Protective effect of compound Danshen (Salvia miltiorrhiza) dripping pills alone and in combination with carbamazepine on kainic acid-induced temporal lobe epilepsy and cognitive impairment in rats.
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ABSTRACT: Temporal lobe epilepsy (TLE) is resistant to antiepileptic drugs (AEDs) and is associated with cognitive impairment. The modern Chinese medicine, compound Danshen dripping pills (CDDP), is clinically effective in treating epilepsy and improving cognitive impairment.This study evaluated the protective effects of CDDP alone and in combination with carbamazepine (CBZ) on kainic acid-induced TLE and cognitive impairment in rats.Sprague-Dawley rats were randomly divided into five groups: control (sham operated), model, CDDP, CBZ and combined. A TLE model was then created via bilateral intrahippocampal injection of 0.35??g kainic acid (KA). Rats received CDDP (85?mg/kg), CBZ (100?mg/kg) or combined (85?mg/kg CDDP +100?mg/kg CBZ) via intragastric administration for 90?d, respectively. Seizure intensity, apoptosis and glial cell line-derived neurotrophic factor (GDNF) were measured. Furthermore, the improvement in cognitive impairment and hippocampal neuronal damage was evaluated.CDDP combined with CBZ significantly decreased seizure severity and frequency (p?CONCLUSIONThese findings support the use of CDDP as an adjuvant drug for the treatment of TLE and cognitive deficit. Its mechanism might be related to an anti-apoptosis effect and up-regulation of GDNF.
Protective effect of compound Danshen (Salvia miltiorrhiza) dripping pills alone and in combination with carbamazepine on kainic acid-induced temporal lobe epilepsy and cognitive impairment in rats.
<h4>Context</h4>Temporal lobe epilepsy (TLE) is resistant to antiepileptic drugs (AEDs) and is associated with cognitive impairment. The modern Chinese medicine, compound Danshen dripping pills (CDDP), is clinically effective in treating epilepsy and improving cognitive impairment.<h4>Objective</h4>This study evaluated the protective effects of CDDP alone and in combination with carbamazepine (CBZ) on kainic acid-induced TLE and cognitive impairment in rats.<h4>Materials and methods</h4>Sprague- ...[more]
Project description:Danshen, the dried root of Salvia miltiorrhiza, is a Chinese medicine used to promote blood flow and treat vascular disease. The present article reviews the pharmacological effects of Danshen on cerebral infarction and possible interactions between Danshen and Western drugs. Danshen may reduce or prolong the development of atherosclerosis and may have anti-hypertensive and anti-platelet aggregation effects, which prevent cerebral infarction. Danshen may enhance endogenous anti-oxidative enzyme activities such as the expression of endothelial nitric oxide synthase and may scavenge oxygen free radicals. Prevention and treatment of cerebral infarction by Danshen involves multiple pathways, including anti-atherosclerosis, anti-hypertension, anti-platelet aggregation, anti-inflammatory and anti-oxidative effects.
Project description:Background and Objective. The aim was to evaluate the synergistic effects of clopidogrel and FDDP by modulating the metabolism target and the pharmacokinetics. Methods. The inhibition effect of FDDP on the CES1 was first investigated by the molecular simulation method, and the synergistic effects on the pharmacokinetics of CPGS were studied as follows: SD rats were treated with oral clopidogrel alone at a dosage of 30 mg/kg or the combination of clopidogrel and FDDP at dosages of 30 mg/kg and 324 mg/kg, respectively, for 21 days. The concentrations of CPGS in the blood plasma samples were determined and the calculated concentrations were used to determine the pharmacokinetic parameters. Results. 20 compounds in FDDP potentially interacted with CES1 target. The CPGS showed a two-compartment model pharmacokinetic profile. The concentration-time course of CPGS was not changed by FDDP, but FDDP decreased the peak plasma concentration and area under the curve of CPGS. Conclusion. The CES1's activity could be partly inhibited by FDDP through the molecular simulation investigation. The concentration-time course of CPGS was altered slightly by FDDP. The results demonstrated the synergistic effects of clopidogrel and FDDP by modulating both the pharmacokinetics and the target metabolism.
Project description:The continuous administration of compound danshen dripping pills (CDDP) showed good efficacy in relieving myocardial ischemia clinically. To probe the underlying mechanism, metabolic features were evaluated in a rat model of acute myocardial ischemia induced by isoproterenol (ISO) and administrated with CDDP using a metabolomics platform. Our data revealed that the ISO-induced animal model showed obvious myocardial injury, decreased energy production, and a marked change in metabolomic patterns in plasma and heart tissue. CDDP pretreatment increased energy production, ameliorated biochemical indices, modulated the changes and metabolomic pattern induced by ISO, especially in heart tissue. For the first time, we found that ISO induced myocardial ischemia was accomplished with a reduced fatty acids metabolism and an elevated glycolysis for energy supply upon the ischemic stress; while CDDP pretreatment prevented the tendency induced by ISO and enhanced a metabolic shift towards fatty acids metabolism that conventionally dominates energy supply to cardiac muscle cells. These data suggested that the underlying mechanism of CDDP involved regulating the dominant energy production mode and enhancing a metabolic shift toward fatty acids metabolism in ischemic heart. It was further indicated that CDDP had the potential to prevent myocardial ischemia in clinic.
