score and time spent in center zone). In addition, etazolate and fluoxetine treatment significantly (p<0.05) increased the BDNF level and inhibited the hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity, as evidenced by low serum CORT level in stressed mice. In addition, etazolate and fluoxetine also showed significant antidepressant- and anxiolytic-like effects in normal control mice. In this study no significant changes were observed in locomotor activity in actophotometer test. Moreover, we did not find any effect of etazolate and fluoxetine on CORT and BDNF levels in normal control mice. In conclusion, the results of the present study suggested compelling evidences that etazolate has more marked effect on depression-like behavior in mice, which is atleast in part may be related to their modulating effects on the HPA axis and BDNF level.
[Mh] Termos MeSH primário: Comportamento Animal/efeitos dos fármacos
Fator Neurotrófico Derivado do Encéfalo/metabolismo
Etazolato/farmacologia
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos
Sistema Hipófise-Suprarrenal/efeitos dos fármacos
Estresse Fisiológico/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Brain-Derived Neurotrophic Factor); I89Y79062L (Etazolate)
[Em] Mês de entrada:1406
[Cu] Atualização por classe:131021
[Lr] Data última revisão:
131021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130827
[St] Status:MEDLINE


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[PMID]:23926692
[Au] Autor:Ankur J; Mahesh R; Bhatt S
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333 031, India. kumarjindal26@gmail.com
[Ti] Título:Anxiolytic-like effect of etazolate, a type 4 phosphodiesterase inhibitor in experimental models of anxiety.
[So] Source:Indian J Exp Biol;51(6):444-9, 2013 Jun.
[Is] ISSN:0019-5189
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:Etazolate is a selective inhibitor of type 4 phosphodiesterase (PDE4) class enzyme. Antidepressant-like effect of etazolate has been previously demonstrated in the rodent models of depression. The present study was designed to investigate the anxiolytic-like activity of etazolate in experimental mouse models of anxiety. The putative anxiolytic effect of etazolate (0.25-1 mg/kg, ip) was studied in mice by using a battery of behavioural tests of anxiety such as elevated plus maze (EPM), light/dark (L/D) aversion, hole board (HB) and open field (OFT) with diazepam (2 mg/kg, ip) as reference anxiolytic. Like diazepam (2 mg/kg, ip), etazolate (0.5 and 1 mg/kg, ip) significantly increased the percentage of both time spent and entries into open arms in the EPM test. In the L/D test etazolate (0.5 and 1 mg/kg, ip) increased the both total time spent in and latency time to leave the light compartment. Etazolate (0.5 and 1 mg/kg, ip) also significantly increased head dipping scores and time spent in head dipping, whereas significantly decreased the head dipping latency in HB test. In addition, etazolate (0.5 and 1 mg/kg, ip) significantly increased the ambulation scores (square crossed) and number of rearing in OFT. In conclusion, these findings indicated that etazolate exhibited an anxiolytic-like effect in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.
[Mh] Termos MeSH primário: Ansiolíticos/farmacologia
Antidepressivos/farmacologia
Ansiedade/tratamento farmacológico
Comportamento Animal/efeitos dos fármacos
Etazolato/farmacologia
Inibidores da Fosfodiesterase 4/farmacologia
[Mh] Termos MeSH secundário: Animais
Escuridão
Diazepam/farmacologia
Emoções/efeitos dos fármacos
Luz
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Anxiety Agents); 0 (Antidepressive Agents); 0 (Phosphodiesterase 4 Inhibitors); I89Y79062L (Etazolate); Q3JTX2Q7TU (Diazepam)
[Em] Mês de entrada:1308
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130810
[St] Status:MEDLINE


