Acute effect of antidiabetic 1,4‐dihydropyridine compound cerebrocrast on cardiac function and glucose metabolism in the isolated, perfused normal rat heart

Brīede, Janïna; Stivrina, Mãra; Vı̄gante, Brigita; Stoldere, Dzintra; Дубурс, Г.

doi:10.1002/cbf.1442

Cited by 43 publications

(19 citation statements)

References 53 publications

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“…Cerebrocrast has long-lasting effects on these parameters and on thymus and adrenal gland weight. Cerebrocrast significantly decreases plasma glucose levels in normal rats, and in streptozotocin (STZ)-induced diabetic rats, 26 stimulates glucose uptake in isolated perfused hearts of rats, 27 glucose uptake in rat brain, and promotes the transport of glucose into isolated healthy human erythrocytes. 28 It intensifies the release of insulin from pancreatic beta cells, 26 and promotes formation de novo of insulin receptors in several tissues and cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats

Brīede

Stivrina

Stoldere

et al. 2008

Cell Biochemistry & Function

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Type 2 diabetes is associated with obesity, insulin resistance, hyperglycemia, hyperphagia, polyuria, body weight gain, excessive secretion of glucocorticoids (GCs), thymus involution, adrenal gland hypertrophy, diabetic nephropathy, etc. We examined the effect of cerebrocrast, a new antidiabetic agent (synthesized in the Latvian Institute of Organic Synthesis), on body weight, food and water intake, urine output, and on changes of organ weight: that is, kidney, thymus, adrenal gland of normal rats. Cerebrocrast was administered at doses of 0.05 and 0.5 mg kg(-1) per os (p.o.) once a day for three consecutive days, and its effects were observed from 3 to 27 days after the last administration. Cerebrocrast, during the experimental period, decreased body weight by an average of approximately 32.3%, food intake by about 10-15% at the beginning of the experiments and by 22.6% at the end of the experiments, especially at a dose of 0.5 mg kg(-1). Water intake and urine output in comparison with controls were decreased. The daily food intake decreased about 1.0 and 2.1 g by administering single cerebrocrast doses of 0.05 and 0.5 mg kg(-1) body weight (b.w.), respectively, but by administering for three consecutive days, food intake decreased by about 2.2 and 3.4 g, respectively. The weekly body weight gain decreased by administering a single dose of cerebrocrast by 2.61 and 2.51 g, respectively, and by triple administration it decreased by 4.36 and 3.07 g, respectively. Cerebrocrast has long-lasting effects on these parameters and on thymus and adrenal gland weight. As cerebrocrast decreased glucose levels in normal and streptozotocin (STZ)-induced diabetic rats, it also promoted glucose uptake by the brain, intensified insulin action and formation de novo of insulin receptors. We can conclude that cerebrocrast may regulate food intake and body weight through glucose sensing by proopiomelanocortin (POMC) neurons, that are involved in control of glucose homeostasis, stimulation of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion, activation of MC4-Rs and inhibition of neuropeptide Y (NPY) in the ARC of the hypothalamus, affecting the kidney, and causing decreased urine output and water intake. Moreover, it could stimulate secretion of vasopressin. By administration of cerebrocrast thymus mass was increased, thereby preventing the action of GCs. As cerebrocrast inhibited L- and T-type calcium channels, it can prevent vasoconstriction of kidney arterioles and aldosterone secretion that have significant roles in the development of hypertension and diabetic nephropathy. These properties of cerebrocrast are important for treatment of Type 2 diabetes and its consequent development of hypertension and diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats

Brīede

Stivrina

Stoldere

et al. 2008

Cell Biochemistry & Function

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“…Step Total Protein (mg) Total Activity (U) Specific Activity (U/mg) Fold Yield (%) and HIV protease inhibitors [19][20][21][22]. However, the lack of efficient methods to synthesize 2,5-dihydropyridine has restricted studies on its biological activity and applications [18].…”

