Erdostein patří mezi běžně používaná mukolytika. Mechanismus účinku této látky spočívá v ovlivnění viskozity hlenu, jeho tvorby a také mukociliárního transportu. Zvláštností erdosteinu je ale také antioxidační, protizánětlivé či antibakteriální působení. Článek zmíněné charakteristiky diskutuje v kontextu aktuálních informací s cílem zaměřit se i na dětskou populaci.

Erdosteine belongs to the commonly used mucolytic. The mechanism of action of this substance lies in regulating the mucus viscosity, its formation and also mucociliary transport. However, the peculiarity of erdosteine consists in its antioxidant, anti-inflammatory and antibacterial effect. The article discusses these characteristics in the context of current information with a focus also on the paediatric population.

• Keywords
• ERDOSTEIN,
• MeSH
• Child MeSH
• Expectorants * therapeutic use   MeSH
• Homocysteine analogs & derivatives   pharmacology   therapeutic use   MeSH
• Respiratory Tract Infections drug therapy   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Thiophenes * pharmacology   therapeutic use   MeSH
• Thioglycolates * pharmacology   therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH

Erdostein patří mezi běžně používaná mukolytika. Mechanismus účinku této látky spočívá v ovlivnění viskozity hlenu, jeho tvorby a také mukociliárního transportu. Zvláštností erdosteinu je ale také antioxidační, protizánětlivé či antibakteriální působení. Článek zmíněné charakteristiky diskutuje v kontextu aktuálních informací s cílem zaměřit se i na dětskou populaci.

Erdosteine belongs to the commonly used mucolytic. The mechanism of action of this substance lies in regulating the mucus viscosity, its formation and also mucociliary transport. However, the peculiarity of erdosteine consists in its antioxidant, anti-inflammatory and antibacterial effect. The article discusses these characteristics in the context of current information with a focus also on the paediatric population.

• Keywords
• ERDOSTEIN,
• MeSH
• Child MeSH
• Expectorants * therapeutic use   MeSH
• Homocysteine analogs & derivatives   pharmacology   therapeutic use   MeSH
• Respiratory Tract Infections drug therapy   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Thiophenes * pharmacology   therapeutic use   MeSH
• Thioglycolates * pharmacology   therapeutic use   MeSH
• Check Tag
• Child MeSH
• Humans MeSH

Mechanism of ictogenesis of D- and L-stereroisomers of homocysteic acid was studied in 12-day-old rats by means of antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. There was no qualitative difference between the two stereoisomers in generation of emprosthotonic (flexion) as well as generalized tonic-clonic seizures. Moderate differences were observed in the first, nonconvulsive effects of the two isomers. As generation of the two types of seizures is concerned, NMDA and AMPA participate in generalized tonic-clonic seizures whereas NMDA receptors play a dominant role in generation of flexion seizures.

• MeSH
• 2-Amino-5-phosphonovalerate analogs & derivatives   MeSH
• Receptors, AMPA antagonists & inhibitors   MeSH
• Benzodiazepines MeSH
• Quinoxalines MeSH
• Dizocilpine Maleate MeSH
• Homocysteine analogs & derivatives   chemistry   toxicity   MeSH
• Rats, Wistar MeSH
• Receptors, N-Methyl-D-Aspartate antagonists & inhibitors   MeSH
• Stereoisomerism MeSH
• Seizures chemically induced   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Antioxidants have not reduced the burden of cardiovascular disease, and current evidence suggests a beneficial role of oxidative stress, via NADPH oxidase (Nox) upregulation, in endothelial function. Homocysteine thiolactone (HcyT) induces blood vessel dysfunction and this correlates with increased vascular oxidative stress. This study aimed to determine if pharmacological inhibition of Nox could impair HcyT induced blood vessel dysfunction. Abdominal aorta were excised from New Zealand White rabbits (n = 6), cut into rings and sequentially mounted in organ baths. Rings were preincubated with 0.55 μmol/L homocysteine thiolactone for 1 h, or combinations of putative Nox inhibitors (plumbagin for Nox4, gp91ds-tat for Nox2, and ML090 for Nox1), 30 min prior to the addition of HcyT, followed by a dose response curve to acetylcholine on phenylephrine preconstricted rings. Plumbagin, ML090 + gp91ds-tat and HcyT reduced responses to acetylcholine, and Plumbagin + Hcyt caused constriction to acetylcholine, which was normalised to plumbagin by ML090. Plumbagin + ML090 or plumbagin + gp91ds-tat completely impaired the effect of acetylcholine. ML090 inhibited the effect of HcyT on reduced response to acetylcholine, whereas gp91ds-tat had no effect. This study concludes that inhibition of Nox1 prevents, whereas inhibition of Nox4 worsens, acetylcholine induced blood vessel relaxation caused by HcyT, while Nox2 inhibition has no effect. However combinations of Nox inhibitors worsen acetylcholine induced blood vessel relaxation. These results suggest that there is cross-talk between Nox isoforms during physiological and pathophysiological processes.