Project description:Danshen (Salvia miltiorrhiza) is a well-known herb in Traditional Chinese Medicine (TCM) for treating cardiovascular diseases, but the underlying mechanism remains to be fully elucidated. Here, we showed that Danshen and its active ingredient rosmarinic acid exhibited antiplatelet effects through the inhibition of ERp57, a member of protein disulfide isomerase (PDI) with potential roles in platelet aggregation. Danshen extract (DSE) exhibited potent inhibitory effects on the platelet aggregation induced by arachidonic acid- (AA-) induced platelet aggregation and the enzymatic activity of ERp57. Rosmarinic acid was identified by virtual screening and molecular docking as one of the hit compounds for ERp57. In line with this, rosmarinic acid displayed significant inhibitory effect on ERp57 activity and inhibited AA-induced platelet aggregation. Taken together, we demonstrated for the first time that DSE and rosmarinic acid displayed inhibitory effects on the catalytic activity of ERp57, providing evidence of the regulatory role of ERp57 underlying the antiplatelet effects of Danshen.
Project description:Danshen was able to reduce the risk of the patients with coronary heart disease (CHD), but the mechanism is still widely unknown. Biochemical indices (lipid profile, markers of renal and liver function, and homocysteine (Hcy)) are closely associated with CHD risk. We aimed to investigate whether the medicine reduces CHD risk by improving these biochemical indices. The patients received 10 Danshen pills (27?mg/pill) in Dashen group, while the control patients received placebo pills, three times daily. The duration of follow-up was three months. The serum biochemical indices were measured, including lipid profiles (LDL cholesterol (LDL-C), HDL-C, total cholesterol (TC), triglycerides (TG), apolipoprotein (Apo) A, ApoB, ApoE, and lipoprotein (a) (Lp(a))); markers of liver function (gamma-glutamyl transpeptidase (GGT), total bilirubin (TBil), indirect bilirubin (IBil), and direct bilirubin (DBil)); marker of renal function (uric acid (UA)) and Hcy. After three-month follow-up, Danshen treatment reduced the levels of TG, TC, LDL-C, Lp(a), GGT, DBil, UA, and Hcy (P < 0.05). In contrast, the treatment increased the levels of HDL-C, ApoA, ApoB, ApoE, TBil, and IBil (P < 0.05). Conclusion. Danshen can reduce the CHD risk by improving the biochemical indices of CHD patients.
Project description:BACKGROUND:Danshen (Salvia miltiorrhiza Bunge), also known as Chinese red sage, is a member of Lamiaceae family. It is valued in traditional Chinese medicine, primarily for the treatment of cardiovascular and cerebrovascular diseases. Because of its pharmacological potential, ongoing research aims to identify novel bioactive compounds in danshen, and their biosynthetic pathways. To date, only expressed sequence tag (EST) and RNA-seq data for this herbal plant are available to the public. We therefore propose that the construction of a reference genome for danshen will help elucidate the biosynthetic pathways of important secondary metabolites, thereby advancing the investigation of novel drugs from this plant. FINDINGS:We assembled the highly heterozygous danshen genome with the help of 395?×?raw read coverage using Illumina technologies and about 10?×?raw read coverage by using single molecular sequencing technology. The final draft genome is approximately 641 Mb, with a contig N50 size of 82.8 kb and a scaffold N50 size of 1.2 Mb. Further analyses predicted 34,598 protein-coding genes and 1,644 unique gene families in the danshen genome. CONCLUSIONS:The draft danshen genome will provide a valuable resource for the investigation of novel bioactive compounds in this Chinese herb.
Project description:The roots of Salvia miltiorrhiza ("Danshen") have been used in Chinese herbal medicine for centuries for a host of different conditions. While the exact nature of the active components of this material are unknown, large amounts of tanshinones are present in extracts derived from these samples. Recently, the tanshinones have been demonstrated to be potent human carboxylesterase (CE) inhibitors, with the ability to modulate the biological activity of esterified drugs. During the course of these studies, we also identified more active, irreversible inhibitors of these enzymes. We have purified, identified, and synthesized these molecules and confirmed them to be the anhydride derivatives of the tanshinones. These compounds are exceptionally potent inhibitors ( Ki < 1 nM) and can inactivate human CEs both in vitro and in cell culture systems and can modulate the metabolism of the esterified drug oseltamivir. Therefore, the coadministration of Danshen extracts with drugs that contain the ester chemotype should be minimized since, not only is transient inhibition of CEs observed with the tanshinones, but also prolonged irreversible inhibition arises via interaction with the anhydrides.
