Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.

Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior.

INTRODUCTION: Separate α1- and ß-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and ß-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. METHODS: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers ( n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. RESULTS: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. CONCLUSION: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and ß-adrenergic antagonism on smoking outcomes.

Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission.

G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP8-37, accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP8-37-cholestanol, but not unconjugated CGRP8-37, prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP8-37-cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund's adjuvant more effectively than unconjugated CGRP8-37 Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention.

Freeze dried extracts of Bidens biternata (Lour.) Merr. and Sheriff. show significant antidiarrheal activity in in-vivo models of diarrhea.

ETHNOPHARMACOLOGICAL RELEVANCE OF THE STUDY: Diarrhea remains one of the main killers of children aged below five years. Traditional antidiarrheal remedies form a potentially viable source of novel low cost efficacious treatments in low resource settings. There is therefore a pressing need to scientifically evaluate these remedies. AIM OF THE STUDY: This study aimed to investigate the in vivo and in vitro antidiarrheal activity of freeze dried Bidens biternata, a herb used in traditional Ayurvedic medicine in the management of diarrhea. MATERIALS AND METHODS: In the castor oil test, twenty (20) adult Sprague-Dawley rats were randomized to a negative control (normal saline, n=5), a positive control (5mg/kg loperamide, n=5), and two test groups. The low dose test group received 200mg/kg Bidens biternata extract (n=5) while the high dose test group received 400mg/kg B. biternata extract (n=5). Castor oil (4ml/kg) was then administered to the animals one hour after administration of the respective treatments after which the total mass of fecal output excreted after four (4) hours was determined. In the charcoal meal test fifteen (15) Sprague Dawley rats were randomized to a control group (normal saline 5ml/kg orally, n=5), a positive control group (atropine sulfate 0.1mg/kg i.p., n=5) and a test group (400mg/kg B. biternata extract, n=5). Charcoal meal was then administered via oral gavage to each rat thirty (30) minutes after the administration of the various treatments. The distance covered by the charcoal meal from the pylorus was then determined after sacrifice of the animals thirty minutes after the meal. In the enteropooling test twenty (20) Sprague-Dawley rats were randomized to a control group (5% v/v ethanol in normal saline, n=5), a positive control group (5mg/kg loperamide, n=5) and a test group (400mg/kg B. biternata extract, n=5). For each group prostaglandin E2 (PGE2) (100µg/kg) was administered immediately after the treatments. The animals were then sacrificed half an hour later and the volume of the small intestine contents determined. The effects of different concentrations of B. biternata extract (0.5. 1.0, 2.0, 3.0 and 5.0mg/ml) on jejunal contraction were investigated and a dose-response curve constructed using the experimental data after which The ED50 dose was determined. The effect of tamsulosin (α1 adrenergic blocker), yohimbine (α2 adrenergic blocker), propranolol (ß adrenergic blocker) and naloxone (µ opioid blocker) on the contractile activity of the extract were also investigated. The experimental data were expressed as mean±standard error of mean (SEM) and then analyzed using one-way ANOVA followed by Tukey's post hoc test in cases of significance (set at p<0.05). RESULTS: The freeze dried extracts of B. biternata had significant antidiarrheal effects in the castor oil induced diarrhea model (p<0.01) with the highest activity being observed at the 400mg/kg dosage level (1.66±0.81g vs. 4.54±0.51g control, p=0.01). B. biternata extract had significant effects on intestinal motility in the charcoal meal test compared to the control group (43.61±4.42% vs. 60.54±3.33%: p<0.05). B. biternata extract had a significant effect on PGE2 induced enteropooling (3.06±0.07ml vs. 4.74±0.10ml; p<0.001). The freeze dried extracts of B. biternata had a significant negative effect on the contractility of the isolated rabbit jejunum (p<0.001). The effects of the extract were significantly attenuated by tamsulosin (53.94±4.20% vs. 80.57±4.09%; p<0.01) and naloxone (53.94±4.20% vs. 73.89±7.26%; p<0.05). Yohimbine (p>0.05) and propranolol (p>0.05) however did not have any significant effect on the contractile activity of the extract. CONCLUSIONS: The freeze dried extract of B. biternata possess significant antidiarrheal activity in both in vitro and in vivo models which appears to be mediated by modulating both the intestinal motility as well as the secretory activity. The results of this study also validate its traditional use as an antidiarrheal remedy.

