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Transdermal formulations of deprenyl: guinea pig and pig models. 去戊烯醇透皮制剂:豚鼠和猪模型。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
J Gaál, G Szebeni, G Székács, E Fejér, O Wágner, I Szatmári, K Magyar, M Mezei
{"title":"Transdermal formulations of deprenyl: guinea pig and pig models.","authors":"J Gaál,&nbsp;G Szebeni,&nbsp;G Székács,&nbsp;E Fejér,&nbsp;O Wágner,&nbsp;I Szatmári,&nbsp;K Magyar,&nbsp;M Mezei","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The efficacy of many drugs relies on their presence at the site of action over a period of time. The retardation or programmed release capability of the conventional dosage forms like oral and parenteral are limited and toxic and undesired side-effects may occur after their applications. These problems may be solved using transdermal delivery systems. Transdermal systems are aimed for local, or systemic action. In the letter case controlling the rate of delivery or modulating the distribution in the organism. The selection of an adequate biological method of evaluating a new transdermal formulation is a critical point of the development. The in vitro methods can help in the characterization of the different formulas, but without an in vivo disposition study they cannot give relevant information about the expectable therapeutic behavior. We adapted and improved an in vivo test system for the evaluation of new transdermal particulate systems (patches) and liposomes containing deprenyl selegiline as active ingredient. The in vivo evaluation system consists of two steps: 1. Full biodisposition study on guinea pig, using isotope labeled selegiline. 2. Biodisposition studies on domestic pigs including dose, area, surface dependence and comparative bioavailability with traditional dosage forms and application moods. Specific examples of these studies and experimental technology are presented.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 2","pages":"143-66"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21889395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Anti-apoptotic function of L-(-)deprenyl (Selegiline) and related compounds. L-(-)去戊烯基(Selegiline)及其相关化合物的抗凋亡功能。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
M Naoi, W Maruyama, K Yagi, M Youdim
{"title":"Anti-apoptotic function of L-(-)deprenyl (Selegiline) and related compounds.","authors":"M Naoi,&nbsp;W Maruyama,&nbsp;K Yagi,&nbsp;M Youdim","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>(-)Deprenyl has been proposed to be neuroprotective to dopamine neurons in the parkinsonian brains. To clarify the mechanism, the effects of (-)deprenyl and structurally related compounds on apoptosis induced by a neurotoxin, N-methyl(R)-salsolinol, and reactive oxygen species, nitric oxide and peroxynitrite, were examined in dopaminergic SH-SY5Y cells. DNA damage was quantified by the single cell gel electrophoresis (comet) assay. (-)-Deprenyl protected the cells from apoptosis in a dose-dependent way, which required pre-treatment at least for 20 min. The effect was confirmed even after washing out of (-)deprenyl, indicating that (-)-deprenyl initiates the intracellular process to antagonize the apoptotic death program. The studies on the structure-activity relationship reveal that N-propargyl residue with hydrophobic structure is essential for the anti-apoptotic function. These results suggest that (-)deprenyl and related compounds may be applicable as neuroprotective agents in neurodegenerative diseases.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 1","pages":"69-80"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21842411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
N-methyl(R)salsolinol and a neutral N-methyltransferase as pathogenic factors in Parkinson's disease. n -甲基(R)salsolinol和中性n -甲基转移酶在帕金森病中的致病作用
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
W Maruyama, M Strolin-Benedetti, M Naoi
{"title":"N-methyl(R)salsolinol and a neutral N-methyltransferase as pathogenic factors in Parkinson's disease.","authors":"W Maruyama,&nbsp;M Strolin-Benedetti,&nbsp;M Naoi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The pathogenesis of Parkinson's disease is still an enigma. As an endogenous MPTP-like neurotoxin, N-methyl(R)salsolinol was proved to induce parkinsonism in rats and apoptosis in dopaminergic neurons. It is synthesized in the human brain by two enzymes; an (R)salsolinol synthase and an N-methyltransferase, and accumulates in the nigro-striatum in human brains. The activity of a neutral N-methyltransferase in the striatum was found to determine the level of MPP+-like 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, an oxidation product of N-methyl(R)salsolinol in the substantia nigra. The activity of this N-methyltransferase was found to increase significantly in lymphocytes prepared from parkinsonian patients. In cerebrospinal fluid from untreated parkinsonian patients, N-methyl(R)-salsolinol increases significantly. These results suggest that N-methyl(R)salsolinol and a neutral N-methyltransferase may be endogenous factors in the pathogenesis of Parkinson's disease.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 1","pages":"55-68"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21842410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unusual pattern of beta-phenylethylamine deamination in the rat heart. 大鼠心脏中不寻常的-苯乙胺脱胺模式。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
