Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate

Sjakste, Nikolajs; Kleschyov, Andrei L.; Boucher, Jean‐Luc; Баумане, Л.; Dzintare, Maija; Meirena, Dainuvite; Sjakste, Jelizaveta; Sydow, Karsten; Münzel, Thomas; Kalvinsh, Ivars

doi:10.1016/j.ejphar.2004.05.006

Cited by 19 publications

(19 citation statements)

References 12 publications

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“…Показано, что у диабетических животных усиливается продукция окиси азота в кровеносных сосудах [24]. Сам по себе милдронат тоже вызывает, хотя незначительное и преходящее, но воспроизводимое в экспериментах усиление биосинтеза окиси азота [25]. Увеличение концентрации циркулирующих жирных кислот в результате торможения их бета-окисления, с одной стороны, и усиленная продукция оксида азота, обусловленная как диабетом, так и действием милдроната, с другой стороны, должны усилить синтез нитро-производных жирных кислот.…”

Section: рисунок3unclassified

“…Снижение гликирования гемоглобина и, возможно, других белков тоже могло бы предотвращать развитие невропатии, но и этот эффект развивался только на шестой неделе лечения. Остается предположить, что милдронат может взаимодействовать со многими внутриклеточными медиаторами воспаления, например с оксидом азота [25] и фактором NF-kB [15]. Кроме того, препарат может влиять на процессы митохондриального дыхания [14] и таким образом снижать болевой порог.…”

Section: рисунок3unclassified

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The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

Sokolovska¹,

Rumaks²,

Karajeva³

et al. 2011

BIOMED KHIM

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Крысам со стрептозотоциновой моделью сахарного диабета перорально или внутрибрюшинно вводили милдронат (100 мг/кг ежедневно) в течение 6 недель. Вес животных, развитие невропатических болей, концентрацию глюкозы, триглицеридов и кетоновых тел в крови, процент гликированного гемоглобина, тест толерантности глюкозы определяли в течение всего эксперимента. Милдронат полностью предотвращал развитие диабетической невропатии, с первой недели и до конца эксперимента. В группе животных, получавших милдронат, наблюдали значимое снижение среднего уровня глюкозы на четвертой неделе курса, триглицеридов с третьей по шестую недели. Милдронат также замедлял накопление гликированного гемоглобина на шестой неделе и улучшал показатели теста толерантности глюкозы по сравнению с нелеченными животными. Полученные данные подтверждают возможность применения препарата для лечения сахарного диабета и его осложнений.Ключевыеслова: милдронат, стрептозотоцин, сахарный диабет, периферическая невропатия.ВВЕДЕНИЕ. Сахарный диабет и его осложнения остаются острой медицинской и социальной проблемой в развитых странах. Диабетическая невропатия является одним из самых тяжелых осложнений сахарного диабета [1][2][3]. В настоящее время для лечения невропатической боли при диабете наиболее часто применяются трициклические антидепрессанты (имипрамин, амитриптилин), противоэпилептические средства из класса блокаторов натриевых каналов (карбамазепин, окскарбазепин) и лиганды a2d-субъединицы потенциал-зависимых каналов ЦНС (габапентин, прегабалин). Однако, применение всех этих препаратов ограничивается их слабой эффективностью и побочными эффектами [2,3]. Это побуждает к поиску новых средств для лечения осложнений диабета.Ингибиторы бета-окисления жирных кислот считаются перспективными противодиабетическими средствами, поскольку они способствуют потреблению глюкозы [4]. Представитель данной группы препаратов милдронат широко применяется как противоишемическое средство. Этот фармакологический эффект милдроната достигается путем ингибирования гамма-бутиробетаингидроксилазы и снижения бета-окисления жирных кислот [5]. В клинике милдронат оказался эффективным для лечения некоторых осложнений инсулин-независимого сахарного диабета [6][7][8][9]. В экспериментальных исследованиях милдронат 490 * -адресат для переписки

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Section: рисунок3unclassified

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

Sokolovska¹,

Rumaks²,

Karajeva³

et al. 2011

BIOMED KHIM

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“…It was demonstrated that in dia betic animals nitric oxide production increased in blood vessels [24]. Mildronate also caused insignifi cant and transient but reproducible under the experi mental conditions increase of nitric oxide biosynthesis [25]. The increase in concentration of circulating fatty acids caused by inhibition of their beta oxidation and also increased nitric oxide production induced by both diabetes and mildronate administration should Mean values of blood glucose in the glucose tolerance test performed after treatment with mildronate for 4 weeks (a) and 6 weeks (b).…”