Antidepressant-like Potentials of Buchholzia Coriacea Seed Extract: Involvement of Monoaminergic and Cholinergic Systems, and Neuronal Density in the Hippocampus of Adult Mice.

Buchholzia coriacea, taken by elderly, has phytochemicals that have neuro-active metabolites, and the folkloredocumented its use in neuro-behavioral despairs. Previous study in our laboratory shows that methanol extracts of Buchholziacoriacea (MEBC) seeds possess antidepressant-like potentials in laboratory rodents. This present study was conducted toinvestigate the probable mechanism(s) of action by which MEBC potentiates its effects using laboratory rodents.Involvements of serotonergic, cholinergic and adrenergic systems were studied using Forced Swimming Test (FST) and TailSuspension Test (TST) models of behavioral despair. Antagonists which including: Prazosin, an alpha-1-adrenergic receptorblocker (62.5 µg/kg, i.p.), metergoline, a 5HT2 receptor blocker (4 mg/kg, i.p.) and atropine, a -muscarinic cholinergicreceptor blocker (1mg/kg i.p.) were administered before effective dose of MEBC (50mg/kg). Also, the hippocampi of theanimals were studied for changes in neuronal density using Nissl Staining. Our findings showed that mobility was reversedin animals pre-treated with atropine, prazosin, and metergoline significantly (P˂0.05), showing a possible involvement ofthe corresponding systems. However, there was a significant reduction in immobility time (P<0.001) during FST afterchronic administration of the MEBC. The hippocampus showed no significant changes (P<0.05) in neuronal density. Inconclusion, MEBC probably potentiates its antidepressant-like potentials via the cholinergic, adrenergic and partly byserotonergic systems.

Higenamine 4'-O-ß-d-glucoside in the lotus plumule induces glucose uptake of L6 cells through ß2-adrenergic receptor.

Hypoglycemic effect is an efficient means to modulate elevated blood glucose levels in patients with diabetes. We found that the extract of lotus plumule (the germ of Nelumbo nucifera Gaertn. seed) showed potent glucose uptake enhancement activity against L6 myotubes, which results in a hypoglycemic effect. This activity was further investigated, and an active constituent was identified as a single bioactive compound, higenamine 4'-O-ß-d-glucoside. Mechanistic studies employing phosphatidylinositol 3-kinase (PI3K) inhibitor, AMP-activated protein kinase (AMPK) inhibitor, or adrenergic receptor antagonist showed that the compound induced its activity through ß2-adrenergic receptor. Patients with type II diabetes mellitus frequently develop insulin resistance. Owing to the differences between the mechanism of action of insulin and of the isolated compound, the compound or lotus plumule itself may have the possibility of modulating blood glucose levels in insulin-resistant patients effectively.

Roles for the sympathetic nervous system, renal nerves, and CNS melanocortin-4 receptor in the elevated blood pressure in hyperandrogenemic female rats.

Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS.

A review of the receptor binding and pharmacological effects of N-methyltyramine.

N-methyltyramine (NMT) is a protoalkaloid isolated from various plant species. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an α-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis). Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown to fats to energy.

Antidepressant and anxiolytic effects of the methanol root extract of Capparis thonningii: involvement of monoaminergic, cholinergic and GABAergic systems.

