A mechanism-based pharmacological evaluation of efficacy of Trigonella foenum graecum (fenugreek) seeds in regulation of dyslipidemia and oxidative stress in hyperlipidemic rats.

: Alcoholic extract of Trigonella foenum graecum seeds [fenugreek seed extract (FSE)] was studied in triton-induced and high-fat diet-induced hyperlipidemia to evaluate antidyslipidemic effect. Plasma cholesterol (26.19%) and triglycerides (36.6%) were found to be lowered by FSE maximum at a dose of 200 mg/kg body weight in triton-treated hyperlipidemic rats. Chronic feeding of FSE (200 mg/kg body weight) caused lowering in plasma and hepatic lipid levels by activating lecithin-cholesterol acyltransferase (47%), postheparin lipolytic activity (35%), triglyceride lipase (34%), lipoprotein lipase (20.8%), and increased excretion of fecal bile acids (36%-45%). The FSE shows potent antioxidant activity in both in vitro and in vivo systems. It inhibited generation of superoxide anion and hydroxyl free radicals in both enzymatic and nonenzymatic systems significantly at 200 µM concentration. Furthermore, FSE normalizes the activities of antioxidant enzymes, that is, superoxide dismutase and catalase, and reduces plasma lipid peroxidation (33.9%), hepatic 4-hydroxynonenal (27%), and isoprostanes (28%). Data of the present study demonstrated that the T. foenum graecum seed extract has both antidyslipidemic and antioxidant properties.

Synthesis of 5-aryl-6-cinnamoyl-7-methyl-flavanones as novel antioxidants and antihyperlipidemics.

An economical and efficient one-pot synthesis of a series of novel 5-aryl-6-cinnamoyl-7-methyl-flavanones has been developed by simple refluxing of cinnamoyl chalcones with NaOAc in aqueous ethanol in quantitative yields. These flavanones were screened for their in vitro antioxidant and in vivo antidyslipidemic activities. Among 24 compounds screened, four compounds 28, 29, 30, and 48 showed significant antidyslipidemic activities. However, out of all the compounds, only compound 28 exhibited significant antioxidant activity and other compounds showed moderate antioxidant activities.

Synthesis and anti-inflammatory activity of novel biscoumarin-chalcone hybrids.

A series of synthesized novel biscoumarin-chalcone hybrids were evaluated for their anti-inflammatory and antioxidant activity. The tested compounds significantly inhibit the carrageenin induced paw oedema in albino rats and also exhibit important scavenging activities. These compounds thus constitute an interesting template for the design of new therapeutic tools against inflammation.

Novel coumarin derivatives as potential antidyslipidemic agents.

A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo antidyslipidemic and in vitro antioxidant activities. Among 11 compounds tested, 2 compounds showed potent antidyslipidemic activity and 3 compounds showed potent antioxidant activity.

Synthesis of novel benzocoumarin derivatives as lipid lowering agents.

A series of novel benzocoumarin derivatives were synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Preliminary screening indicates compound 4 as potential lead with significant lipid lowering and antioxidant activities. The study revealed that such attempts on benzocoumarin-based pharmacophores which is a biologically important scaffold might result in identification of new lead for anti-dyslipidemia.

Design and synthesis of 2,4-disubstituted polyhydroquinolines as prospective antihyperglycemic and lipid modulating agents.

A series of 2,4-disubstituted polyhydroquinoline were synthesized and evaluated for their in vivo antihyperglycemic as well as antidyslipidemic activities. Several synthesized compounds have exhibited promising in vivo antihyperglycemic in SLM, STZ-S, and db/db mice model along with significant lipid and TG modulating activity. All these compounds were evaluated in various in vitro models of diabetes to know the possible mechanism of their antihyperglycemic action. Interestingly, compounds 3a-r (diaryl substitution) have exhibited promising protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity whereas, compounds 5a-d (acid substituted) have shown significant glycogen phosphorylase activity.

Syntheses and evaluation of glucosyl aryl thiosemicarbazide and glucosyl thiosemicarbazone derivatives as antioxidant and anti-dyslipidemic agents.

A series of N-per-O-acetyl-glucosyl arylthiosemicarbazide and thiosemicarbazone derivatives have been synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Among 16 compounds tested, 3 compounds showed potent anti-dyslipidemic activity and 6 compounds showed potent antioxidant and scavenger of oxygen free radicals activity.

Pyranocoumarins: a new class of anti-hyperglycemic and anti-dyslipidemic agents.

A series of pyranocoumarin derivatives were synthesized and evaluated in vivo for their anti-hyperglycemic as well as anti-dyslipidemic activities. Compounds 7a, 7c, 8a, 8b, 8c, 8e and 8f have shown promising anti-hyperglycemic activities in sucrose loaded model (SLM) as well as sucrose challenged streptozotocin induced diabetic rat model (STZ). Compounds 8a and 8b were showing 38.0% and 42.0% blood glucose lowering activity in db/db mice model. In vitro anti-hyperglycemic activity evaluation exhibited that compounds 8a (IC(50)=24.5 microM) and 8b (IC(50)=36.2 microM) are potential PTP-1B inhibitors thereby revealing their possible mechanism of anti-diabetic action. Compounds 7a, 7b, 8a, 8b, 8d, 8e and 8f have shown significant anti-dyslipidemic activity in triton induced dyslipidemia in rats.

Novel keto-enamine Schiffs bases from 7-hydroxy-4-methyl-2-oxo-2H-benzo[h] chromene-8,10-dicarbaldehyde as potential antidyslipidemic and antioxidant agents.

A series of Schiff bases have been synthesized from dicarbaldehyde of benzocoumarin, in which the reactions were regioselective and the products existed in the keto-enamine form, in which the aromaticity of the relevant ring was disrupted. The compounds were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic activity for the first time. Compounds 3 and 7 possess significant lipid lowering and antioxidant activity.

Pharmacological evaluation of the efficacy of Dysoxylum binectariferum stem bark and its active constituent rohitukine in regulation of dyslipidemia in rats.

The antidyslipidemic effect of the ethanolic extract of Dysoxylum binectariferum stem bark and its major active constituent rohitukine was evaluated in a high fat diet (HFD)-fed dyslipidemic rat model. Chronic feeding of ethanolic extract (200 mg/kg) in HFD-fed rats showed significant lipid lowering activity. The bioassay guided fractionation of ethanolic extract resulted in the identification of known alkaloid rohitukine as major active constituent. Rohitukine (50 mg/kg) significantly decreased the plasma levels of total cholesterol (24 %), phospholipids (25 %), triglycerides (27 %), very low density lipoprotein (27 %) and low density lipoprotein (32 %) accompanied with an increase in high density lipoprotein (21 %). The present study demonstrated that ethanolic extract of Dysoxylum binectariferum stem bark and its major constituent rohitukine both have antidyslipidemic as well as antioxidant potentials. The antidyslipidemic activity of rohitukine can be correlated to its effect on enzymes involved in lipid metabolism.

A mechanism-based pharmacological evaluation of efficacy of Flacourtia indica in management of dyslipidemia and oxidative stress in hyperlipidemic rats.

BACKGROUND: Flacourtia indica (Burm. f.) Merr. is a medicinal plant indigenous to India and is broadly used worldwide for the treatment of a variety of health ailments. The present study was experimented on hyperlipidemic Charles Foster rats with the aim to explore the possible mechanism responsible for the antidyslipidemic activity of the hydromethanolic extract from F. indica leaves (FIL). METHODS: Hyperlipidemia was induced by a single intraperitoneal dose of Triton WR-1339 in Charles Foster rats. The plasma lipid levels were estimated in control and treated groups. The antioxidant potential of F. indica was assessed in both enzymatic and non-enzymatic systems. An acute toxicity study of high-performance liquid chromatography (HPLC)-fingerprinted extract was carried out in Swiss albino mice. RESULTS: The F. indica extract at a dose of 150 mg/kg significantly lowers the plasma level of total cholesterol (17%), triglycerides (13%), and phospholipids (16%) by increasing post-heparin lipolytic activity (19%) and lecithin-cholesterol-acyltransferase activity (20%) in Triton-induced hyperlipidemic rats. In addition, the F. indica extract showed significant in vitro antioxidant and anti-adipogenic activity. HPLC analysis indicates the presence of flavanones and flavones in the extract, and the extract was found to be non-toxic up to a dose of 2000 mg/kg body weight in the acute oral toxicity study. CONCLUSIONS: These finding suggest that F. indica holds significant potential in preventing clinical deterioration induced by dyslipidemia along with oxidative stress.

Adaptogenic and anti-amnesic properties of Evolvulus alsinoides in rodents.

Evolvulus alsinoides (EA) is well known for its memory enhancement, antiepileptic and immunomodulatory properties in the traditional Indian system of medicine, Ayurveda. In view of the increasing attention towards plants offering non-specific resistance (adaptogens) towards stress, we have evaluated crude ethanolic extract of EA for its adaptogenic and memory enhancing properties in rodents. Adaptogenic activity was assessed in rats subjected to acute and chronic unpredictable stress. Male Sprague-Dawley rats, weighing 180-200 g were immobilized for 150 min once only in acute stress (AS) model, whereas in chronic unpredictable stress (CUS) model rats were subjected to different types of stressors daily for 7 days. Stress exposure has induced gastric ulceration with increase in adrenal gland weight, plasma creatine kinase (CK), and corticosterone level in AS and CUS. However plasma glucose was increased only in AS. Rats were treated with graded doses of crude ethanolic extract of EA (100, 200 and 400 mg/kg p.o.) for 3 days and subjected to AS on 3 day after 45 min of last dose. In CUS, EA at a dose of 200 mg/kg p.o. found effective in acute studies was administered 45 min prior to stress regimen for 7 days. EA reduced the stress induced perturbations similar to Panax quinquefolium (PQ) (100 mg/kg p.o.), a well known adaptogen. EA (100 mg/kg) administered orally for 3 days in adult male Swiss mice, was effective in decreasing scopolamine induced deficit in passive avoidance test. The improvement in the peripheral stress markers and scopolamine induced dementia by EA in the present study indicates the adaptogenic and anti-amnesic properties of EA.

Adaptogenic effect of Bacopa monniera (Brahmi).

As stress is linked to many diseases, research on an effective antistress agent (adaptogen) from plants has gained importance. We report the investigations on the adaptogenic property of a standardized extract of Bacopa monniera against acute (AS) and chronic stress (CS) models in rats. Panax root powder (Panax quinquefolium) was taken as a standard. Male SD rats, weighing 180-200 g, exposed to immobilization stress for 150 min once only for AS and for seven consecutive days in CS, were fed with B. monniera or Panax root powder daily for 3 days in AS and for 7 days in CS, 45 min prior to each exposure of stress. Rats were sacrificed immediately after stress, the blood was collected, and the plasma was separated out for biochemical estimation. Adrenals, spleen, and thymus were dissected for organ weight and stomach for ulcer score. AS exposure significantly increased the ulcer index, adrenal gland weight, plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) but significantly decreased the spleen weight. Pretreatment with B. monniera at 40 mg/kg po significantly reduced the AS-induced increase in the ulcer index, adrenal gland weight, plasma glucose, AST, and CK. A dose of 80 mg/kg po significantly reversed the AS-induced changes in adrenal gland weight, spleen weight, plasma glucose, ALT, and AST. Panax root powder, 100 mg/kg po, significantly reversed the AS-induced changes in spleen weight, plasma ALT, AST, and CK. CS exposure resulted in a significant increase in the ulcer index, adrenal gland weight, plasma AST, and CK with a significant decrease in the thymus and spleen weight, plasma triglyceride, and cholesterol. Pretreatment with low dose of B. monniera extract at 40 mg/kg significantly reversed changes in ulcer index and plasma AST only, whereas the pretreatment with higher dose significantly reversed CS-induced changes in ulcer index, adrenal gland weight, CK, and AST. Panax root powder significantly reversed CS-induced increase in ulcer index, adrenal gland weight, CK, and AST. On the basis of our result, it is concluded that the standardized extract of B. monniera possesses a potent adaptogenic activity.

In vivo model for dyslipidemia with diabetes mellitus in hamster.

Due to similarities in lipid metabolism to those in humans, hamster is considered as a good model for the study of regulatory mechanisms of plasma lipoproteins in response to cholesterol or fatty acid-enriched diet. This model of hyperlipidemia has been modified to produce dyslipidedmia with diabetes complexities by feeding with high fat diet added with 9% (w/w) fructose. Feeding this diet to hamster for 10 days markedly increases plasma levels of triglyceride, cholesterol, fatty acids followed by a significant increase in glycerol, beta lipoproteins, high density lipoprotein, glucose and glycosylated proteins. This model is being used for research and development of lipid lowering drugs with hypoglycemic activity in collaboration with Novo Nordisk, Denmark. The modified high fat diet formulation has now been prepared (Research diet D.99122211) and supplied by Research Diets Inc, Burnswick USA.

Antidyslipidemic and antioxidant activities of different fractions ofTerminalia arjuna stem bark.

Terminalia arjuna (T. arjuna) stem bark was successively extracted with petroleum ether (A), solvent ether (B), ethanol (C) and water (D). The lipid lowering activity of these four fractions A, B, C, and D was evaluatedin vivo in two models viz., triton WR-1339 induced hyperlipemia in rats as well as fructose rich high fat diet (HFD) fed diabetic- dyslipidemic hamsters. Hyperlipidemia induced by triton caused marked increase in the plasma levels of total cholesterol (Tc), triglyceride (Tg) and phospholipids (PL) in rats. After treament withT. arjuna fractions A, B, C, and D at the doses of 250 mg/kg per oral (p.o.),only the ethanolic fraction (C) exerted significant lipid lowering effect as assessed by reversal of plasma levels of Tc, Tg and PL in hyperlipidemic rats. In another experiment, feeding with HFD produced marked dyslipidemia as observed by increased levels of plasma Tc, Tg, glucose (Glu), glycerol (Gly) and free fatty acids (FFA) in hamsters. After treatment withT. arjuna fractions at the doses of 250 mg/kg p.o. only two fraction (B and C) could exert significant lowering in the plasma levels of lipids and Glu. in dyslipidemic hamsters.In vitro experimentT. arjuna fractions at tested concentrations (50-500 µg/ml) inhibited the oxidative degradation of lipids in human low density lipoprotein and rat liver microsomes induced by metal ions. These fractions when tested against generation of oxygen free radicals at the concentrations (50-500 µg/ml), counteracted the formation of superoxide anions (O(-2)) and hydrodyl radicals (OH) in non enzymic test systems. The efficacy ofT. arjuna fractions as antidyslipidemic and antioxidant agents was found, fraction C> fraction B> fraction A.

Synthesis of new N-acryl-1-amino-2-phenylethanol and N-acyl-1-amino-3-aryloxypropanols and evaluation of their antihyperlipidemic, LDL-oxidation and antioxidant activity.

As a part of our drug discovery program, we identified an alkaloidal amide i.e. Aegeline (V) isolated from the leaves of Aegle marmelos as a dual acting agent (antihyperlipidemic and antihyperglycemic). In continuation of this program, we synthesized new N-acyl-1-amino-2-alcohols (N-acrylated-1-amino-2-phenylethanol and N-acylated-1-amino-3-aryloxypropanols) via Ritter reaction and screened for their in-vivo antihyperlipdemic activity in Triton induced hyperlipidemia model, LDL-oxidation and antioxidant activity. Compounds 3, 11 and 13 showed good antihyperlipidemic activity, LDL-oxidation as well as antioxidant activity and comparable activity with marketed antidyslipidemic drug.

Design and synthesis of novel indole-chalcone fibrates as lipid lowering agents.

A series of novel indole-chalcone fibrates were synthesized and their hypolipidemic activity was evaluated in triton WR-1339 induced hyperlipidemic rat model. Preliminary studies indicated that the hybrids 19, 24 and 29 exhibited potent in vitro antioxidant and significant in vivo antidyslipidemic effects. Our results suggest that these new hybrid architectures may serve as promising leads for the development of next generation lipid lowering agents.

Antidyslipidemic effect and antioxidant activity of anthraquinone derivatives from Rheum emodi rhizomes in dyslipidemic rats.

The aim of the present study was to evaluate the antidyslipidemic effect of ethanolic extract of Rheum emodi rhizomes and its constituents in Triton-WR-1339 and high-fat diet (HFD)-induced dyslipidemic rats. In preliminary screening, the ethanolic extract showed significant activity in Triton-treated rats. Bioassay-guided fractionation of the ethanolic extract resulted in the identification of four anthraquinone derivatives, viz. chrysophanol, emodin, chrysophanol 8-O-ß-D-glucopyranoside and emodin 8-O-ß-D-glucopyranoside as active constituents. All these compounds significantly reduced plasma lipid levels. The most active compound emodin showed significant lipid-lowering activity in the HFD-fed model. In addition, these compounds showed significant antioxidant activity. The effect of emodin on enzymes modulating lipid metabolism confirms and supports the efficiency of emodin as a potent antidyslipidemic agent.

Synthesis of new andrographolide derivatives and evaluation of their antidyslipidemic, LDL-oxidation and antioxidant activity.

Andrographis paniculata, native to Taiwan, Mainland China and India, is a medicinal herb, which possesses various biological activities including anti-atherosclerosis. Andrographolide (1) has been identified as one of the active constituents against atherosclerosis. In continuation of our drug discovery program we synthesized few novel derivatives of 1 to improve their antidyslipidemic, LDL-oxidation and antioxidant activity. The tosylated derivative 7 has been turned out to be more potent than the parent compound and comparable activity with marketed antidyslipidemic drugs.

Lipid lowering and antioxidant effect of miglitol in triton treated hyperlipidemic and high fat diet induced obese rats.

Miglitol, an anti-diabetic drug, has been shown to reduce plasma lipids and inhibit free radical generation. The anti-hyperlipidemic and antioxidant effects of miglitol were studied in triton-induced hyperlipidemic rats and high fat diet-fed obese rats. Plasma cholesterol and triglycerides levels were significantly lowered by miglitol at 100 mg/kg body weight doses. Miglitol inhibited generation of superoxide anion and hydroxyl free radicals by 14 and 31 % in enzymatic systems and 19 and 25 % in non-enzymatic systems, respectively. The in-vitro effect of the drug on adipogenesis using 3T3-L1 preadipocytes at 2-, 5- and 10-µM concentrations showed significant inhibition of adipogenesis (34.2 %) at 10-µM concentration. High fat diet-fed rat model was used to investigate anti-hyperlipidemic, anti-obesity and antioxidant effect of miglitol. Miglitol increased the activities of lecithin-cholesterol-acyltransferase (19 %), post heparin lipolytic activity (26 %), lipoprotein lipase (26 %) and triglyceride lipase (31 %) which result in a decrease in plasma lipid levels. The antioxidant enzymes viz., catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and thioredoxin reductase were increased by the drug in the treated animals. The antihyperlipidemic and antioxidant effect of miglitol can be correlated to its effect on different enzymes and it can be used for inhibiting the development of cardiovascular diseases.