Vilskersts R, Kuka J, Svalbe B, Cirule H, Liepinsh E, Grinberga S, Kalvinsh Dambrova M. Administration of L-carnitine and mildronate improves endothelial function and decreases mortality in hypertensive Dahl rats. Pieņemts publicēšanai Pharmacological Reports, 2011, vol. 63(3), (May -June).
http://www.ncbi.nlm.nih.gov/pubmed/21857086
Kopsavilkums
Hypertension is a well established risk factor for the development of cardiovascular diseases and increased mortality. This study was performed to investigate the effects of the administration of L-carnitine or mildronate, an inhibitor of L-carnitine biosynthesis, or their combination on the development of hypertension-related complications in Dahl salt-sensitive (DS) rats fed with a high salt diet. Male DS rats were fed laboratory chow containing 8% NaCl from 7 weeks of age. Experimental animals were divided into five groups and treated for 8 weeks with vehicle (water; n = 10), L-carnitine (100 mg/kg, n = 10), mildronate (100 mg/kg, n = 10) or a combination of L-carnitine and mildronate at the doses above (n = 10). During the experiment, control group animals continued to consume a diet with normal salt content. Administration of the combination significantly improved the survival rate for 50% of the population. None of the tested compounds or their combination influenced high salt intake-induced hypertension, while treatment with mildronate and the combination for 8 weeks significantly decreased resting heart rate by 12% and 10%, respectively. Feeding with high salt diet had no influence on systolic function of the heart, but it induced thickening of the ventricular walls and development of heart hypertrophy that was not improved by the administration of tested compounds. In addition, administration of the combination attenuated the development of endothelial dysfunction in isolated aortic rings. In conclusion, our results demonstrate that treatment with a combination of L-carnitine and mildronate is protective against hypertension-induced complications in an experimental model of salt-induced hypertension.
Zvejniece L, Svalbe B, Makrecka M, Liepinsh E, Kalvinsh I, Dambrova M, Mildronate exerts acute anticonvulsant and antihypnotic effects, Behavioral Pharmacology, 2010, 21(5-6):548-55.
http://journals.lww.com/behaviouralpharm/Abstract/2010/09000/Mildronate…
Kopsavilkums
The effects of mildronate [3-(2,2,2-trimethylhydrazinium) propionate], an inhibitor of L-carnitine biosynthesis and an anti-ischaemic drug, were examined in various in-vivo conditions to investigate the neuropharmacological profile after acute administration. Mildronate (200 mg/kg, acute intraperitoneal administration) exerted anticonvulsant activity in a chemoconvulsant pentylenetetrazole-induced clonic and tonic seizure test but did not change the effects of a convulsion-inducing dose of (+)-bicuculline, a γ-aminobutyric acid receptor antagonist. Mildronate also dose-dependently inhibited the sleeping time in ethanol-induced loss of righting reflex test. However, in a pentylenetetrazole-induced seizure test, mildronate significantly stimulated the anticonvulsant activity of ethanol. The anticonvulsant activity of mildronate was completely blocked after pre-treatment with α2-adrenergic receptor antagonist yohimbine (2 mg/kg) and nitric oxide synthase inhibitor NG-nitro-L-arginine (10 mg/kg). These results show that the acute administration of mildronate induces anticonvulsant and antihypnotic effects, which involve α2-adrenergic receptor and nitric oxide -dependent mechanisms. These findings indicate that the acute administration of mildronate could be beneficial for the treatment of seizures and alcohol intoxication.
Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Sharipo J, Viksna A, Kuka J, Liepinsh E, Dambrova M. Crystal structure of human gamma-butyrobetaine hydroxylase. Biochem Biophys Res Commun. (2010) 398:634-9.
http://www.ncbi.nlm.nih.gov/pubmed/20599753
Kopsavilkums
Gamma-butyrobetaine hydroxylase (GBBH) is a 2-ketoglutarate-dependent dioxygenase that catalyzes the biosynthesis of l-carnitine by hydroxylation of gamma-butyrobetaine (GBB). l-carnitine is required for the transport of long-chain fatty acids into mitochondria for generating metabolic energy. The only known synthetic inhibitor of GBBH is mildronate (3-(2,2,2-trimethylhydrazinium) propionate dihydrate), which is a non-hydroxylatable analog of GBB. To aid in the discovery of novel GBBH inhibitors by rational drug design, we have solved the three-dimensional structure of recombinant human GBBH at 2.0A resolution. The GBBH monomer consists of a catalytic double-stranded beta-helix (DBSH) domain, which is found in all 2KG oxygenases, and a smaller N-terminal domain. Extensive interactions between two monomers confirm earlier observations that GBBH is dimeric in its biological state. Although many 2KG oxygenases are multimeric, the dimerization interface of GBBH is very different from that of related enzymes. The N-terminal domain of GBBH has a similar fold to the DUF971 superfamily, which consists of several short bacterial proteins with unknown function. The N-terminal domain has a bound Zn ion, which is coordinated by three cysteines and one histidine. Although several other 2KG oxygenases with known structures have more than one domain, none of them resemble the N-terminal domain of GBBH. The N-terminal domain may facilitate dimer formation, but its precise biological role remains to be discovered. The active site of the catalytic domain of GBBH is similar to that of other 2KG oxygenases, and Fe(II)-binding residues form a conserved His-X-Asp-X(n)-His triad, which is found in all related enzymes.