BACKGROUND: Capparis thonningii Schum. (Capparaceae) is used in traditional African Medicine for the treatment of mood disorders. OBJECTIVE: The study investigates antidepressant and anxiolytic activities of methanol root extract of C. thonningii (CT). METHODS: CT (25-100 mg/kg, p. o.) was administered 1 h before behavioral studies were carried out in mice. Antidepressant effect was investigated using the forced swimming test (FST) and tail suspension test (TST). The anxiolytic effect was evaluated using the elevated-plus maze test (EPM), hole-board test (HBT), and light-dark test. RESULTS: CT (25 and 50 mg/kg) increased swimming activity (P<0.05) by 92.73% and attenuated immobility time by 35.72%, similar to anti-immobility effect of imipramine (33.87%) in FST. In addition, CT (50 mg/kg) significantly (P<0.01) reduced immobility time by 30.24% in TST. -However, the antidepressant-like effect elicited by CT was reversed by metergoline, cyproheptadine, and sulpiride (40.81, 45.93, and 48.52%, respectively) pretreatment but prazosin, and yohimbine failed to reverse this antidepressant-like effect. Similar to diazepam, CT (25 mg/kg) increased duration of open arms exploration (P<0.05) by 43.73% in EPM, number of head-dips (HBT) (90.32%), and time spent in the light compartment by 45.77% in light/dark test indicating anxiolytic-like effect. The anxiolytic-like effect of CT was reversed by flumazenil pretreatment. CONCLUSION: The findings from this study suggest antidepressant-like effect of C. thonningii involving interaction with serotonergic (5-HT2), dopaminergic (D2), noradrenergic (α1 and α2), and muscarinic cholinergic systems; and anxiolytic effect through an interaction with GABAA benzodiazepine receptor.

Antidepressant-like activity of dehydrozingerone: involvement of the serotonergic and noradrenergic systems.

Dehydrozingerone (DHZ) is a phenolic compound isolated from ginger rhizomes (Zingiber officinale). It is known for its diverse spectrum of biological activities as an antioxidant, anti-inflammatory and antitumor compound. The present study was designed to assess the antidepressant effect of DHZ and the involvement of the monoaminergic system and to evaluate its in vitro antioxidant activity in the hippocampus, cortex and cerebellum of mice. For this study, the tail suspension test (TST), forced swim test (FST) and yohimbine lethality test were performed. DHZ administered orally 30min prior to testing reduced the immobility time in the TST (1-40mg/kg) and the FST (10-40mg/kg), with no change in locomotor activity in the open field test. The antidepressant-like effect of DHZ (1mg/kg) was prevented by ketanserin (1mg/kg, i.p.; a 5-HT2A/2C receptor antagonist), ondansetron (1mg/kg, i.p.; a 5-HT3 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist) pretreatments. Furthermore, DHZ administered at doses of 10 and 20mg/kg increased the lethality of yohimbine (35mg/kg, i.p.). DHZ had antioxidant activity on in vitro lipid peroxidation induced by sodium nitroprusside in all brain regions tested. The results revealed that DHZ has a potent antidepressant effect, which seems to involve the serotonergic and noradrenergic systems.

Analgesic and anti-inflammatory effects of honey: the involvement of autonomic receptors.

The use of honey for therapeutic purposes is on the increase and many studies have shown that honey has the ability to influence biological systems including pain transmission. Therefore, this study was designed to investigate the analgesic and anti-inflammatory effects of honey and the effects of concurrent administration of autonomic nervous system blocking drugs. Studies on analgesic activities was carried out using hotplate and formalin-induced paw licking models while the anti-inflammatory activity was by the carrageenan paw oedema method. Animals were distributed into six groups consisting of five animals each. They were administered saline, honey (600 mg/kg), indomethacin (5 mg/kg), autonomic blockers (3 µg/kg of tamsulosin, 20 mg/kg (intraperitoneally) of propranolol, 2 ml/kg of atropine or 10 mg/kg (intra muscularly) of hexamethonium) or honey (200 and 600 mg/kg) with one of the blockers. The results showed that honey reduced pain perception especially inflammatory pain and the administration of tamsulosin and propranolol spared the effect of honey. Hexamethonium also spared the effects of honey at the early and late phases of the test while atropine only inhibited the early phase of the test. However, atropine and hexamethonium spared the anti-inflammatory effects of honey but tamsulosin abolished the effects while propranolol only abolished the anti-inflammatory effects at the peak of the inflammation. The results suggest the involvement of autonomic receptors in the anti-nociceptive and anti-inflammatory effects of honey although the level of involvement depends on the different types of the receptors.