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[PMID]:23384434
[Au] Autor:Jindal A; Mahesh R; Bhatt S
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India. kumarjindal26@gmail.com
[Ti] Título:Etazolate, a phosphodiesterase 4 inhibitor reverses chronic unpredictable mild stress-induced depression-like behavior and brain oxidative damage.
[So] Source:Pharmacol Biochem Behav;105:63-70, 2013 Apr.
[Is] ISSN:1873-5177
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Etazolate, a pyrazolopyridine class compound is selective inhibitor of type 4 phosphodiesterase (PDE4). Previous study in our laboratory has demonstrated that etazolate produced antidepressant-like effect in rodent models of behavioral despair. The present study was designed to investigate whether etazolate could affect the chronic unpredictable mild stress (CUMS)-induced depression in mice. The effect of etazolate on CUMS-induced depression was examined by measuring behavioral parameters and oxidant/antioxidant status of brain tissue. Mice were subjected to different stress paradigms daily for a period of 28days to induce depressive-like behavior. The results showed that CUMS caused depression-like behavior in mice, as indicated by significant (p<0.05) decrease in sucrose consumption and increase in duration of immobility. Moreover, CUMS also significantly (p<0.05) increased the oxidative stress markers and decreased the antioxidant enzymes activity. Chronic administration of etazolate (0.5 and 1mg/kg., p.o.) and fluoxetine (20mg/kg., p.o.) significantly (p<0.05) inhibited the CUMS-induced behavioral (decreased sucrose consumption and increased duration of immobility) and biochemical (increased lipid peroxidation and nitrite level; decreased glutathione, superoxide dismutase and catalase activity) changes. No alteration was observed in locomotor activity. Additionally, in the present study, the efficacy of etazolate (1mg/kg., p.o.) on the behavioral and biochemical paradigms was found comparable to that of fluoxetine, used as standard antidepressant. In conclusion, the results of the present study suggested that etazolate alleviated the CUMS-induced depression in mice, which is at least in part mediated by modulating oxidative-nitrosative stress status in mice brain.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Etazolato/farmacologia
Estresse Oxidativo
Inibidores de Fosfodiesterase/farmacologia
Estresse Psicológico/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Antidepressivos de Segunda Geração/farmacologia
Comportamento Animal/efeitos dos fármacos
Encéfalo/metabolismo
Doença Crônica
Fluoxetina/farmacologia
Seres Humanos
Peroxidação de Lipídeos/efeitos dos fármacos
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents, Second-Generation); 0 (Phosphodiesterase Inhibitors); 01K63SUP8D (Fluoxetine); I89Y79062L (Etazolate)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130207
[St] Status:MEDLINE


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[PMID]:23178198
[Au] Autor:Siopi E; Llufriu-Dabén G; Cho AH; Vidal-Lletjós S; Plotkine M; Marchand-Leroux C; Jafarian-Tehrani M
[Ad] Endereço:Laboratoire de Pharmacologie de la Circulation Cérébrale (EA 4475), Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 4, avenue de l'Observatoire, 75006 Paris, France.
[Ti] Título:Etazolate, an α-secretase activator, reduces neuroinflammation and offers persistent neuroprotection following traumatic brain injury in mice.
[So] Source:Neuropharmacology;67:183-92, 2013 Apr.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Traumatic brain injury (TBI) evokes an intense neuroinflammatory reaction that is essentially mediated by activated microglia and that has been reported to act as a secondary injury mechanism that further promotes neuronal death. It involves the excessive production of inflammatory cytokines and the diminution of neuroprotective and neurotrophic factors, such as the soluble form alpha of the amyloid precursor protein (sAPPα), generated by the activity of α-secretases. Hence, the aim of this study was to examine the effects of etazolate, an α-secretase activator, on acute and belated post-TBI consequences. The mouse model of TBI by mechanical percussion was used and injured mice received either the vehicle or etazolate at the dose of 1, 3 or 10 mg/kg at 2 h post-TBI. Neurological score, cerebral Å“dema, IL-1ß and sAPPα levels, microglial activation and lesion size were evaluated from 6 to 24 h post-TBI. Spontaneous locomotor activity was evaluated from 48 h to 12 weeks post-TBI, memory function at 5 weeks and olfactory bulb lesions at 13 weeks post-TBI. A single administration of etazolate exerted a dose-dependent anti-inflammatory and anti-Å“dematous effect accompanied by lasting memory improvement, reduction of locomotor hyperactivity and olfactory bulb tissue protection, with a therapeutic window of at least 2 h. These effects were associated with the restoration of the levels of the sAPPα protein post-TBI. Taken together, these results highlight for the first time the therapeutic interest of an α-secretase activator in TBI.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/metabolismo
Edema Encefálico/enzimologia
Edema Encefálico/prevenção & controle
Lesões Encefálicas/enzimologia
Lesões Encefálicas/prevenção & controle
Etazolato/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Ativação Enzimática/efeitos dos fármacos
Ativação Enzimática/fisiologia
Etazolato/farmacologia
Inflamação/enzimologia
Inflamação/prevenção & controle
Masculino
Camundongos
Fármacos Neuroprotetores
Distribuição Aleatória
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Neuroprotective Agents); EC 3.4.- (Amyloid Precursor Protein Secretases); I89Y79062L (Etazolate)
[Em] Mês de entrada:1311
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121127
[St] Status:MEDLINE


