Effects of <Emphasis Type="Italic">Bidens pilosa</Emphasis> L. var. <Emphasis Type="Italic">radiata</Emphasis> S<Emphasis Type="SmallCaps">cherff</Emphasis> on experimental gastric lesion

Bidens pilosa L. var. radiata Scherff (BP) is a plant used as a traditional folk medicine. BP, cultivated with only green manure on Miyako Island, Okinawa prefecture, was processed to powder and is referred to as MMBP. We have reported that MMBP has antioxidant, anti-inflammatory, and anti-allergy properties. In this study, we investigated the effects of MMBP on several experimental gastric lesions induced by HCl/EtOH, a non-steroidal anti-inflammatory drug, or cold-restraint stress, comparing these results with those of rutin or anti-ulcerogenic drugs (cimetidine or sucralfate) based on the lesion index and hemorrhage from the gastric lesions. Orally administered MMBP prevented the progression of the gastric lesions. Moreover, treatment with MMBP, rutin, or sucralfate, which had potent antioxidative activity, inhibited increases in the levels of thiobarbituric acid reactive substances (TBARS) in the gastric mucosal lesions. The inhibition of the gastric mucosal TBARS content by MMBP may have been due to the antioxidant effects of MMBP. These results indicate that MMBP prevents the progression of acute gastric mucosal lesions, possibly by suppressing oxidative stress in the gastric mucosa.     

Differential effects of the <Emphasis Type="SmallCaps">d-</Emphasis> and <Emphasis Type="SmallCaps">l-</Emphasis> isomers of amphetamine on pharmacological MRI BOLD contrast in the rat

Rationale

The d- and l-amphetamine sulphate isomers are used in the formulation of Adderall XR®, which is effective in the treatment of attention-deficit hyperactivity disorder (ADHD). The effects of these isomers on brain activity has not been examined using neuroimaging.

Objectives

This study determines the pharmacological magnetic resonance imaging blood-oxygenation-level-dependent (BOLD) response in rat brain regions after administration of each isomer.

Materials and methods

Rats were individually placed into a 2.35 T Bruker magnet for 60 min to achieve basal recording of variation in signal intensity. Either saline (n?=?9), d-amphetamine sulphate (2 mg/kg, i.p.; n?=?9) or l-amphetamine sulphate (4 mg/kg, i.p.; n?=?9) were administered, and recording continued for a further 90 min. Data were analysed for BOLD effects using statistical parametric maps. Blood pressure, blood gases and respiratory rate were monitored during scanning.

Results

The isomers show overlapping effects on the BOLD responses in areas including nucleus accumbens, medial entorhinal cortex, colliculi, field CA1 of hippocampus and thalamic nuclei. The l-isomer produced greater global changes in the positive BOLD response than the d-isomer, including the somatosensory and motor cortices and frontal brain regions such as the orbitofrontal cortices, prelimbic and infralimbic cortex which were not observed with the d-isomer.

Conclusions

The amphetamine isomers produce different BOLD responses in brain areas related to cognition, pleasure, pain processing and motor control probably because of variations on brain amine systems such as dopamine and noradrenaline. The isomers may, therefore, have distinct actions on brain regions affected in ADHD patients.

     

Hypermagnesemia disturbances in rats,NO-related: pentadecapeptide BPC 157 abrogates, <Emphasis Type="SmallCaps">l</Emphasis>-NAME and <Emphasis Type="SmallCaps">l</Emphasis>-arginine worsen

Aim

Stable gastric pentadecapeptide BPC 157, administered before a high-dose magnesium injection in rats, might be a useful peptide therapy against magnesium toxicity and the magnesium-induced effect on cell depolarization. Moreover, this might be an NO-system-related effect. Previously, BPC 157 counteracts paralysis, arrhythmias and hyperkalaemia, extreme muscle weakness; parasympathetic and neuromuscular blockade; injured muscle healing and interacts with the NOS-blocker and NOS-substrate effects.

Main methods

Assessment included magnesium sulfate (560 mg/kg intraperitoneally)-induced muscle weakness, muscle and brain lesions, hypermagnesemia, hyperkalaemia, increased serum enzyme values assessed in rats during and at the end of a 30-min period and medication (given intraperitoneally/kg at 15 min before magnesium) [BPC 157 (10 µg, 10 ng), l-NAME (5 mg), l-arginine (100 mg), alone and/or together]. In HEK293 cells, the increasing magnesium concentration from 1 to 5 mM could depolarize the cells at 1.75 ± 0.44 mV.