Purgative components in rhubarbs: adrenergic receptor inhibitors linked with glucose carriers.

Rhubarbs and their extractives have been used as cathartic for many years. There have been numerous breakthroughs in the pharmacological research of the drug. However, as the key point of the mechanism, the targets of the effective components still remain unclear. In this paper, with an in vitro system of isolated intestine, we found that both the rhubarb extractives and the anthraquinone derivatives can antagonize the adrenaline effectively. Furthermore, computer based docking provided the binding model of the anthraquinone derivatives and adrenergic receptor. Then, based on the results of the small intestinal promotion and purgative effect experiments in vivo, we built an "inhibitor-carrier" hypothesis to elucidate the mechanism of rhubarb. This work provided key massages for the pharmacological research of rhubarb, such a common and active medicinal plant, and might be of help for the development of new purgative drugs.

Involvement of monoaminergic systems in the antidepressant-like effect of Eugenia brasiliensis Lam. (Myrtaceae) in the tail suspension test in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Several species of Eugenia L. are used in folk medicine for the treatment of various diseases. Eugenia brasiliensis is used for the treatment of inflammatory diseases, whereas Eugenia. uniflora is used for the treatment of symptoms related to depression and mood disorders, and is used in Brazil by the Guarani Indians as a tonic stimulant. AIM OF THE STUDY: To investigate the antidepressant-like effect of hydroalcoholic extracts of different plant species of genus Eugenia and to characterize the participation of the monoaminergic systems in the mechanism of action of the specie that afforded the most prominent antidepressant-like efficacy. MATERIALS AND METHODS: In the first set of experiments, the effects of hydroalcoholic extracts of Eugenia beaurepaireana, Eugenia brasiliensis, Eugenia catharinae, Eugenia umbelliflora and Eugenia uniflora and the antidepressant fluoxetine (positive control) administered acutely by p.o. route were evaluated in the tail suspension test (TST) and locomotor activity was assessed in the open-field test in mice. In the second set of experiments, the involvement of the monoaminergic systems in the antidepressant-like activity of Eugenia brasiliensis was evaluated by treating mice with several pharmacological agonists and antagonists. The effects of the combined administration of sub-effective doses of Eugenia brasiliensis and the antidepressants fluoxetine, imipramine and bupropion were also evaluated. RESULTS: The administration of the extracts from Eugenia brasiliensis, Eugenia catharinae and Eugenia umbelliflora, but not Eugenia beaurepaireana and Eugenia uniflora, exerted a significant antidepressant-like effect, without altering locomotor activity. The behavioral profile was similar to fluoxetine. Pre-treatment of mice with ketanserin, haloperidol, SCH23390, sulpiride, prazosin and yohimbine prevented the reduction of immobility time induced by Eugenia brasiliensis. Treatment with sub-effective doses of WAY100635, SKF38393, apomorphine, phenylephrine, but not clonidine, combined with a sub-effective dose of Eugenia brasiliensis decreased the immobility time in the TST. Furthermore, the combined administration of sub-effectives doses of Eugenia brasiliensis with fluoxetine, imipramine and bupropion produced an antidepressant-like effect. CONCLUSIONS: This study show, for the first time, the antidepressant-like effect of species of the genus Eugenia, especially Eugenia brasiliensis, whose effects in the TST seem to be mediated by serotoninergic (5-HT(1A) and 5-HT(2) receptors), noradrenergic (α(1)-adrenoceptor) and dopaminergic (dopamine D(1) and D(2) receptors) systems.

Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure.

BACKGROUND: Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Because AF electrograms (EGMs) are thought to reflect the underlying structural substrate, we sought to (1) determine the differences in AF EGMs in normal versus HF atria and (2) assess how fibrosis and nerve-rich fat contribute to AF EGM characteristics in HF. METHODS AND RESULTS: AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240 beats per minute). AF EGMs were analyzed for dominant frequency (DF), organization index, fractionation intervals (FIs), and Shannon entropy. In 8 HF dogs, AF EGM correlation with underlying fibrosis/fat/nerves was assessed. In HF compared with normal dogs, DF was lower and organization index/FI/Shannon entropy were greater. DF/FI were more heterogeneous in HF. Percentage fat was greater, and fibrosis and fat were more heterogeneously distributed in the posterior left atrium than in the left atrial appendage. DF/organization index correlated closely with %fibrosis. Heterogeneity of DF/FI correlated with the heterogeneity of fibrosis. Autonomic blockade caused a greater change in DF/FI/Shannon entropy in the posterior left atrium than left atrial appendage, with the decrease in Shannon entropy correlating with %fat. CONCLUSIONS: The amount and distribution of fibrosis in the HF atrium seems to contribute to slowing and increased organization of AF EGMs, whereas the nerve-rich fat in the HF posterior left atrium is positively correlated with AF EGM entropy. By allowing for improved detection of regions of dense fibrosis and high autonomic nerve density in the HF atrium, these findings may help enhance the precision and success of substrate-guided ablation for AF.

Antidepressant-like effect of extract from Polygala paniculata: involvement of the monoaminergic systems.

CONTEXT: Polygala paniculata Linnaeus (Polygalaceae) has shown neuroprotective effects, but there is no report about its antidepressant potential. OBJECTIVE: The antidepressant-like effect of the hydroalcoholic extract from P. paniculata and some of the possible mechanisms involved in this effect were investigated in forced swimming test (FST). MATERIALS AND METHODS: Mice received extract by oral route and were submitted to FST and open-field test. Animals were forced to swim and the total immobility time was registered (6-min period). A reduction in the immobility time is considered an antidepressant-like effect. In order to investigate the involvement of the monoaminergic systems, mice were treated with pharmacological antagonists before administration of the extract. RESULTS: The acute administration of the hydroalcoholic extract from P. paniculata produced an antidepressant-like effect, since it significantly reduced the immobility time in FST (0.01-30 mg/kg) as compared to control group, without changing locomotor activity. Pretreatment of mice with yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist), propranolol (1 mg/kg, i.p., ß-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., dopamine D1 receptor antagonist) or sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist) prevented the antidepressant-like effect of the extract in FST (30 mg/kg). Moreover, ketanserin (5 mg/kg, i.p., preferential 5-HT(2A) receptor antagonist) enhanced the effect of the extract in FST. DISCUSSION AND CONCLUSION: The results of the present study indicate that the extract from P. paniculata has an antidepressant-like action that is likely mediated by an interaction with the serotonergic (5-HT2A receptors), noradrenergic (α2 and ß-receptor) and dopaminergic (D1 and D2 receptors) systems.

Effect and mechanism of action of resveratrol: a novel melanolytic compound from the peanut skin of Arachis hypogaea.

