Metabolite alterations in basal ganglia associated with psychiatric symptoms of abstinent toluene users: a proton MRS study.

Long-term toluene abuse causes a variety of psychiatric symptoms. However, little is known about abnormalities at the neurochemical level in the living human brain after long-term exposure to toluene. To detect neurochemical changes in the basal ganglia of subjects with a history of long-term toluene use, proton magnetic resonance spectroscopy (1H MRS) was performed in 12 abstinent toluene users and 13 healthy comparisons with no history of drug abuse. N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr + PCr), choline-containing compounds (Cho), and myo-inositol (MI) levels were measured in the left and right basal ganglia. The Cho/Cr + PCr ratio, a marker of membrane metabolism, was significantly increased in the basal ganglia of toluene users in comparison to that of the control subjects. Furthermore, the increase in the Cho/Cr + PCr ratio was significantly correlated with the severity of residual psychiatric symptoms. These findings suggest that long-term toluene use causes membrane disturbance in the basal ganglia, which is associated with residual psychiatric symptoms that persist even after long-term abstinence from toluene use.     

HIV-1 integrase inhibitory substances from Coleus parvifolius

For the purpose of discovering anti-HIV-1 agents from natural sources, water and EtOH extracts of 50 Thai plants were screened for their inhibitory activity against HIV-1 integrase (IN), an enzyme essential for viral replication. Of these plants, an EtOH extract of Coleus parvifolius Benth. (aerial parts) showed potent activity against HIV-1 IN with an IC50 value of 9.2 microg/mL. From this extract, 11 compounds were isolated and identified as luteolin 5-O-beta-d-glucopyranoside (1), luteolin (2), luteolin 7-methyl ether (3), luteolin 5-O-beta-d-glucuronide (4), 5-O-beta-d-glucopyranosyl-luteolin 7-methyl ether (5), rosmarinic acid (6), rosmarinic acid methyl ester (7), daucosterol (8), a mixture of alpha- and beta-amyrin (9, 10) and phytol (11). Of these compounds, rosmarinic acid methyl ester (7), rosmarinic acid (6), luteolin (2) and luteolin 7-methyl ether (3) exhibited inhibitory activities against HIV-1 IN with IC50 values of 3.1, 5.0, 11.0 and 11.0 microM, respectively. Among rosmarinic acid derivatives, the HIV-1 IN inhibitory activity increased in turn for a dimer (IC50 = 5.0 microM), a trimer (IC50 = 1.4 microM), and a tetramer (IC50 = 1.0 microM).     

Augmentation of milnacipran by risperidone in treatment for major depression

Milnacipran, one of the serotonin noradrenaline reuptake inhibitors (SNRIs) to which venlafaxine and duloxetine belong, is a new antidepressant that has recently become available in many countries. Despite the advances in pharmacotherapy, almost one third of patients with depressive illness respond inadequately to monotherapy with such an antidepressant. We herein describe five patients with major depression who responded partially, but not fully, to milnacipran alone and remarkably improved with an adjunct of risperidone. In addition, milnacipran plus risperidone was found to be a useful augmentation for treatment-refractory depression in 3 of the 5 patients. The minimum dose of risperidone, 0.5 or 1 mg/d, was efficacious. The time of response after addition of risperidone was within 4 d. Our experience suggests that an augmentation therapy of milnacipran plus risperidone is useful for treating patients with depression who only partially respond to various types of antidepressants and for treatment-refractory depression.     

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean +/- SD: 34.5 +/- 16.6 versus 66.2 +/- 19.2 ng/mL, P < 0.01) and total area under the plasma concentration-time curve (490.1 +/- 277.5 vs 812.1 +/- 267.2 ng x h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.     

Functional regulation of serotonin transporter, a molecule involved in the pathogenesis of anxiety disorder]

The serotonin transporter (SET) is a member of the Na+/Cl(-)-dependent neurotransmitter transporter family and functions as a membrane protein which terminates the serotonergic neuronal transmission by re-uptaking serotonin into the pre-synaptic terminal. SET is thought to be involved in the pathogenesis of affective disorders, drug abuse and anxiety disorder. We have focused on SET regulation by phosphorylation/dephosphorylation since SET has many putative phosphorylation sites in its intracellular region. Our previous studies have revealed that phorbolesters, activators of PKC, decreased in SET uptake activity. Based on a mutagenesis analysis of PKC phosphorylation sites and an in vivo phosphorylation study of SET, we have concluded that PKC regulates SET activity via an indirect mechanism, probably via alternating actin cytoskeleton status. Recent reports and our investigation have demonstrated that the SET C-terminal region interacts with actin binding proteins, suggesting the crucial roles of this region in functional regulation of SET.     

Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways

Berberine, an isoquinoline alkaloid isolated from several medicinal plants, has been reported to possess anti-bacterial, anti-inflammatory and antitumor properties. Although berberine also inhibits osteoclastogenesis and bone resorption, the molecular machinery for its inhibitory effects remains unknown. This study focused on the suppressive effects of berberine on receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL)-induced osteoclastogenesis and survival. Berberine inhibited RANKL-mediated osteoclast formation and survival while having no cytotoxic effects on bone marrow macrophages or osteoblastic cells. Berberine attenuated RANKL-induced activation of NF-kappaB through inhibiting phosphorylation at the activation loop of IkappaBalpha kinase beta, phosphorylation and degradation of IkappaBalpha, and NF-kappaB p65 nuclear translocation. RANKL-induced Akt phosphorylation was strongly inhibited by berberine; however, neither monocyte/macrophage-colony stimulating factor (M-CSF)-induced nor insulin-induced Akt activation was inhibited by the drug. Under M-CSF- and RANKL-deprived condition, berberine increased the active form of caspase-3 in osteoclasts. By contrast, berberine did not potentiate the activation of caspase-3 in M-CSF-deprived bone marrow macrophages. These findings indicate that berberine inhibits osteoclast formation and survival through suppression of NF-kappaB and Akt activation and that both pathways in the osteoclast lineage are highly sensitive to berberine treatment.     

Descending facilitation in chronic stress and chronic pain state]

The spino-thalamic tract consists of two systems; the lateral system terminates in the somato-sensory cortex, and participates in the sensory discrimination of pain, and the medial system terminates in the anterior cingulated cortex (ACC) and insular cortex (IC) to mediate affective components of pain. Persistent pain induces plastic changes in cortical neurons, especially in the ACC and IC. Activation of these neurons is transmitted to the periaqueductal gray and rostroventromedial medulla (RVM) (descending pain control system). This system has long been considered to exert descending inhibition, but recent studies revealed that it also causes facilitation in certain pathological conditions. A variety of stressful stimuli have been shown to affect pain sensitivity. We demonstrated that chronic restraint stress induced thermal hyperalgesia in rats, in which phosphorylated ERK and levels of tryptophan hydroxylase, a key enzyme of 5-HT production, were increased in the RVM. 5HT released from the bulbospinal neurons may exert facilitatory effects on spinal nociceptive processing probably through 5HT3 receptors. Patients suffering chronic pain originating from deep tissues, such as temporo-mandibular disorder, fibromyalgia, or low back pain, often complain of pain and tenderness in various parts of the body. We injected complete Freund's adjuvant into a temporo-mandibular joint of rats unilaterally, and then injected 5% formalin into the ipsilateral or contralateral masseter muscle 2 weeks later. Pain-related behavior and neuronal activation in the spinal trigeminal nucleus were enhanced on both sides compared to those in non-inflammatory controls. Systemic enhancement of pain and hyperalgesia induced by unilateral joint inflammation may have been caused by the central sensitization and descending facilitation.     

Quantitative analysis of toxin extracts from various tissues of wild and cultured puffer fish by an electrophysiological method.

We observed the effects of the toxin extracted from various tissues of wild and cultured puffer fish on voltage-dependent sodium current (I(Na)) using single rat CA1 neurons, and compared the results with that of tetrodotoxin (TTX). Toxin extracts from wild puffer fish inhibited I(Na) in a dilution-dependent manner, and toxin extracts from liver or ovary produced 300 times greater inhibition than that from muscle, and corresponded to about 65 microg TTX/g tissue. We also used puffer fish cultured in net cages or in tanks set up on land, in an attempt to isolate them from the food chain. The toxin extracts from cultured puffer fish also suppressed I(Na), but the inhibition was much weaker, and the effects of toxin extracts were almost the same in all tissues examined including liver, ovary, muscle, etc. We calculated the maximum edible amount for each tissue, assuming that the lethal dose of TTX is 1-10 microg/kg, and we found that the liver or ovary was edible in the case of cultured puffer fish.     

Platelet count and indoor cold exposure among elderly people: A cross-sectional analysis of the HEIJO-KYO study

Background

Excess mortality from cardiovascular disease during cold seasons is a worldwide issue. Although some physiologic studies suggests that platelet activation via cold exposure may cause an increased incidence of cardiovascular disease in winter, the influence of indoor cold exposure in real-life situations on platelet (PLT) count remains unclear.