Key findings

l-NAME + magnesium-rats and l-arginine + magnesium-rats exhibited worsened severe muscle weakness and lesions, brain lesions, hypermagnesemia and serum enzymes values, with emerging hyperkalaemia. However, l-NAME + l-arginine + magnesium-rats exhibited all control values and normokalaemia. BPC 157 abrogated hypermagnesemia and counteracted all of the magnesium-induced disturbances (including those aggravated by l-NAME or l-arginine). Thus, cell depolarization due to increasing magnesium concentration was inhibited in the presence of BPC 157 (1 µM) in vitro.

Significance

BPC 157 likely counteracts the initial event leading to hypermagnesemia and the life-threatening actions after a magnesium overdose. In contrast, a worsened clinical course, higher hypermagnesemia, and emerging hyperkalaemia might cause both l-NAME and l-arginine to affect the same events adversely. These events were also opposed by BPC 157.

     

Discriminative stimulus and reinforcing effects of <Emphasis Type="Italic">p</Emphasis>-fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-deprenyl in monkeys

Rationale para-Fluoro-l-deprenyl (Fludepryl), a halogenated derivative of l-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives p-Fluoro-l-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Results Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-l-deprenyl. l-Deprenyl and the metabolites of p-fluoro-l-deprenyl, p-fluoro-l-amphetamine, and p-fluoro-l-methylamphetamine were more potent, producing full generalization at doses of 1.0–3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-l-deprenyl up to 1.0 mg/kg. However, p-fluoro-l-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-l-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or d-amphetamine. Conclusions p-Fluoro-l-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, l-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.     

The effect of <Emphasis Type="SmallCaps">l</Emphasis>-NAME and <Emphasis Type="SmallCaps">l</Emphasis>-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice

Rationale. Morphine and nitric oxide (NO) have important functional interactions in different neural processes, and both modulate learning and memory although their interaction in cognitive performance has not been elucidated. Objective. To examine the effect of the NO synthase (NOS) inhibitor N^G-nitro-l-arginine methyl ester (l-NAME) and NOS substrate l-arginine on morphine-induced impairment of memory formation and the state-dependent retrieval of a passive avoidance task learned under morphine influence. Methods. All drugs were administered intraperitoneally, and a one-trial step-down paradigm was used for the assessment of memory in adult male NMRI mice. Morphine was administered 30 min before training to induce impairment of memory formation and 30 min before test to induce state-dependent retrieval of the memory acquired under pre-training morphine influence. l-NAME or l-arginine was administered either 5 min after training or 45 min before the test. Results. Pre-training morphine induced impairment of memory formation that was reversible by pre-test morphine but not saline. Post-training administration of l-arginine (200 mg/kg) and l-NAME (3, 10 and 30 mg/kg), respectively, facilitated and impaired the memory consolidation, but their pre-test injections did not affect retention. However, post-training l-arginine at per se non-effective doses of 20 mg/kg and 60 mg/kg reversed the morphine-induced impairment of memory formation. Pre-test administration of l-NAME (3 mg/kg and 10 mg/kg) could restore the memory impairment induced by pre-training morphine, and this effect was blocked by concomitant pre-test l-arginine (60 mg/kg). Concomitant administration of low doses of l-NAME (1 mg/kg) and morphine (0.5 mg/kg) pre-test also revealed an additive effect in restoring the morphine state of memory. Conclusion. These results suggest that the impairment of memory formation and the facilitation of retrieval induced by morphine involves decreased synthesis/release of NO and can be counteracted by NOS substrate. Electronic Publication     

Glycine and <Emphasis Type="SmallCaps">d</Emphasis>-serine,but not <Emphasis Type="SmallCaps">d</Emphasis>-cycloserine,attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

RATIONALE: Several agents that stimulate the glycine site of N-methyl-D: -aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed. OBJECTIVES: We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D: -serine, and a partial agonist, D: -cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site. RESULTS: High doses of glycine (1.6 g/kg) and D: -serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D: -cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L: -serine levels, but decreased D: -serine levels in the prefrontal cortex. CONCLUSIONS: The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.     