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[PMID]:22698578
[Au] Autor:Jindal A; Mahesh R; Gautam B; Bhatt S; Pandey D
[Ad] Endereço:Department of Pharmacy, Birla Institute of Technology & Science, Pilani-333031, Rajasthan, India. kumarjindal26@gmail.com
[Ti] Título:Antidepressant-like effect of etazolate, a cyclic nucleotide phosphodiesterase 4 inhibitor--an approach using rodent behavioral antidepressant tests battery.
[So] Source:Eur J Pharmacol;689(1-3):125-31, 2012 Aug 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Etazolate, a pyrazolopyridine class derivative is selective inhibitor of type 4 phosphodiesterase (PDE4), an enzyme catalyzes the hydrolysis of cyclic nucleotide viz. cAMP & regulates cAMP signal transduction. Enhancing cAMP signal transduction by inhibition of PDE4 is known to be beneficial in depression disorders. Thus, the present study was designed to investigate thoroughly the antidepressant potential of etazolate using rodent behavioral models of depression. Acute treatment of etazolate (0.25-1 mg/kg, i.p.) exhibited antidepressant-like effects in forced swim test (FST) & tail suspension test (TST) in mice without influencing the baseline locomotion in actophotometer test. Interaction studies of etazolate sub-effective dose (0.12 mg/kg, i.p.), were carried out with sub-effective dose of conventional antidepressants like fluoxetine (5mg/kg, i.p.), venlafaxine (4 mg/kg, i.p.) & desipramine (5 mg/kg, i.p.) in FST. Etazolate at sub-effective dose produced synergistic antidepressant-like effect with conventional antidepressants in the mouse FST. In addition, combined treatment of etazolate & conventional antidepressants had no significant effect on baseline locomotion. Moreover, etazolate (0.5 and 1 mg/kg, i.p.) increased head twitch scores in mice & antagonized the reserpine-induced hypothermia in rats. Chronic treatment (14 days) with etazolate (0.5 and 1 mg/kg, p.o.) & fluoxetine (10 mg/kg, p.o.) significantly reversed the behavioral anomalies induced by bilateral olfactory bulbectomy in rats in modified open field exploration. In conclusion, taken together, our results suggested that etazolate exhibited antidepressant-like activity in acute & chronic rodent models of depression & deserves as a therapeutic tool that could help the conventional pharmacotherapy of depression.
[Mh] Termos MeSH primário: Antidepressivos/uso terapêutico
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4
Depressão/tratamento farmacológico
Etazolato/uso terapêutico
Inibidores da Fosfodiesterase 4/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo
Depressão/enzimologia
Depressão/psicologia
Relação Dose-Resposta a Droga
Masculino
Camundongos
Ratos
Ratos Wistar
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Phosphodiesterase 4 Inhibitors); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4); I89Y79062L (Etazolate)
[Em] Mês de entrada:1305
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120616
[St] Status:MEDLINE
[do] DOI:10.1016/j.ejphar.2012.05.051


