In the present study, the anti-stress effects of yeast hydrolysate (YH) were investigated. The YH consisted of crude carbohydrate (23.6%) and crude protein (68.3%) with low contents of crude ash (3.1%) and crude fat (0.3%). Also, acidic amino acids (glutamic acid + aspartic acid) were present in large quantities (14.2 and 5.0 mol%, respectively). Pronase digestion had little effect on the affinity of the YH on 5-hydroxytryptamine (serotonin) and norepinephrine transporters, whereas NaIO(4) oxidation of the hydrolysate decreased the affinity by about 10% at 1,000 microg/mL, indicating that the periodate-labile carbohydrate moiety played a leading role in the affinity effects of the carbohydrate in YH As a result of brain mapping after the administration of the YH for 3 days in human subjects, a symmetrical distribution of theta and alpha waves in the central and parietal lobes was observed. This brain mapping pattern of theta and alpha wave distribution appears in a psychologically stable state. The YH groups showed improvements in Beck Depression Inventory and Beck Anxiety Inventory scores after YH administration for 2 weeks. Treatment also seemed to have a more significant (P < .05) impact on the somatic manifestations of anxiety as indexed by the Beck Anxiety Inventory scores. Food materials used as a source of YH have been found to be associated with increases in alertness and adaptation to stress. less...

Rett syndrome caused by mutations in Mecp2 gene shows abnormalities in autonomic functions in which brainstem norepinephrinergic systems play an important role. Here we present systematic comparisons of intrinsic membrane properties of locus coeruleus (LC) neurons between Mecp2( horizontal line /Y) and wild-type (WT) mice. Whole-cell current clamp was performed in brain slices of 3-4 week-old mice. Mecp2( horizontal line /Y) neurons showed stronger inward rectification and had shorter time constant than WT cells. The former was likely due to over-expression of Kir4.1 channel, and the latter was attributable to the smaller cell surface area. The action potential duration was prolonged in Mecp2( horizontal line /Y) cells with an extended rise time. This was associated with a significant reduction in the voltage-activated Na(+) current density. Following action potentials, over 60% Mecp2( horizontal line /Y) neurons displayed fast and medium afterhyperpolarizations (fAHP and mAHP), while nearly 90% WT neurons showed only mAHP. The mAHP amplitude was smaller in Mecp2( horizontal line /Y) neurons. The firing frequency was higher in neurons with mAHP, and the frequency variation was greater in cells with both fAHP and mAHP in Mecp2( horizontal line /Y) mice. Small but significant differences in spike frequency adaption and delayed excitation were found in Mecp2( horizontal line /Y) neurons. These results indicate that there are several electrophysiological abnormalities in LC neurons of Mecp2( horizontal line /Y) mice, which may contribute to the dysfunction of norepinephrine system in the central nervous system. less...

The vascular system secretes many bioactive factors. In a gene chip database, we searched for novel genes with signal sequences that are specifically expressed in murine aorta, and focused on one gene previously named CCDC3 (NCBI nucleotide entry NM_028804). Northern blot analysis revealed that CCDC3 was expressed abundantly in the aorta and adipose tissues. The mRNA levels of CCDC3 were higher in adipose tissues of obese db/db mice than control mice, and induced during differentiation of rat primary adipocytes. In differentiated adipocytes, CCDC3 mRNA expression was enhanced by insulin and pioglitazone, a PPARgamma agonist, and suppressed by TNF-alpha, isoproterenol and norepinephrine. Transient expression experiments followed by N-terminal amino acid sequence analysis revealed secretion of CCDC3 protein into the culture medium, which was dose-dependently reduced by brefeldin A, an inhibitor of Golgi-mediatedsecretory pathway. When expressed in COS-7 cells, CCDC3 protein was post-transcriptionally modified with N-glycosylation, and formed a dimer complex. These results indicate that CCDC3 is a protein secreted by adipocytes and endothelial cells, and that its level is regulated both hormonally and nutritionally. less...