Section: Zz-5 (Hsph Zz )mentioning

confidence: 99%

Characterization of a Novel Nicotine Hydroxylase from Pseudomonas sp. ZZ-5 That Catalyzes the Conversion of 6-Hydroxy-3-Succinoylpyridine into 2,5-Dihydroxypyridine

et al. 2017

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A novel nicotine hydroxylase was isolated from Pseudomonas sp. ZZ-5 (HSPH ZZ ). The sequence encoding the enzyme was 1206 nucleotides long, and encoded a protein of 401 amino acids. Recombinant HSPH ZZ was functionally overexpressed in Escherichia coli BL21-Codon Plus (DE3)-RIL cells and purified to homogeneity after Ni-NTA affinity chromatography. Liquid chromatography-mass spectrometry (LC-MS) analyses indicated that the enzyme could efficiently catalyze the conversion of 6-hydroxy-3-succinoylpyridine (HSP) into 2,5-dihydroxypyridine (2,5-DHP) and succinic acid in the presence of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD). The kinetic constants (K m , k cat , and k cat /K m ) of HSPH ZZ toward HSP were 0.18 mM, 2.1 s −1 , and 11.7 s −1 mM −1 , respectively. The optimum temperature, pH, and optimum concentrations of substrate and enzyme for 2,5-DHP production were 30 • C, 8.5, 1.0 mM, and 1.0 µM, respectively. Under optimum conditions, 85.3 mg/L 2,5-DHP was produced in 40 min with a conversion of 74.9%. These results demonstrated that HSPH ZZ could be used for the enzymatic production of 2,5-DHP in biotechnology applications.

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“…The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A group of 1,4‐dihydropyridine (1,4‐DHP) derivatives capable to produce antidiabetic and antimutagenic effects were tested in this study. We determined modifications of proteasomal protein Psma6 mRNA expression levels in rat kidneys and blood under diabetes mellitus (DM) and treatment with 1,4‐DHPs.…”

Section: Introductionmentioning

confidence: 99%

1,4‐Dihydropyridine derivatives without Ca2+‐antagonist activity up‐regulate Psma6 mRNA expression in kidneys of intact and diabetic rats

Ošiņa

Rostoka

Sokolovska

et al. 2015

Cell Biochemistry & Function

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Impaired degradation of proteins by the ubiquitin-proteasome system (UPS) is observed in numerous pathologies including diabetes mellitus (DM) and its complications. Dysregulation of proteasomal degradation might be because of altered expression of genes and proteins involved in the UPS. The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A novel group of 1,4-dihydropyridine (1,4-DHP) derivatives lacking Ca2+-antagonists activities, but capable to produce antidiabetic, antioxidant and DNA repair enhancing effects, were tested for ability to modify Psma6 mRNA expression levels in rat kidneys and blood in healthy animals and in rats with streptozotocin (STZ) induced DM. Psma6 gene was chosen for the study, as polymorphisms of its human analogue are associated with DM and cardiovascular diseases. 1,4-DHP derivatives (metcarbatone, etcarbatone, glutapyrone, J-9-125 and AV-153-Na) were administered per os for three days (0.05 mg/kg and/or 0.5 mg/kg). Psma6 gene expression levels were evaluated by quantitative PCR. Psma6 expression was higher in kidneys compared to blood. Induction of diabetes caused increase of Psma6 expression in kidneys, although it was not changed in blood. Several 1,4-DHP derivatives increased expression of the gene both in kidneys and blood of control and model animals, but greater impact was observed in kidneys. The observed effect might reflect coupling of antioxidant and proteolysis-promoting activities of the compounds.

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Acute effect of antidiabetic 1,4‐dihydropyridine compound cerebrocrast on cardiac function and glucose metabolism in the isolated, perfused normal rat heart

Cited by 43 publications

References 53 publications

Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats

Effect of cerebrocrast on body and organ weights, food and water intake, and urine output of normal rats

Characterization of a Novel Nicotine Hydroxylase from Pseudomonas sp. ZZ-5 That Catalyzes the Conversion of 6-Hydroxy-3-Succinoylpyridine into 2,5-Dihydroxypyridine

1,4‐Dihydropyridine derivatives without Ca2+‐antagonist activity up‐regulate Psma6 mRNA expression in kidneys of intact and diabetic rats

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