Rostoka E, Baumane L, Isajevs S, Line A, Dzintare M, Svirina D, Sharipova J, Silina K, Kalvinsh I, Sjakste N. Effects of kaempferol and myricetin on inducible nitric oxide synthase expression and nitric oxide production in rats. Basic Clin Pharmacol Toxicol. 2010; 106(6):461-466.
http://www.ncbi.nlm.nih.gov/pubmed/20088846
Kopsavilkums
When administered as drugs or consumed as food components, polyphenolic compounds synthesized in plants interfere with intracellular signal transduction pathways, including pathways of nitric oxide synthase expression. However, effects of these compounds in vivo do not always correlate with nitric oxide synthase-inhibiting activities revealed in experiments with cultured cells. The initial goal of this work was to compare effects of flavonoids kaempferol and myricetin on inducible nitric oxide synthase mRNA and protein expression monitored by real-time RT-PCR and immunohistochemistry and to evaluate the impact of these effects on nitric oxide production in rat organs measured by means of electron paramagnetic resonance spectroscopy. Kaempferol and myricetin attenuated the lipopolysaccharide-induced outburst of inducible nitric oxide synthase gene expression; kaempferol also significantly decreased the lipopolysaccharide-induced outburst of inducible nitric oxide synthase protein expression in the liver. Myricetin decreased nitric oxide production in intact rat liver. Kaempferol did not decrease nitric oxide production neither in intact rats nor in the lipopolysaccharide-treated animals. Kaempferol even enhanced the lipopolysaccharide-induced increase of nitric oxide production in blood. Myricetin did not interfere with lipopolysaccharide effects. As both kaempferol and myricetin are known as inhibitors of inducible nitric oxide synthase expression, our results suggest that modifications of nitric oxide level in tissues by these compounds cannot be predicted from data about its effects on nitric oxide synthase expression or activity.
E. Rostoka, L. Baumane, S. Isajevs, A. Line, K. Silina, M. Dzintare, D. Svirina, J. Sharipova, I. Kalvinsh and N. Sjakste Effects of indole- 3 carbinol and flavonoids administered separately and in combination on nitric oxide production and iNOS expression in rats. Chinese Medicine, 2010, V.1, No 1, P.5-17.
http://www.scirp.org/Journal/PaperInformation.aspx?paperID=2124
Kopsavilkums
Beneficial effects of natural compounds are often attributed to modulation of NO production; however effects produced by plant extracts do not correlate with effects of purified components. The goal of our work was to study ability of flavonoids and indole-3-carbinol, as well as their combinations to modify NO production, iNOS gene and protein expression in rat tissues. Baicalein and luteolin decreased NO concentration in both intact and LPS-treated animals. Baicalein decreased iNOS gene expression. Luteolin decreased NO production in the liver and heart and number of iNOS-positive cells in the liver of LPS-treated animals. Combination of the two substances did not decrease the NO synthesis triggered by LPS, although it decreased iNOS gene expression. Quercetin decreased NO production in the heart, kidneys and blood of intact rats, but enhanced the LPS effect in testes, spleen and blood on NO production and iNOS protein expression in the liver. Indole-3-carbinol decreased NO concentration in the cerebellum, blood, lungs and skeletal muscles. The drug enhanced the LPS-triggered increase of NO production in all rat organs. It increased iNOS protein expression in intact liver; however it decreased the LPS-triggered outburst of the enzyme biosynthesis. Combination of indole3-carbinol with quercetin decreased NO production in LPS-treated animals however it slightly increased iNOS gene expression. Taken together our results suggest that modifications of NO level in tissues by a natural compound cannot be predicted from data about its effects on NOS expression or activity. Combination of substances can produce an effect differing from that of individual substances. This stresses importance of direct measurements of NO in the tissues.
E. Rostoka, L. Baumane, S. Isajevs, A. Line, K. Silina, M. Dzintare, D. Svirina, J. Sharipova, I. Kalvinsh and N. Sjakste Effects of Lycopene, Indole-3-Carbinol, and Luteolin on Nitric Oxide Production and iNOS Expression Are Organ-Specific in Rats Arh Hig Rada Toksikol 2010; 61, No 1, P.275-285
http://www.ncbi.nlm.nih.gov/pubmed/20860968
Kopsavilkums
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 significantly 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.
Sokolovska J, Rumaks J, Karajeva N, Grīnvalde D, Sharipova J,Kluša V, Kalvinsh I and Sjakste N Influence of mildronate on peripheral neuropathy and some characteristics of glucose and lipid metabolism in rat streptozotocin-induced diabetes mellitus model Biochemistry (Moscow) Supplement series B: Biomedical Chemistry, accepted
Konrāde, I., Škapare, E., Makrecka, M., Gulbe, L., Liepiņš, E., Lejnieks, A., Dambrova, M., Glioksalāzes II aktivitātes metodes izstrāde cukura diabēta komplikāciju molekulāro mehānismu pētījumiem, RSU Zinātniskie raksti, 2010