Previous studies suggest that noradrenaline may regulate serotonergic (5-HT) neurotransmission at the serotonin cell body and noradrenaline nerve terminal. Using microdialysis coupled to HPLC, we investigated the effects of alpha1-adrenoceptor manipulation on extracellular serotonin levels - in the ventral hippocampus, prefrontal cortex, and raphe nuclei - in the presence or absence of the serotonin reuptake inhibitor (SSRI), citalopram. Extracellular 5-HT levels from prefrontal cortex, ventral hippocampus and raphe nuclei were markedly increased following citalopram administration (3.0 mg/kg s.c.). In the prefrontal cortex and ventral hippocampus, local blockade of the alpha1-adrenoceptor (3.0muM prazosin infusion) significantly decreased this citalopram-induced increase in serotonin, while cirazoline (alpha1-adrenoceptor agonist) and reboxetine (noradrenaline reuptake inhibitor) further increased extracellular serotonin levels when administered systemically (0.02mg/kg i.p. and 5.0 mg/kg s.c. respectively) or locally infused (10.0muM and 1.0muM respectively). Moreover, prazosin pre-infusion into terminal areas prevented the increase in citalopram-induced increase in serotonin levels with systemic cirazoline or reboxetine administration. Prazosin also decreased the citalopram-induced increase in serotonin levels in the raphe nuclei; however no enhancement of the SSRI response was observed with systemic or local administration of cirazoline or reboxetine, suggesting that alpha1-adrenoceptors may already be maximally activated under these conditions. These data provide strong evidence that after acute citalopram administration, the alpha1-adrenoceptor exerts a modulatory role on serotonin levels. less...

The phylogenetic relationship between the relict leopard frog Lithobates (Rana) onca (Cope,1875) and the lowland leopard frog Lithobates (Rana) yavapaiensis (Platz and Frost, 1984) is unclear. Chromatographic analysis of norepinephrine-stimulated skin secretions from L. onca led to the identification of six peptides with antimicrobial activity. Determination of their primary structures indicated that four of the peptides were identical to brevinin-1Ya, brevinin-1Yb, brevinin-1Yc and ranatuerin-2Ya previously isolated from skin secretions of L. yavapaiensis. However, a peptide belonging to the temporin family (temporin-ONa: FLPTFGKILSGLF.NH(2)) and an atypical member of the ranatuerin-2 family containing a C-terminal cyclic heptapeptide domain (ranatuerin-2ONa: GLMDTVKNAAKNLAGQMLDKLKC KITGSC) were isolated from the L. onca secretions but were not present in the L. yavapaiensis secretions. Ranatuerin-2ONa inhibited the growth of Escherichia coli (MIC=50muM) and Candida albicans (MIC=100muM ) and showed hemolytic activity (LC(50)=90muM) but was inactive against Staphylococcus aureus. The data indicate a close phylogenetic relationship between L. onca and L. yavapaiensis but suggest that they are not conspecific species. less...

Androgens appear to enhance whereas estrogens mitigate cardiac hypertrophy. However, signaling pathways in cells for short (3 minute) and longer-term (48 hour) treatment with 17beta-estradiol (E2) or 5alpha-dihydrotestosterone (DHT) are understudied. We compared the effect of adrenergic stimulation by norepinephrine (NE, 1 muM) alone or in combination with DHT (10nM) or E2 (10nM) treatment in neonatal rat ventricular myocytes (NRVMs) by cell area, protein synthesis, sarcomeric structure, gene expression, phosphorylation of extracellular signal-regulated (ERK) and focal adhesion (FAK) kinases, and phospho-FAK nuclear localization. NE alone elicited the expected hypertrophy, and strong sarcomeric organization, DHT alone gave a similar but more modest response whereas E2 did not alter cell size. Effects of NE dominated when used with either E2 or DHT with all combinations. Both sex hormones alone rapidly activated FAK but not ERK. Long-term or brief exposure to E2 attenuated NE-induced FAK phosphorylation whereas DHT had no effect. Neither hormone altered NE-elicited ERK activation. Longer-term exposure to E2 alone reduced FAK phosphorylation and reduced nuclear phospho-FAK whereas its elevation was seen in the presence of NE with both sex hormones. The mitigating effects of E2 on NE-elicited increase in cell size and hypertrophic effect of DHT in NRVMs are in accordance with results observed in whole animal models. This is the first report of rapid, non-genomic sex hormone signaling via FAK activation and altered FAK trafficking to the nucleus in heart cells. Key words: nuclear cytoplasmic shuttle, focal adhesion kinase, sarcomere organization, rapid hormone response. less...

Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days, 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha(1)-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in alpha(2)-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a LOSS of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD. less...

Antidepressant and antipsychotic drugs, predominantly serotonin and/or norepinephrine reuptake inhibitors and dopamine D2-antagonizing antipsychotic compounds, have several limitations. In addition, the exact pathophysiological mechanism leading to serotonergic, noradrenergic and dopaminergic dysfunction in psychotic disorders remains unclear. It has been postulated that an inflammatory mechanism may be involved in the pathogenesis of both depression and psychotic disorders. Furthermore, the differential activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and of the tryptophan/kynurenine metabolic pathway, resulting in the increased production of kynurenic acid in schizophrenia, and a possible increase in quinolinic acid in depression, also may play a key role in these diseases. Such differences are associated with an imbalance in glutamatergic neurotransmission that may contribute to increased levels of NMDA agonism in depression and NMDA antagonism in schizophrenia. In addition, immunological imbalance results in the increased production of PGE2 in schizophrenia and depression, as well as increased COX-2 expression in schizophrenia. Although there is evidence supporting the hypothesis that interactions between immune system components, IDO, the serotonergic system and glutamatergic neurotransmission play a key role in schizophrenia and depression, several gaps in knowledge remain, such as regarding the role of genetics, disease course, gender and different psychopathological states. There is evidence indicating that anti-inflammatory therapy may have beneficial effects in schizophrenia and major depression (MD). COX-2 inhibitors have been tested in animal models and in preliminary clinical trials, demonstrating favorable activity compared with placebo, both in schizophrenia and MD. However, the effects of COX-2 inhibition in the CNS, as well as toward different components of the inflammatory system, kynurenine metabolism and glutamatergic neurotransmission, require further evaluation, which should include clinical trials with larger numbers of patients. The potential inflammatory mechanism in schizophrenia and MD, and the possible therapeutic advantages of targeting this mechanism in the treatment of these disorders is discussed in this review. less...

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nm) and selective (>50-fold) alpha2A-adrenoceptor antagonist (KB=7.9 nm). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain. less...

Chronic activation of the sympathetic nervous system is a key component of cardiac hypertrophy and fibrosis. However, previous studies have provided evidence that also implicate inflammatory cells, including mast cells (MCs), in the development of cardiac fibrosis. The current study investigated the potential interaction of cardiac MCs with the sympathetic nervous system. Eight-week-old male spontaneously hypertensive rats were sympathectomized to establish the effect of the sympathetic nervous system on cardiac MC density, myocardial remodeling, and cytokine production in the hypertensive heart. Age-matched Wistar Kyoto rats served as controls. Cardiac fibrosis and hypertension were significantly attenuated and left ventricular mass normalized, whereas cardiac MC density was markedly increased in sympathectomized spontaneously hypertensive rats. Sympathectomy normalized myocardial levels of interferon-gamma, interleukin 6, and interleukin 10, but had no effect on interleukin 4. The effects of norepinephrine and substance P on isolated cardiac MC activation were investigated as potential mechanisms of interaction between the two. Only substance P elicited MC degranulation. Substance P was also shown to induce the production of angiotensin II by a mixed population of isolated cardiac inflammatory cells, including MCs, lymphocytes, and macrophages. These results demonstrate the ability of neuropeptides to regulate inflammatory cell function, providing a potential mechanism by which the sympathetic nervous system and afferent nerves may interact with inflammatory cells in the hypertensive heart. less...