Project description:Four novel compounds (1-4) as well as fourteen reported compounds (5-18) were isolated and purified from Salvia miltiorrhiza Bunge (Danshen). The structures of novel compounds were determined by 1D and 2D NMR, HRESIMS data, etc. The anti-inflammatory properties of all the compounds on RAW264.7 macrophages and their cytotoxicity on H1299 and Bel-7402 cell lines coupled with a structure-activity relationship (SAR) were investigated. Compound 4 demonstrated the best anti-inflammatory activity and was chosen for further research. Compound 4 greatly suppressed secretion of nitric oxide (NO), tumor necrosis factor (TNF)-? and interleukin-6 (IL-6) in the RAW264.7 macrophages stimulated by LPS. Additionally, the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was decreased and the nuclear translocation of NF-?B was attenuated after treatment with compound 4 in vitro. Compound 4 was able to dramatically inhibit LPS-induced activation of JNK1/2 and ERK1/2 and remarkably disrupted the TLR4 dimerization in LPS-induced RAW264.7 macrophages. Thus, the new compound 4 suppressed LPS-induced inflammation partially is due to the blocking TLR4 dimerization. In addition, the anti-cancer activity investigation indicated that most of isolated compounds exhibited cytotoxicity and the SAR analysis showed that the intact D ring was indispensable and unsaturated D ring played vital role.
Project description:Background: Danshen (Radix et rhizoma Salviae miltiorrhizae; Salvia miltiorrhiza Bunge, Lamiaceae) is commonly used in Asia, including China, Japan, and Korea with markets in America and Europe growing substantially. It is included in multiple pharmacopeias and salvianolic acid B and tanshinone IIA are used as quality markers. However, on the markets, substitutes and different processing methods often are a concern. a concern regarding patients' safety and expected outcomes. Aims: This study aims at understanding the quality of Danshen-derived products on the market, and the relationship between the chemistry, biological activity and the processing and storage methods. Methods: For heavy metal analysis, inductively coupled plasma optical emission spectrometry was used. High performance thin-layer chromatography and proton nuclear magnetic resonance coupled with principal component analysis were used to understand the variation of metabolite composition. MTT assay and LPS induced NO production assay were used to evaluate the cytotoxicity effect and anti-inflammatory activity, respectively. Result and Discussion: Six out of sixty samples exceed the limits of cadmium according to the Chinese or United States Pharmacopoeia. Arsenic, lead and copper contents are all below pharmacopoeial thresholds. With more complex processing procedure, the risk of heavy metal contamination increases, especially with arsenic and cadmium. The metabolite compositions show a variability linked to processing and storage methods. Authenticated samples and Vietnamese primary samples contain higher salvianolic acid B, and their chemical compositions are more consistent compared to Chinese online store samples. Overall, a significant chemical variation can be observed in Danshen products directly linked to processing and storage method. In the MTT assay, fourteen samples show cytotoxicity while seven samples increase the proliferation of RAW264.7. In the LPS induced NO production of RAW 264.7, only seven samples show significant inhibitory effects. Conclusion: This is the first interdisciplinary investigation focusing on understanding the current market and the quality of Danshen. The quality of Danshen products on the high street are inferior to the authenticated samples. The results of the bioassays selected is not useful to differentiate the quality and composition according to the current definition in the pharmacopoeias. Overall, this approach highlights the tremendous variability of the products linked to processing and the need for more systematic and stringent quality assurance.
Project description:Compound Danshen dripping pills (CDDP) is widely used for the treatment of coronary arteriosclerosis and ischemic heart diseases for decades of years. In our study, we interestingly discovered the effects and mechanism of CDDP on insulin resistance that increase the risk factor of cardiovascular diseases. Effects of CDDP on fasting blood glucose, the insulin tolerance test (ITT), the oral glucose tolerance test (OGTT), hepatic function, and underlying mechanism were analyzed in ob/ob mice. CDDP was found improving the impaired insulin signal sensitivity of ob/ob mice by ameliorating insulin and glucose tolerance, improving hepatic phosphorylation of the insulin receptor substrate-1 on Ser 307 (pIRS1) of ob/ob mice, and restoring hepatic function by decreasing serum ALT and AST, which increased in ob/ob mice serum. Decreasing hepatic phosphorylation of pancreatic ER kinase (PERK) and inositol-requiring enzyme-1 (IRE1) regulating hepatic ER stress in the liver of ob/ob mice were increased by CDDP. Furthermore, CDDP was also found stimulating ob/ob mice hepatic autophagy by increasing the expression of Beclin1 and LC3B, while decreasing P62 expression. Our study discovered an important role of CDDP on improving ob/ob mice insulin resistance and liver function probably through relieving hepatic ER stress and stimulating hepatic autophagy, which would broaden the application value and provide more benefits for treating cardiovascular patients. This trial is registered with NCT01659580.