Section: Possible Mechanisms Of the Hypoglycemic Effect Of Mildronatementioning

confidence: 97%

“…The decrease in glycated hemoglobin and possibly other proteins would prevent the development of neuropathy, but this effect was noted at week 6. It is possible that mildr onate may interact with many intracellular inflamma tory mediators, for example, with nitric oxide [25] and NF κB [15]. Mildronate may also influence mito chondrial respiration [14] and thus decrease the pain threshold.…”

Section: Influence Of Mildronate On Some Characteristics In Diabetic mentioning

confidence: 98%

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rats with the streptozotocin model of diabetes mellitus

Sokolovska

Rumaks

Karajeva

et al. 2012

Biochem. Moscow Suppl. Ser. B

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Rats with the streptozotocin (STZ) model of diabetes mellitus were treated with mildronate (100 mg/kg daily, per os or intraperitoneally) for 6 weeks. Body weight, blood glucose, triglycerides, ketone body concentrations, percent of glycated hemoglobin (HbA1c%), glucose tolerance, and the development of neuropathic pain were monitored throughout the whole experiment. The mildronate treatment completely prevented the development of the diabetic neuropathy from the first week up to the end of experiment. In the group of diabetic animals treated with mildronate a significant decrease of blood glucose was observed on the fourth week of the treatment, the level of triglycerides decreased from the third to sixth weeks. Mildronate also decreased accumulation of glycated hemoglobin on the sixth week and improved glucose tolerance compared with untreated animals. The data obtained confirm applicability of mildronate for therapy of diabetes mellitus and its complications.

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“…NO mass fraction (ng g -1 of tissue) was calculated on the basis of calibration curves, as described previously (22)(23)(24)(25)(26). Briefl y, different quantities of NaNO 2 [in fi nal concentrations of (10,20,30,40,60, and 100) µmol L -1 ] were mixed with DETC (33 mg mL -1 ) and…”

Section: Esr Measurementsmentioning

confidence: 99%

Effects of Lycopene, Indole-3-Carbinol, and Luteolin on Nitric Oxide Production and iNOS Expression are Organ-Specific in Rats

Rostoka

Isajevs

Баумане

et al. 2010

Archives of Industrial Hygiene and Toxicology

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Natural compounds are known to modify NO content in tissues; however, the biological activity of polyphenol-rich food often does not correspond to the effects of individual polyphenols on NO synthase activity. The aim of this study was to see how natural compounds luteolin, indole-3-carbinol, and lycopene modify NO production in rat tissues and change the expression of the iNOS gene and protein. Indole-3-carbinol produced multiple effects on the NO level; it signifi cantly decreased NO concentration in blood, lungs, and skeletal muscles and increased it in the liver. Indole-3-carbinol enhanced lipopolyssaccharide (LPS)-induced NO production in all rat organs. It decreased iNOS gene expression in the brain cortex of animals that did not receive LPS and up-regulated it in the LPS-treated animals. Lycopene increased the iNOS gene transcription rate in the brain cortex of LPS-treated animals. Luteolin did not modify NO production in any organ of LPS-untreated rats, nor did it affect gene expression in the liver. In the brain it slightly decreased iNOS gene expression. Luteolin decreased NO production in the blood of LPS-treated animals and the number of iNOS-positive cells in these animals. Our results suggest that changes in tissue NO levels caused by natural compounds cannot be predicted from their effect on NOS expression or activity obtained in model systems. This stresses the importance of direct measurements of NO and NOS expression in animal tissues. Toksikol 2010;61:275-285 Natural biologically active compounds of plant origin such as flavonoids are widely used as dietary supplements with detoxicating effects. The detoxicating effect of many plant-derived compounds is based on their antioxidant, anti-mutagenic, and anti-carcinogenic effects (1, 2). These substances are also known to infl uence the enzymatic production of nitric oxide (NO) and its stability. (3). This underlines the signifi cance of the uptake of fl avonoid and other natural compound for the defence of cardiovascular, immune, and nervous systems against toxins. However, the biological activity of polyphenol-rich food does not correspond to the effects of individual compounds on NO synthase activity. For example, red wine is known as a vasodilator (4) and is rich in quercetin. Purifi ed quercetin inhibits inducible nitric oxide synthase (iNOS) gene expression (3, 5), destabilises endothelial NOS (eNOS) mRNA (6), KEY WORDS: ESR spectroscopy, inducible nitric oxide synthase, natural compounds, NO Rostoka E, et al. EFFECTS OF NATURAL COMPOUNDS ON NO AND iNOSArh Hig Rada

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Endothelium- and nitric oxide-dependent vasorelaxing activities of gamma-butyrobetaine esters: possible link to the antiischemic activities of mildronate

Cited by 19 publications

References 12 publications

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model

The influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rats with the streptozotocin model of diabetes mellitus

Effects of Lycopene, Indole-3-Carbinol, and Luteolin on Nitric Oxide Production and iNOS Expression are Organ-Specific in Rats

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