J Tiago Guimarães, P Soares-da-Silva
{"title":"Unusual pattern of beta-phenylethylamine deamination in the rat heart.","authors":"J Tiago Guimarães,&nbsp;P Soares-da-Silva","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The present study was aimed to determine type A and B MAO activities in rat heart and renal cortex homogenates and evaluate the sensitivity of deamination of 3H-5-HT and 14C-beta-PEA to selective MAO-A and MAO-B inhibitors, respectively Ro 41-1049 and lazabemide. Deamination of beta-PEA in the rat heart was not affected (Vmax = 53+/-10 vs 42+/-6 nmol mg protein(-1) h(-1)) by lazabemide (250 nM), but was significantly reduced (Vmax = 10+/-1 nmol mg protein(-1) h(-1)) by Ro 41-1049 (250 nM). Deamination of beta-PEA in the rat heart is a low affinity process (when compared with that in the kidney) with high Km values (244+/-98 vs 18.6+/-5.8 microM). On the other hand, deamination of 5-HT in the rat heart and renal cortex revealed high Km values, which were similar to those for beta-PEA in the heart. Deamination of beta-PEA (1000 microM) in the rat heart was inhibited in a concentration-dependent manner by Ro 41-1049 with a Ki value of 32 nM (22, 48; 95% confidence limits), but not by the selective MAO-B inhibitor lazabemide (up to 500 nM). Inhibition of 5-HT (1000 microM) deamination in the rat heart by Ro 41-1049 was also a concentration-dependent process with a Ki value of 21 (16, 26) nM. Deamination of 5-HT (1000 microM) in the rat renal cortex, was inhibited in a concentration-dependent manner by Ro 41-1049 with a Ki value of 12 (8, 17) nM. Deamination of beta-PEA in the renal cortex was inhibited by lazabemide with a Ki of 5 (3, 7) nM. In the rat heart, in contrast to that in the renal cortex, the specific MAO-B substrate beta-PEA is deaminated by a form of MAO which most probably corresponds to MAO-A.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 1","pages":"109-18"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21843064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
(-)Deprenyl (Selegiline): past, present and future. (-)去戊烯醇(Selegiline):过去、现在和未来。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
J Knoll
{"title":"(-)Deprenyl (Selegiline): past, present and future.","authors":"J Knoll","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>(-)Deprenyl (Selegiline), the N-propargyl analogue of (-)methamphetamine, is the only drug in clinical case which, by enhancing the impulse propagation mediated release of noradrenaline and dopamine in the brain (catecholaminergic activity enhancer, CAE, effect), keeps in small doses without side-effects the catecholaminergic brain system on a higher activity level. (-)Deprenyl stimulates the catecholaminergic neurons selectively in the brain because, in contrast to PEA and the amphetamines which induce the continuous release of noradrenaline and dopamine from their intraneuronal stores, (-)deprenyl is devoid of this property. It is due to the CAE effect that a) the maintenance of rats on (-)deprenyl during the postdevelopmental phase of their life slows the age-related decline of sexual and learning performances and prolongs life significantly; b) patients with early, untreated Parkinson's disease maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers, and when on levodopa plus (-)deprenyl, they live significantly longer than patients on levodopa alone; and c) in patients with moderately severe impairment from Alzheimer's disease, treatment with (-)deprenyl slows the progression of the disease. It is reasonable to expect that a prophylactic low dose administration of a safe catecholaminergic activity enhancer substance during the postdevelopmental phase of life will slow the age-related decline of behavioral performances, delay natural death and decrease susceptibility to Parkinson's disease and Alzheimer's disease.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 2","pages":"179-99"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21889397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural approach of human MAO-A using fold recognition (threading) techniques.