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[PMID]:21222604
[Au] Autor:Vellas B; Sol O; Snyder PJ; Ousset PJ; Haddad R; Maurin M; Lemarié JC; Désiré L; Pando MP; EHT0202/002 study group
[Ad] Endereço:CHU La Grave-Casselardit and INSERM U558, Toulouse, France.
[Ti] Título:EHT0202 in Alzheimer's disease: a 3-month, randomized, placebo-controlled, double-blind study.
[So] Source:Curr Alzheimer Res;8(2):203-12, 2011 Mar.
[Is] ISSN:1875-5828
[Cp] País de publicação:United Arab Emirates
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: EHT0202 (etazolate hydrochloride) is a new compound exhibiting both potential disease-modifying and symptomatic treatment properties in Alzheimer's Disease increasing alpha-secretase activity and sAPP alpha secretion, as well as acting as a GABA-A receptor modulator and as a PDE-4 inhibitor. METHODS: This pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, Phase IIA study was conducted in 159 randomized patients suffering from mild to moderate Alzheimer's Disease. EHT0202 (40 or 80 mg bid) or placebo was administered as adjunctive therapy to one acetylcholinesterase inhibitor over a 3-month period. This study was designed to assess the clinical safety and tolerability of EHT0202 as a primary objective, with secondary endpoints (cognitive function, daily living activities, behaviour, caregiver burden and global functioning) included to explore clinical efficacy of EHT0202 versus placebo. RESULTS: EHT0202 was shown to be safe and generally well tolerated. Dose-dependent numbers of early withdrawal and central nervous system related adverse events were observed. As expected, since the study was not powered and not designed to show drug efficacy, and except for ratings on the ADCS-ADL scale, no significant differences were seen between treatment groups. CONCLUSIONS: These first encouraging safety results do support further development of EHT0202 in order to assess its clinical efficacy and to confirm its tolerability in a larger cohort of Alzheimer patients and for a longer period.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Etazolato/efeitos adversos
Inibidores de Fosfodiesterase/efeitos adversos
[Mh] Termos MeSH secundário: Idoso
Método Duplo-Cego
Feminino
Seres Humanos
Masculino
Projetos Piloto
Fatores de Tempo
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Phosphodiesterase Inhibitors); I89Y79062L (Etazolate)
[Em] Mês de entrada:1108
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110113
[St] Status:MEDLINE


  10 / 69 MEDLINE  
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[PMID]:20223232
[Au] Autor:Drott J; Desire L; Drouin D; Pando M; Haun F
[Ad] Endereço:NeuroDetective International, 1422 Hopeland Rd., Wyncote, PA 19095, USA.
[Ti] Título:Etazolate improves performance in a foraging and homing task in aged rats.
[So] Source:Eur J Pharmacol;634(1-3):95-100, 2010 May 25.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Etazolate is a phosphodiesterase 4 (PDE4) inhibitor and GABAA receptor modulator that also stimulates alpha-secretase activity and neurotrophic soluble amyloid precursor protein (sAPPalpha) production, currently developed as a possible Alzheimer's disease therapeutic. In this study two doses of etazolate were tested for cognitive effects in normally aged rats, using a complex spatial learning and memory task that emphasized two naturally occurring behaviors in rodents, foraging for food and returning large pieces of found food to a safe home location. Both etazolate doses completely prevented both (1) a foraging deficit that developed in untreated aged rats over the course of the test, as well as (2) a trial-specific deficit in memory for previously visited food locations that also developed over the course of the test in untreated aged rats. Both doses also significantly reduced a separate memory deficit for changing locations of the animals' home box, plus completely prevented a significant tendency for untreated aged animals to attempt entry into similar-appearing but incorrect home boxes. The combined behavioral data demonstrate positive effects of etazolate on separate age-related cognitive deficits, using a complex task based on naturally occurring rodent behaviors.
[Mh] Termos MeSH primário: Envelhecimento/efeitos dos fármacos
Etazolato/farmacologia
Comportamento Alimentar/efeitos dos fármacos
Comportamento de Retorno ao Território Vital/efeitos dos fármacos
Desempenho Psicomotor/efeitos dos fármacos
[Mh] Termos MeSH secundário: Envelhecimento/fisiologia
Envelhecimento/psicologia
Animais
Transtornos Cognitivos/tratamento farmacológico
Transtornos Cognitivos/psicologia
Etazolato/uso terapêutico
Comportamento Alimentar/fisiologia
Comportamento Alimentar/psicologia
Comportamento de Retorno ao Território Vital/fisiologia
Masculino
Desempenho Psicomotor/fisiologia
Ratos
Ratos Endogâmicos BN
Ratos Endogâmicos F344
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
I89Y79062L (Etazolate)
[Em] Mês de entrada:1011
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:100313
[St] Status:MEDLINE
[do] DOI:10.1016/j.ejphar.2010.02.036



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