3-4-dihydroxyphenyllactic-acid and Myocardial-Ischemia

Myocardial ischemia is a primary cause of sudden death worldwide. Numerous active ingredients of traditional Chinese medicines including danshensu (DSS) and tetramethylpyrazine (TMP) have been widely used for the treatment of myocardial ischemia. To enhance their therapeutic efficacy and improve their drugability, in this work, we designed new DSS and TMP conjugates. Their water solubility and protective effects were studied in vitro and in experimental animal models. The new compounds demonstrated higher activities than the positive control agents acetylated danshensu and tetramethylpyrazine conjugate (ADTM) and salvianolic acid B (SAB) in preventing cells from oxidative insult. Among the new compounds, 14, bearing two glycine moieties, was more water soluble. In addition, compound 14 was much more potent in preventing cells from oxidative injury, at least 10- and 20-fold as potent as ADTM and SAB, respectively. The protective effects of compound 14 may be attributed to its anti-radical activity and anti-apoptotic activity. These results suggest that compound 14 is a promising candidate for the treatment of myocardial ischemia.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Lactates; Male; Molecular Structure; Myocardial Ischemia; Oxidative Stress; Pyrazines; Rats; Rats, Sprague-Dawley; Solubility; Structure-Activity Relationship

In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O

Topics: Animals; Cell Line; Cell Survival; Free Radicals; Heme Oxygenase-1; Iodoacetic Acid; Lactates; Ligusticum; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; NF-E2-Related Factor 2; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phytotherapy; Plant Extracts; Pyrazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Salvia miltiorrhiza; tert-Butylhydroperoxide; Up-Regulation

Salvianolic acid A (Sal A), an important constituent of Radix Salviae Miltiorrhizae (RSM), is effective for the treatment of myocardial infarction (MI) and coronary heart disease due to its potential in the improvement of acute myocardial ischemia. However, its content is very low in RSM. So it is obvious to find a rich source of Sal A or to improve its content by conversion of other related components into Sal A modifying reaction conditions. In this research we focused on the conversion of Sal B into Sal A in aqueous solutions of RSM by using different reaction conditions including pH, temperature, pressure and humidity. During the reactions, the contents of Sal A, Sal B and danshensu in the RSM were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS). The results indicated that the conversion of Sal B into Sal A in RSM tissues under the conditions of a high temperature, high pressure and high humidity was efficient and thereby, was readily utilized to prepare rich Sal A materials in practice.

Topics: Benzofurans; Caffeic Acids; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Hot Temperature; Humidity; Lactates; Mass Spectrometry; Myocardial Ischemia; Phytotherapy; Plant Roots; Pressure; Salvia miltiorrhiza

The synthesis and bioactivities of Danshensu derivatives (R)-methyl 2-acetoxy-3-(3,4-diacetoxyphenyl)propanoate (1a), (R)-methyl 2-acetoxy-3-(3,4-methylenedioxyphenyl)propanoate (1b) and their racemates 7 and 10 were reported in this paper. These derivatives were designed to improve their chemical stability and liposolubility by protecting Danshensu's phenolic hydroxyl groups with acetyl or methylene which could be readily hydrolyzed to release bioactive Danshensu. The asymmetric synthesis of 1a and 1b were achieved by catalytic hydrogenation of (Z)-methyl 2-acetoxy-3-(3,4-diacetoxyphenyl)-2-propenoate (6a) and (Z)-methyl 2-acetoxy-3-(3,4-methylenedioxyphenyl)-2-propenoate (6b) in excellent enantiomeric excesses (92% ee and 98% ee, respectively) and good yields (>89%). An unexpected intermediate product, (Z)-2-acetoxy-3-(3,4-dihydroxyphenyl)acrylic acid (4c) was obtained with high chemoselectivity in 86% yield by keeping the reaction temperature at 60 degrees C and its structure was identified by X-ray single crystal diffraction analysis. 1a, 1b and their racemates 7, 10 as well as 4c exhibited potent protective activities against hypoxia-induced cellular damage. The in vitro test showed that all these compounds could increase cell viability, and inhibit lipid hyperoxidation. Furthermore, 1a and 4c could inhibit apoptosis by regulating the expression of apoptosis-related molecule in gene and protein levels, up-regulating the expression of bcl-2 and down-regulating bax and caspase-3. The in vivo test indicated that 4c exhibited anti-myocardial ischemic effects featured by reducing infarction size and increasing the level of the intracellular enzymes detectable in serum. Therefore, these Danshensu derivatives may be good drug candidates for anti-myocardial ischemia therapy and merit further investigation.

Topics: Animals; Cardiotonic Agents; Caspase 3; Cell Hypoxia; Cell Survival; Cells, Cultured; Heart; Humans; Lactates; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Stereoisomerism

Ischemic heart diseases are the leading cause of death in both developed and developing countries over the past decades. The aim of this study was to investigate the cardioprotective effects of the complex preparation (called Shenge), made of puerarin and Danshensu, on acute ischemic myocardial injury in rats and its underlying mechanisms. The left anterior descending (LAD) coronary artery was occluded to induce myocardial ischemia in hearts of SD rats. Shenge was injected into the tail vein 15 min after occlusion at doses of 0, 30, 60 or 120 mg/kg. Then, the ST elevation was measured at 60, 120 and 240 min after Shenge administration. The infarct size, serum levels of creatine kinase isoenzyme-MB (CK-MB), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA), and the ST elevation were measured after the rats were killed. Shenge decreased the ST elevation induced by acute myocardial ischemia, reduced infarct size, serum levels of CK-MB, LDH and MDA and increased the serum activity of SOD in a dose-dependent manner. The combined use of puerarin and Danshensu at a ratio of 1:1 shows the most effective activity. In conclusion, Shenge exerts significant cardioprotective effects against acute ischemic myocardial injury in rats, likely through its antioxidant and antilipid peroxidation properties, and thus may be used as an effective and promising medicine for both prophylaxis and treatment of ischemic heart disease.

Topics: Animals; Cardiotonic Agents; Diltiazem; Dose-Response Relationship, Drug; Drug Combinations; Isoflavones; Lactates; Molecular Conformation; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Time Factors; Vasodilator Agents

Using low temperature electron spin resonance (ESR) technique, we found that Salvia miltiorrhiza injection could scavenge the oxygen free radicals generated from ischemia-reperfusion injury in the myocardium as effectively as SOD. Using ESR spin trapping technique we found that one of its effective components, Danshensu, could scavenge superoxide anion free radicals generated from the reaction system of xanthine and xanthine oxidase, and that lipid free radicals generated from lipid peroxidation of myocardial mitochondrial membranes could be scavenged by another effective component, Tanshinone. The membrane fluidity of the mitochondria isolated from the ischemia-reperfused hearts was studied with the ESR spin labelling technique, and the TBA-method was used to detect the lipid peroxidation. It was found that Danshensu could protect the mitochondrial membrane from the ischemia-reperfusion injury and lipid peroxidation.

Topics: Abietanes; Animals; Antioxidants; Drugs, Chinese Herbal; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Intracellular Membranes; Lactates; Lipid Metabolism; Lipid Peroxidation; Mitochondria, Heart; Myocardial Ischemia; Myocardial Reperfusion Injury; Phenanthrenes; Plant Extracts; Rabbits; Salvia miltiorrhiza; Spin Trapping; Superoxides; Thiobarbituric Acid Reactive Substances