PURPOSE: The present work was carried out to determine the effects of ethanolic extracts of Arachis hypogaea and its active ingredient resveratrol on the isolated tail melanophores of the Bufo melanostictus to find the mechanism of skin lightening at the cellular level. METHODS: The tail melanophores of the tadpole B. melanostictus were assayed using the mean melanophore size index and their responses were recorded in presence of various concentrations of the plant extract and its active ingredient along with specific antagonists and potentiator. RESULTS: Significant skin lightening activity of the extract of A. hypogaea and its active ingredient resveratrol was observed on the tail melanophores of tadpole. The pigment cells responded by distinct aggregation leading to skin lightening, this effect was reversible, as re-immersion in physiological saline made the melanophores return to their normal intermediate state. These melanin aggregating effects were completely blocked by propanolol (beta blocker) and partially blocked by prazosin (alpha blocker) and were also found to be highly potentiated by reserpine. CONCLUSION: These studies suggest that the active ingredient of A. hypogaea such as resveratrol can act as a sympathomimetic compound and induce aggregation of melanophores of tadpole B. melanostictus via the induction of beta type of the adrenoceptors. The present study opens new vistas for the use of A. hypogaea and its active ingredient, resveratrol for its clinical application as a nontoxic melanolytic compound for the treatment of hyperpigmentation.

Colon electrical stimulation: potential use for treatment of obesity.

Obesity is one of the most prevalent health problems in the United States. Current therapeutic strategies for the treatment of obesity are unsatisfactory. We hypothesized the use of colon electrical stimulation (CES) to treat obesity by inhibiting upper gastrointestinal motility. In this preliminary study, we aimed at studying the effects of CES on gastric emptying of solid, intestinal motility, and food intake in dogs. Six dogs, equipped with serosal colon electrodes and a jejunal cannula, were randomly assigned to receive sham-CES or CES during the assessment of: (i) gastric emptying of solids, (ii) postprandial intestinal motility, (iii) autonomic functions, and (iv) food intake. We found that (i) CES delayed gastric emptying of solids by 77%. Guanethidine partially blocked the inhibitory effect of CES on solid gastric emptying; (ii) CES significantly reduced intestinal contractility and the effect lasted throughout the recovery period; (iii) CES decreased vagal activity in both fasting and fed states, increased the sympathovagal balance and marginally increased sympathetic activity in the fasting state; (iv) CES resulted in a reduction of 61% in food intake. CES reduces food intake in healthy dogs and the anorexigenic effect may be attributed to its inhibitory effects on gastric emptying and intestinal motility, mediated via the autonomic mechanisms. Further studies are warranted to investigate the therapeutic potential of CES for obesity.

Inhibitory effect of schisandrin on spontaneous contraction of isolated rat colon.

This study examined the effect of schisandrin, one of the major lignans isolated from Schisandra chinensis, on spontaneous contraction in rat colon and its possible mechanisms. Schisandrin produced a concentration-dependent inhibition (EC50=1.66 µM) on the colonic spontaneous contraction. The relaxant effect of schisandrin could be abolished by the neuronal Na+ channel blocker tetrodotoxin (1 µM) but not affected by propranolol (1 µM), phentolamine (1 µM), atropine (1 µM) or nicotine desensitization, suggesting possible involvement of non-adrenergic non-cholinergic (NANC) transmitters released from enteric nerves. N(ω)-nitro-l-arginine methyl ester (100-300 µM), a nitric oxide synthase inhibitor, attenuated the schisandrin response. The role of nitric oxide (NO) was confirmed by an increase in colonic NO production after schisandrin incubation, and the inhibition on the schisandrin responses by soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-α]-quinoxalin-1-one (1-30 µM). Non-nitrergic NANC components may also be involved in the action of schisandrin, as suggested by the significant inhibition of apamin on the schisandrin-induced responses. Pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt hydrate (100 µM), a selective P2 purinoceptor antagonist, markedly attenuated the responses to schisandrin. In contrast, neither 8-cyclopentyl-1,3-dipropylxanthine, an antagonist for adenosine A1 receptors, nor chymotrypsin, a serine endopeptidase, affected the responses. All available results have demonstrated that schisandrin produced NANC relaxation on the rat colon, with the involvement of NO and acting via cGMP-dependent pathways. ATP, but not adenosine and VIP, likely plays a role in the non-nitrergic, apamin-sensitive component of the response.