<Emphasis Type="Italic">N</Emphasis>-Methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

Rationale Activation of co-agonist N-methyl-d-aspartate (NMDA) and Glycine_B sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function.Objectives This article outlines the complex regulation of activity at Glycine_B/NMDA receptors by multiple classes of endogenous ligand. It also summarizes the evidence that a hypoactivity of Glycine_B/NMDA receptors contributes to the pathogenesis of psychotic states, and that drugs which enhance activity at these sites may possess antipsychotic properties.Results Polymorphisms in several genes known to interact with NMDA receptors are related to an altered risk for schizophrenia, and psychotic patients display changes in levels of mRNA encoding NMDA receptors, including the NR1 subunit on which Glycine_B sites are located. Schizophrenia is also associated with an overall decrease in activity of endogenous agonists at Glycine_B/NMDA sites, whereas levels of endogenous antagonists are elevated. NMDA receptor open channel blockers, such as phencyclidine, are psychotomimetic in man and in rodents, and antipsychotic agents attenuate certain of their effects. Moreover, mice with genetically invalidated Glycine_B/NMDA receptors reveal similar changes in behaviour. Finally, in initial clinical studies, Glycine_B agonists and inhibitors of glycine reuptake have been found to potentiate the ability of conventional antipsychotics to improve negative and, albeit modestly, cognitive and positive symptoms. In contrast, therapeutic effects of clozapine are not reinforced, likely since clozapine itself enhances activity at NMDA receptors.Conclusions Reduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at Glycine_B sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of Glycine_B sites alone improves psychotic states.     

Identification of medicinal <Emphasis Type="Italic">Dendrobium</Emphasis> species by phylogenetic analyses using <Emphasis Type="Italic">matK</Emphasis> and <Emphasis Type="Italic">rbcL</Emphasis> sequences

Species identification of five Dendrobium plants was conducted using phylogenetic analysis and the validity of the method was verified. Some Dendrobium plants (Orchidaceae) have been used as herbal medicines but the difficulty in identifying their botanical origin by traditional methods prevented their full modern utilization. Based on the emerging field of molecular systematics as a powerful classification tool, a phylogenetic analysis was conducted using sequences of two plastid genes, the maturase-coding gene (matK) and the large subunit of ribulose 1,5-bisphosphate carboxylase-coding gene (rbcL), as DNA barcodes for species identification of Dendrobium plants. We investigated five medicinal Dendrobium species, Dendrobium fimbriatum, D. moniliforme, D. nobile, D. pulchellum, and D. tosaense. The phylogenetic trees constructed from matK data successfully distinguished each species from each other. On the other hand, rbcL, as a single-locus barcode, offered less species discriminating power than matK, possibly due to its being present with little variation. When results using matK sequences of D. officinale that was deposited in the DNA database were combined, D. officinale and D. tosaense showed a close genetic relationship, which brought us closer to resolving the question of their taxonomic identity. Identification of the plant source as well as the uniformity of the chemical components is critical for the quality control of herbal medicines and it is important that the processed materials be validated. The methods presented here could be applied to the analysis of processed Dendrobium plants and be a promising tool for the identification of botanical origins of crude drugs.     

<Emphasis Type="Italic">ent</Emphasis>-Abietane diterpenoids from <Emphasis Type="Italic">Isodon xerophilus</Emphasis>

Three new ent-abietanoids, named xerophilusins XIV–XVI, and four known analogues, as well as four known chemical constituents were isolated from the leaves of Isodon xerophilus. Their structures were elucidated by extensive spectroscopic studies, and comparison with literature data. In addition, the cytotoxic activity of the ent-abietanoids against chronic myelogenous leukemia (K562), stomach adenocarcinoma (MKN45), and hepatocellular carcinoma (HepG2) human cell lines was investigated and no activities were observed.     

MDMA induces <Emphasis Type="Italic">Per1</Emphasis>, <Emphasis Type="Italic">Per2</Emphasis> and <Emphasis Type="Italic">c-fos</Emphasis> gene expression in rat suprachiasmatic nuclei

Rationale  

±3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a psychoactive drug that has marked effects on the serotonergic system. Serotonergic agonists are known to interact with the circadian pacemaker located in the suprachiasmatic nuclei (SCN).     

A new <Emphasis Type="Italic">Erythrina</Emphasis> alkaloid from <Emphasis Type="Italic">Erythrina herbacea</Emphasis>

A new Erythrina alkaloid, 10-hydroxy-11-oxoerysotrine (1), has been isolated from the flowers of Erythrina herbacea together with five known compounds: erytharbine (2), 10,11-dioxoerysotrine (3), erythrartine (4), erysotramidine (5) and erysotrine-N-oxide (6). The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass (MS) spectra. The new compound is a rare C-10 oxygenated Erythrina alkaloid. The antioxidant activities of the isolated compounds 1–6 were evaluated by scavenging with peroxynitrite.     