• MeSH
• Aorta, Abdominal drug effects   physiopathology   MeSH
• Quinoxalines pharmacology   MeSH
• Glycoproteins pharmacology   MeSH
• Homocysteine analogs & derivatives   pharmacology   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Rabbits MeSH
• NADPH Oxidases antagonists & inhibitors   MeSH
• Naphthoquinones pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

We optimized and validated a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of six metabolites of homocysteine metabolism: homocysteine, methionine, cysteine, S-adenosylmethionine, S-adenosylhomocysteine and betaine. The detection limits for these metabolites were in the nanomolar range, and the intra- and inter-day precisions were lower than 20% of the relative standard deviations. The method was specifically designed for the determination of the intracellular concentrations of the metabolites in cultured cells. To study the role of betaine-homocysteine S-methyltransferase (BHMT), HepG2 cells and HepG2 cells that were stably transfected with BHMT ((BHMT) HepG2) were treated with homocysteine or with a specific inhibitor of BHMT, and metabolite levels were subsequently measured. Severely compromised methyl group metabolism in the HepG2 cells, which is typical of cancer-derived cells, prevented clear evaluation of the changes caused by the external manipulations of homocysteine metabolism. However, the ease of handling these cells and the almost unlimited source of experimental material supplied by cells in permanent culture allowed us to develop a reliable methodology. The precautions concerning intracellular metabolite determinations using LC-MS/MS in cultured cells that are expressed in this work will have global validity for future metabolomics studies.

• MeSH
• Betaine-Homocysteine S-Methyltransferase metabolism   MeSH
• Hep G2 Cells MeSH
• Chromatography, Liquid MeSH
• Homocysteine analogs & derivatives   analysis   chemistry   metabolism   MeSH
• Calibration MeSH
• Humans MeSH
• Linear Models MeSH
• Reproducibility of Results MeSH
• Sensitivity and Specificity MeSH
• Tandem Mass Spectrometry MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The widely-held assumption was that oxidative stress does not occur during seizures in the immature brain. The major finding of the present study concerns evidence of oxidative stress in the brain of immature rats during seizures induced by DL-homocysteic acid. Seizures were induced in 12-day-old rats by bilateral intracerebroventricular infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side) and oxidative stress was evaluated by in situ detection of superoxide anion (O(2)·(-)). Using hydroethidine (Het) method, the fluorescent signal of the oxidized products of Het (reflecting O(2)·(-) production) significantly increased (by 50%-60%) following 60 min lasting seizures in all the studied structures, namely CA1, CA3 and dentate gyrus of the hippocampus, cerebral cortex and thalamus. The enhanced O(2)·(-) production was substantially attenuated or completely prevented by substances providing an anticonvulsant effect, namely by a competitive NMDA receptor antagonist AP7, a highly selective and potent group II metabotropic glutamate receptor (mGluR) agonist 2R,4R-APDC and highly selective group III mGluR, subtype 8 agonist (S)-3,4-DCPG. Complete protection was achieved by two SOD mimetics Tempol and MnTMPYP which strongly suggest that the increased fluorescent signal reflects O(2)·(-) formation. In addition, both scavengers provided a partial protection against brain damage associated with the present model of seizures. Signs of neuronal degeneration, as evaluated by Fluoro-Jade B staining, were detected at 4h following the onset of seizures. The present findings thus suggest that the increased superoxide generation precedes neuronal degeneration and may thus play a causative role in neuronal injury. Occurrence of oxidative stress in brain of immature rats during seizures, as demonstrated in the present study, can have a clinical relevance for a novel approach to the treatment of epilepsy in children, suggesting that substances with antioxidant properties combined with the conventional therapies might provide a beneficial effect.

• MeSH
• 2-Amino-5-phosphonovalerate analogs & derivatives   therapeutic use   MeSH
• Anticonvulsants therapeutic use   MeSH
• Time Factors MeSH
• Homocysteine analogs & derivatives   toxicity   MeSH
• Infusions, Intraventricular MeSH
• Rats MeSH
• Metalloporphyrins metabolism   MeSH
• Disease Models, Animal MeSH
• Brain drug effects   metabolism   MeSH
• Statistics, Nonparametric MeSH
• Animals, Newborn MeSH
• Rats, Wistar MeSH
• Proline analogs & derivatives   therapeutic use   MeSH
• Superoxides metabolism   MeSH
• Seizures chemically induced   pathology   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Betaine-homocysteine S-methyltransferase 2 (BHMT-2) catalyzes the transfer of a methyl group from S-methylmethionine to l-homocysteine, yielding two molecules of l-methionine. It is one of three homocysteine methyltransferases in mammals, but its overall contribution to homocysteine remethylation and sulfur amino acid homeostasis is not known. Moreover, recombinant BHMT-2 is highly unstable, which has slowed research on its structural and catalytic properties. In this study, we have prepared the first series of BHMT-2 inhibitors to be described, and we have tested them with human recombinant BHMT-2 that has been stabilized by copurification with human recombinant BHMT. Among the compounds synthesized, (2S,8RS,11RS)-5-thia-2,11-diamino-8-methyldodecanedioic acid (11) was the most potent (K(i)(app) ∼77 nM) and selective inhibitor of BHMT-2. Compound 11 only weakly inhibited human BHMT (IC(50) about 77 μM). This compound (11) may be useful in future in vivo studies to probe the physiological significance of BHMT-2 in sulfur amino acid metabolism.