Characterization of the electrophysiological properties of triple reuptake inhibitors on monoaminergic neurons.

Triple reuptake inhibitors represent a potential new class of antidepressant drugs that block norepinephrine (NE), dopamine (DA) and serotonin [5-hydroxytryptamine (5-HT)] transporters. The present in-vivo electrophysiological study was undertaken to determine the effects of the triple reuptake inhibitors SEP-225289 and DOV216303 on the neuronal activities of locus coeruleus (LC) NE, ventral tegmental area (VTA) DA and dorsal raphe (DR) 5-HT neurons. Administered acutely, SEP-225289 and DOV216303 dose-dependently decreased the spontaneous firing rate of LC NE, VTA DA and DR 5-HT neurons through the activation of α2, D2 and 5-HT(1A) autoreceptors, respectively. Both compounds predominantly inhibited the firing rate of LC NE neurons while producing only a partial decrease in VTA DA and DR 5-HT neuronal discharge. SEP-225289 was equipotent at inhibiting 5-HT and NE transporters since it prolonged to the same extent the time required for a 50% recovery (RT50) of the firing activity of dorsal hippocampus CA3 pyramidal neurons from the inhibition induced by microiontophoretic application of 5-HT and NE. Finally, in the presence of WAY100635, a 5-HT(1A) receptor antagonist, SEP-225289 activated 5-HT neurons at doses that normally did not inhibit them. Taken together, the present results indicate that reciprocal interactions among NE, DA and 5-HT inputs need to be considered to anticipate the net effect of triple reuptake inhibitors on the enhancement of brain monoamine transmission. The results also suggest that the therapeutic action of triple reuptake inhibitors may be potentiated by antagonizing the cell body 5-HT(1A) autoreceptors.

Effects of synephrine and beta-phenethylamine on human alpha-adrenoceptor subtypes.

Synephrine and beta-phenethylamine, two naturally occurring compounds, are structurally related to ephedrine. In this study, the effects of synephrine and beta-phenethylamine on alpha-adrenergic receptor (alpha-AR) subtypes are investigated in human embryonic kidney (HEK293) or Chinese hamster ovary (CHO) cells, and compared to that of 1R,2S-norephedrine. The rank order of binding affinities was found to be the same for the subtypes tested (alpha(1A)-, alpha(2A)-, and alpha(2C)-AR) viz, 1R,2S-norephedrine > beta-phenethylamine > synephrine. Functional studies on the alpha(1A)-AR subtype showed that synephrine was a partial agonist giving a maximal response at 100 microM that was equal to 55.3 % of the L-phenylephrine maximum. In contrast, neither 1R,2S-norephedrine nor beta-phenethylamine exhibited agonist activity at the highest concentration tested (300 microM). beta-Phenethylamine was more potent as an antagonist than 1R,2S-norephedrine and synephrine on the alpha(1A)-AR subtype. Functional studies on the alpha(2A)- and alpha(2C)-AR subtypes indicated that synephrine and beta-phenethylamine did not act as agonists. Similar to 1R,2S-norephedrine, both of these analogs reversed the effect of medetomidine against forskolin-induced cAMP elevations at 300 microM, and the rank order of antagonist potency was: 1R,2S-norephedrine = beta-phenethylamine > synephrine; and beta-phenethylamine > 1R,2S-norephedrine > synephrine, respectively. These differences suggest that the presence of a 4-hydroxy group, as in synephrine, reduced the potency in these subtypes. In conclusion, at the alpha(1A)-AR, synephrine acted as a partial agonist, while beta-phenethylamine did not exhibit any direct agonist activity. Both, synephrine and beta-phenethylamine, may act as antagonists of pre-synaptic alpha(2A/2C)-ARs present in nerve terminals.