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
J Wouters, E Depiereux, F Durant
{"title":"Structural approach of human MAO-A using fold recognition (threading) techniques.","authors":"J Wouters,&nbsp;E Depiereux,&nbsp;F Durant","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The major goal of the present work is to further approach the structure of human monoamine oxidase A (MAO-A). A first partial three-dimensional model of human MAO-A has already been established using secondary structure predictions and fold recognition methods [Wouters and Baudoux, 1998]. In this modeled structure, a segment of the sequence (residues 369-393) located near the covalent linkage to the essential flavin cofactor, and potentially involved in the structure of the active site of the protein, could not be modeled. We here propose a possible fold for that segment, based on threading techniques. The identification of regions of the protein potentially involved in its dimerization was also undertaken by studying hydrophobic areas present at the surface of the structure.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 1","pages":"119-28"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21843065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
On the primary structure of membrane-bound semicarbazide-sensitive amine oxidase (SSAO). 膜结合氨基脲敏感胺氧化酶(SSAO)的一级结构研究。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
J M Lizcano, M Unzeta
{"title":"On the primary structure of membrane-bound semicarbazide-sensitive amine oxidase (SSAO).","authors":"J M Lizcano,&nbsp;M Unzeta","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Mammalian semicarbazide-sensitive amine oxidase (SSAO) activities are a diverse group of copper dependent enzymes within the classification EC 1.4.3.6. [amine:oxygen oxidoreductase (deaminating) (copper-containing)]. They include plasma amine oxidase and the membrane-bound enzyme. Although soluble plasma SSAO from several species have been successfully purified and cloned, relatively little work has been carried out on the molecular properties of the tissue-bound enzyme. At present there is not conclusive evidence that allows to conclude whether or not plasma SSAO is released from the tissue-bound enzyme. This review focuses upon recent progress made in determining the primary structure of the membrane-bound SSAO.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 1","pages":"37-46"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21842408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Possible different fates for the hydrogen peroxide produced by rat white adipocyte amine oxidases. 大鼠白色脂肪细胞胺氧化酶产生的过氧化氢可能的不同命运。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
L Raimondi, G Banchelli, L Sgromo, R Pirisino
{"title":"Possible different fates for the hydrogen peroxide produced by rat white adipocyte amine oxidases.","authors":"L Raimondi,&nbsp;G Banchelli,&nbsp;L Sgromo,&nbsp;R Pirisino","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Monoamine oxidase (MAO) and benzylamine oxidases (Bz-SSAO) of rat white adipocytes, deaminating benzylamine and tyramine produce hydrogen peroxide at different cellular levels. The peroxide produced by their activity has a very short half-life in adipocyte suspension. The addition of a catalase inhibitor allows for the recovery of the intact peroxide within the first 10-min of its production. Thus, benzylamine and tyramine-dependent peroxide recovery is different, suggesting that the fate of the peroxide produced by the two amine oxidases might be different depending on the cellular site of its production.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 1","pages":"99-107"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21843063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibitor sensitivity of human serum and vascular semicarbazide-sensitive amine oxidases. 人血清和血管缩氨基脲敏感胺氧化酶抑制剂的敏感性。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
Z Mészáros, A Csányi, G Vallus, T Szombathy, I Karádi, K Magyar
{"title":"Inhibitor sensitivity of human serum and vascular semicarbazide-sensitive amine oxidases.","authors":"Z Mészáros,&nbsp;A Csányi,&nbsp;G Vallus,&nbsp;T Szombathy,&nbsp;I Karádi,&nbsp;K Magyar","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Recent data suggest that elevated serum semicarbazide-sensitive amine oxidase activity (SSAO) may cause endothelial injury. Formation of cytotoxic metabolites (especially formaldehyde) and increased oxidative stress might lead to initiation or progression of atherosclerosis. Effective and selective inhibitors of human SSAO might exert cytoprotective effect on endothelial cells. To compare the inhibitor sensitivity of human serum and vascular tissue SSAO enzyme, the inhibitory effect of semicarbazide and MDL 72974A was investigated. Serum and vascular SSAO activity has been determined using 14C-benzylamine as a substrate. The IC50 values of semicarbazide were estimated to be 5x10(-3) M and 5x10(-4) M for SSAO from human serum and saphenous vein, respectively. MDL 72974A amine oxidase inhibitor was more than thousand times more effective than semicarbazide. The IC50 values were 10(-7) M and 10(-8) M for SSAO from human serum and saphenous vein, respectively. This finding supports the hypothesis that soluble and membrane-bound vascular SSAO enzymes might have similar structure.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 2","pages":"215-23"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21888008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An autoradiographic method of visualising semicarbazide-sensitive amine oxidase activity in mouse tissue sections. 观察小鼠组织切片中氨基脲敏感胺氧化酶活性的放射自显影方法。
Neurobiology (Budapest, Hungary) Pub Date : 2000-01-01
J L Grönvall, H Garpenstrand, L Oreland, J Ekblom
{"title":"An autoradiographic method of visualising semicarbazide-sensitive amine oxidase activity in mouse tissue sections.","authors":"J L Grönvall,&nbsp;H Garpenstrand,&nbsp;L Oreland,&nbsp;J Ekblom","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Under the influence of semicarbazide-sensitive amine oxidase (SSAO), methylamine is deaminated to formaldehyde, which can react with various macromolecules and form irreversible adducts. We hereby present an autoradiographic method of visualising SSAO activity by measuring the in vivo formation of such adducts from 14C-methylamine. Our results revealed high concentrations of radioactive deposits in the intestinal wall, brown adipose tissue, spleen and bone marrow. Hydralazine is a potent SSAO inhibitor and pretreatment with this irreversible inactivator resulted in a nearly complete loss of radioactive deposits in the tissues. By giving 14C-methylamine at different time-points after irreversible inhibition of SSAO, it was also possible to determine the resynthesis rate of SSAO. Interestingly, the recovery rate of SSAO after such inactivation was tissue-specific. The possible therapeutic value of a specific SSAO inhibitory drug has been discussed.</p>","PeriodicalId":79356,"journal":{"name":"Neurobiology (Budapest, Hungary)","volume":"8 2","pages":"167-77"},"PeriodicalIF":0.0,"publicationDate":"2000-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21889396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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