<Emphasis Type="Italic">In Vitro</Emphasis> hepatoprotective compounds from <Emphasis Type="Italic">Suaeda glauca</Emphasis>

Bioassay-guided fractionation of the MeOH extract of Suaeda glauca yielded four phenolic compounds, methyl 3,5-di-O-caffeoyl quinate (1) and 3,5-di-O-caffeoyl quinic acid (2), isorhamnetin 3-O-beta-D-galactoside (3), and quercetin 3-O-beta-D-galactoside (4). Compounds 1 and 2 were hepatoprotective against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells with the EC(50) values of 72.7+/-6.2 and 117.2+/-10.5 microM, respectively. Silybin as a positive control showed an EC(50) value of 82.4+/-4.1 microM.     

<Emphasis Type="Italic">Perilla frutescens</Emphasis> var. <Emphasis Type="Italic">frutescens</Emphasis> in northern Laos

Twenty-eight samples of mericarps of Perilla frutescens var. frutescens were collected through fieldwork performed in Phongsali and Xieng Khouang provinces in northern Laos. No perilla samples were collected from Savannakhet province in the south although more than 20 sites were investigated. Perilla plants are mostly grown mixed with dry-paddy rice by slash-and-burn cultivation in Laos. The most popular local name for perilla mericarps in the area was “Ma Nga Chan”. Weight of 1,000 grains and hardness of the mericarps were measured, and all mericarps were found to be large (weight of 1,000 grains around 2 g) and soft (limit load weight under 300 g), which were preferred for culinary use in Laos. The composition of the essential oils obtained from the herbaceous plants raised from the mericarps was divided into five types, perillaketone, elemicine plus myristicine, shisofuran, piperitenon, and myristicine, and GC–MS analysis of these Laotian perilla samples showed that they were similar to those of corresponding types of known Japanese perilla strains. One of the shisofuran-type perilla contained large amounts of putative α-naginatene, which is likely to be an intermediate of the biosynthesis of naginataketone. The farmers' indifference to the oil type of the leaf seems to leave Laotian perilla as a good genetic resource for studies of the biosynthesis of oil compounds.     

Biological activity of <Emphasis Type="Italic">Entada phaseoloides</Emphasis> and <Emphasis Type="Italic">Entada rheedei</Emphasis>

The aim of our study is to find functional compounds from natural resources. We focus on plants grown in tropical areas, especially Madagascar and Thailand, because they have unique flora and are expected to contain interesting compounds. We review the functional compounds of the seed kernels of Entada phaseoloides and E. rheedei and their biological activities such as anti-proliferation and melanogenesis inhibitory properties, etc.     

<Emphasis Type="Italic">In Vitro</Emphasis> antioxidant and anti-inflammatory activities of Jaceosidin from <Emphasis Type="Italic">Artemisia princeps</Emphasis> Pampanini <Emphasis Type="Italic">cv.</Emphasis> Sajabal

Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu²⁺-mediated LDL oxidation with IC₅₀ values of 10.2 μM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-κB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-κB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.     

Improvement of the extraction efficiency of <Emphasis Type="SmallCaps">d</Emphasis>-amygdalin from Armeniacae Semen powder through inactivating emulsin and suppressing the epimerization of <Emphasis Type="SmallCaps">d</Emphasis>-amygdalin

Armeniacae Semen contains not only amygdalin but also emulsin, which is an enzyme that hydrolyzes amygdalin. This hydrolysis reaction has been a major problem associated with the water extraction of Armeniacae Semen powder. In this study, the emulsin was inactivated by extracting Armeniacae Semen powder at a constant temperature of 90°C. In addition, in order to suppress the epimerization of d-amygdalin, the extraction time was kept to less than 8 min. The use of a 10 mM sodium phosphate buffer (pH 2.3) containing 13.5% acetonitrile as a mobile phase in reversed-phase HPLC was effective in separating and analyzing the d-amygdalin and neoamygdalin. The linearity between the concentrations and detector responses was obtained in the range of 0.05 to 0.5 mM. The detection limits for d-amygdalin and neoamygdalin were approximately 5 μM per amount injected.     

<Emphasis Type="Italic">NAT2</Emphasis>,<Emphasis Type="Italic"> CYP2C9</Emphasis>,<Emphasis Type="Italic"> CYP2C19</Emphasis>, and<Emphasis Type="Italic"> CYP2E1</Emphasis> genetic polymorphisms in anti-TB drug-induced maculopapular eruption

Purpose  

It has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE.     

Behavioral and molecular evidence for psychotropic effects in <Emphasis Type="SmallCaps">l</Emphasis>-theanine

Rationale  

l-Theanine (N-ethyl-l-glutamine) is an amino acid uniquely found in green tea and historically considered to be a relaxing agent. It is a glutamate derivative and has an affinity for glutamatergic receptors. However, its psychotropic effects remain unclear.