• MeSH
• Betaine-Homocysteine S-Methyltransferase antagonists & inhibitors   chemistry   MeSH
• Enzyme Assays MeSH
• Homocysteine analogs & derivatives   chemical synthesis   chemistry   MeSH
• Kinetics MeSH
• Humans MeSH
• Recombinant Proteins antagonists & inhibitors   MeSH
• Stereoisomerism MeSH
• Sulfides chemical synthesis   chemistry   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.

• MeSH
• Excitatory Amino Acid Agonists pharmacology   MeSH
• Aldehydes metabolism   MeSH
• Time Factors MeSH
• Down-Regulation drug effects   physiology   MeSH
• Energy Metabolism drug effects   physiology   MeSH
• Epilepsy metabolism   physiopathology   MeSH
• Homocysteine analogs & derivatives   toxicity   MeSH
• Convulsants toxicity   MeSH
• Rats MeSH
• Metabolic Networks and Pathways physiology   MeSH
• Survival Rate MeSH
• Mitochondrial Diseases chemically induced   metabolism   physiopathology   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Disease Models, Animal MeSH
• Cerebral Cortex metabolism   pathology   physiopathology   MeSH
• Animals, Newborn MeSH
• Oxidative Stress drug effects   physiology   MeSH
• Rats, Wistar MeSH
• Electron Transport Complex I drug effects   metabolism   MeSH
• Free Radical Scavengers pharmacology   MeSH
• Tyrosine analogs & derivatives   metabolism   MeSH
• Seizures chemically induced   metabolism   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to l-homocysteine, yielding dimethylglycine and l-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH(3)), or N(CH(3))(2) groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH(3)) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors.

• MeSH
• Betaine-Homocysteine S-Methyltransferase antagonists & inhibitors   MeSH
• Homocysteine analogs & derivatives   pharmacology   chemical synthesis   chemistry   MeSH
• Enzyme Inhibitors pharmacology   chemical synthesis   chemistry   MeSH
• Pentanoic Acids pharmacology   chemical synthesis   chemistry   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Drug Design MeSH
• Stereoisomerism MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

The present study has examined the anticonvulsant and neuroprotective effect of 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective agonist for group II metabotropic glutamate receptors (mGluRs) when given 10-15 min after the onset of seizures induced in 12-day-old rats by bilateral icv infusion of DL-homocysteic acid (DL-HCA, 600 nmol/side). For biochemical analyses, rat pups were sacrificed during generalized clonic-tonic seizures, approximately 45-50 min after infusion of DL-HCA. Comparable time intervals were used for sacrificing the animals which received 2R,4R-APDC (0.05 nmol/side) or saline. The severity of seizures was influenced only slightly when the agonist was given after the onset of seizures, as evaluated both from the behavioral symptoms and from EEG recordings. A tendency to lower number and a shorter duration of seizures was outlined in animals posttreated with 2R,4R-APDC, but the differences did not reach the level of statistical significance. Cortical energy metabolite changes which normally accompany seizures in immature rats (large decrease of glucose and glycogen and a marked rise of lactate) were ameliorated only partially. The neuroprotective effect of 2R,4R-APDC was evaluated after 24 h and 6 days of survival following DL-HCA-induced seizures. Massive neuronal degeneration in many brain regions, mainly in the hippocampus and thalamus, following infusion of DL-HCA alone was only partially attenuated after 2R,4R-APDC posttreatment. The present findings clearly indicate that both anticonvulsant and neuroprotective effect of 2R,4R-APDC against DL-HCA-induced seizures is substantially diminished when the agonist is given after the onset of seizures as compared with its efficacy after the pretreatment (Exp. Neurol.192, 420-436, 2005).

• MeSH
• Excitatory Amino Acid Agonists therapeutic use   MeSH
• Cytoprotection physiology   drug effects   MeSH
• Nerve Degeneration chemically induced   physiopathology   prevention & control   MeSH
• Epilepsy drug therapy   metabolism   physiopathology   MeSH
• Hippocampus metabolism   growth & development   drug effects   MeSH
• Homocysteine analogs & derivatives   pharmacology   MeSH
• Convulsants pharmacology   MeSH
• Rats MeSH
• Drug Interactions physiology   MeSH
• Brain metabolism   growth & development   drug effects   MeSH
• Neuroprotective Agents therapeutic use   MeSH
• Rats, Wistar MeSH
• Proline analogs & derivatives   therapeutic use   MeSH
• Receptors, Metabotropic Glutamate agonists   metabolism   MeSH
• Drug Administration Schedule MeSH
• Aging metabolism   MeSH
• Thalamus metabolism   growth & development   drug effects   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH