Cardioprotective Role of Scopoletin on Isoproterenol-Induced Myocardial Infarction in Rats.

Scopoletin is a phenolic coumarin isolated from a variety of plants and was originally used to treat various diseases including arthritis as well as bone-related diseases. The goal of this study was to determine scopoletin's therapeutic potential in an animal model of myocardial infarction induced with ISO. There were five groups of albino male rats. Group I (control) animals were orally treated with olive oil. Group II (scopoletin) animals were pre-treated orally with a 50-mg dosage of scopoletin for 28 days. Group III (ISO-treated) animals were treated with 85 mg/kg of ISO subcutaneously for 2 consecutive days (29th and 30th day). Group IV (scopoletin and ISO) animals were pre-treated orally with 25 mg of scopoletin for 28 days before exposure to ISO. Group V (scopoletin and ISO) animals were pre-treated with 50 mg of scopoletin for 28 days before exposure to ISO. In the ISO-administered animals, a wider heart-to-body weight ratio, a higher heart weight, higher cardiac diagnostic markers, higher MDA levels and related antioxidant levels, inflammatory, and apoptotic markers were observed. Scopoletin pre-treatment with ISO (25 and 50 mg/kg b.wt) significantly reduced heart-to-body weight ratio, cardiac diagnostic markers, MDA, inflammatory markers, and apoptotic markers. Meantime, a pre-treatment with scopoletin increased the levels of antioxidant enzymes. Inflammation and necrosis were observed in the histopathology of heart tissue of ISO-treated animals and these histopathological conditions were reversed by scopoletin pretreatment. The antioxidant and anti-inflammatory properties of ISO-treated rats were shown to be increased by scopoletin, showing its therapeutic potential against cardiovascular diseases. Through the use of its antioxidant and anti-inflammatory properties, scopoletin exhibited anti-myocardial infarction properties. However, further preclinical studies will be required to demonstrate the mechanism of action of scopoletin involved in anti-myocardial infarction.

A hybrid platform featuring nanomagnetic ligand fishing for discovering COX-2 selective inhibitors from aerial part of Saussurea laniceps Hand.-Mazz.

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative "snow lotus" herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. AIM OF THE STUDY: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. MATERIALS AND METHODS: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. RESULTS: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. CONCLUSIONS: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.

Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala sabulosa (Polygalaceae) in mice: evidence for the involvement of monoaminergic systems.

The relationship between depression and monoaminergic systems has been hypothesized for many years. In this study, we have investigated the possible antidepressant-like effect of scopoletin, a coumarin from Polygala sabulosa in the tail suspension test and forced swimming test. Moreover, the ability of scopoletin to reverse the depression-like behavior in the forced swimming test induced by immobility stress in mice was evaluated. Scopoletin reduced the immobility time in the tail suspension test (10-100mg/kg, p.o.), but not in the forced swimming test. Fluoxetine (positive control) decreased the immobility time in the forced swimming and tail suspension tests (20mg/kg, p.o. and 10mg/kg. p.o., respectively). Immobility stress caused an increase in the immobility time in the forced swimming test (depression-like behavior), which was reversed by scopoletin (1-100mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.). Scopoletin produced no psychostimulant effect in the open-field test. The pretreatment of mice with ketanserin (5mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2mg/kg, i.p., a dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist), but not WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) prevented the antidepressant-like effect of scopoletin (10mg/kg, p.o.) in the tail suspension test. The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT(2A) receptors), noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Comparative effects of scopoletin and cyanide on rat brain, 1: histopathology.

Four week old male Wistar rats were used to study the effects of scopoletin and cyanide on the histopathology of rat brain. The rats were divided into a control and three experimental groups (2-4) and fed rations containing 0.07 microg scopoletin/100 g, 0.07 microg scopoletin + 1.8 mg cyanide/100 g and 1.8 mg cyanide/100 g, respectively. These levels of scopoletin and cyanide corresponded to levels found in a processed cassava diet. The first group was fed the same ration as the others but without scopoletin and cyanide. The rats were fed these rations for twelve months. Rats from each group were sacrificed at the third, sixth, ninth and twelfth months; the relative brain weight of the rats (% of body weight) and histology of their brains were studied. The lipid peroxide levels of the rat brains were also studied at the twelfth month. The results showed that the relative brain weights of the rats fed scopoletin + cyanide were significantly (p<0.05) less than that of the control from the third month. There were no significant changes in the lipid peroxide levels of the rat brains in the various groups. Histological examination of the brains of the rats suggested that scopoletin is involved in the pathogenesis of the neuropathy seen in cassava consuming populations.

Coumarin compounds in cassava diets: 2 health implications of scopoletin in gari.

Scopoletin has been isolated and identified in gari, a cassava food consumed in Nigeria (West Africa). Its levels in gari and cassava flour is not altered by post processing treatments such as sundrying, refrigeration and storage. Scopoletin has also been identified as an active principle in the traditional herbal infusion of the fruit of Tetrapleura tetraptera TAUB used in the ethnopharmacology of West Africa. It is a potent hypotensive and non-specific spasmolytic agent. These pharmacological effects of Scopoletin are probably the underlying factors in the slowly developing tropical neuropathy characterised by optic atrophy, nerve deafness and ataxia endemic among populations subsisting on cassava diets such as gari. Hitherto, these toxicities were attributed to cyanogenic glucosides (cyanide) present in cassava.

The sensitizing capacity of coumarins (III).

9 coumarins used as chemical reagents, laser dyes, in perfumery, cosmetics or occurring naturally, were investigated experimentally in guinea pigs to determine their contact sensitizing capacity. 5,7-dihydroxycoumarin, limettin and 5,7-dihydroxy-4-methylcoumarin were found to be moderate sensitizers, while scoparone, isoscopoletin and 4-hydroxycoumarin were weak. The 3 laser dyes were completely negative. The results indicate that substitution in the 6 and 7 or 5 and 7 positions with 2 hydroxy groups supports allergenic capability, while other substituents (e.g., methoxy groups) in the same positions, or an additional (third) substituent, diminish activity.