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This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders., European Archives of Psychiatry and Clinical Neuroscience, ISSN:0940-1334, ISSN:1433-8491

Melatonin (MLT) is widely used to treat sleep disorders although the underlying mechanism is still elusive. In mice, using wheel-running detection, we found that exogenous MLT could completely recover the period length prolonged by N-methyl-D-aspartate receptor (NMDAR) impairment due to the injection of the NMDAR antagonist MK-801, a preclinical model of psychosis. The analysis of the possible underlying mechanisms indicated that MLT could regulate the homeostatic state in the ventrolateral preoptic nucleus (VLPO) instead of the circadian process in the suprachiasmatic nucleus (SCN). In addition, our data showed that MK-801 decreased Ca2+ -related CaMKII expression and CREB phosphorylation levels in the VLPO, and MLT could rescue these intracellular impairments but not NMDAR expression levels. Accordingly, Gcamp6 AAV virus was injected in-vivo to further monitor intracellular Ca2+ levels in the VLPO, and MLT demonstrated a unique ability to increase Ca2+ fluorescence compared with MK-801-injected mice. Additionally, using the selective melatonin MT2 receptor antagonist 4-Phenyl-2-Propionamidotetralin (4P-PDOT), we discovered that the pharmacological effects of MLT upon NMDAR impairments were mediated by melatonin MT2 receptors. Using electroencephalography/electromyography (EEG/EMG) recordings we observed that the latency to the first non-rapid eye movement (NREM) sleep episode was delayed by MK-801, and MLT was able to recover this delay. In conclusion, exogenous MLT by acting upon melatonin MT2 receptors rescues sleep phase delayed by NMDAR impairment via increasing intracellular Ca2+ signaling in the VLPO, suggesting a regulatory role of the neurohormone on the homeostatic system.

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases.

Objectives Mental, personality and substance use disorders are over represented among prisoners and aggressive individuals. The psychopathological and biological markers linked to mental functioning remain still unclear. In particular, the role of trace elements in mental illness is still matter of debate. Here, we investigated whether trace elements are correlated to specific psychopathological phenotype groups. Methods Axis I and II disorders, aggression, impulsivity, adult attention deficit/hyperactivity disorders (ADHD) indices and serum levels of zinc, copper and cadmium were evaluated in 160 male prisoners. Results Using latent class analysis we could subdivide prisoners into three distinct psychopathological classes: Class 1 characterized by low prevalence of aggression, personality disorders and substance abuse/dependence (alcohol, cannabis, cocaine); Class 2 represented by low prevalence of aggression and high prevalence of personality disorders and substance abuse/dependence; Class 3 defined by high prevalence of aggression, personality disorders and substance abuse/dependence. Serum levels of zinc were higher in Class 2 and 3 compared to Class 1. Moreover, Class 3 was associated with higher scores of impulsivity and ADHD indices. Conclusion Our results suggest that impulsivity but also adult ADHD indices are related to aggressive behaviour, and higher zinc levels are linked to personality disorders and addictions, but not to aggression.

Objectives: About 50% of patients with unipolar depression suffer from treatment-resistant depression (TRD). Animal studies have suggested potential antidepressant properties of valproate (VPA) possibly due to its implication in epigenetic programming. Methods: Fourteen TRD patients (seven males and seven females; age 19-59) received VPA (375-1000 mg/day) in addition to their treatment regimen after previously failing to respond to two or more antidepressant trials and/or different combinations. Clinical response to VPA was investigated prior the treatment (T-0) and after 1 (T-1), 4 (T-4) and 7 (T-7) months of therapy using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI). Results: Compared to T-0, VPA significantly decreased MADRS score at T-1 (P < 0.001), T-4 (P < 0.001) and T-7 (P < 0.001) (partial η2=0.86). Importantly, MADRS score at T-7 (13.6 ± 1.6, mean ± SEM) was closer to the reported value of remission (MADRS

Patients with treatment-resistant unipolar depression (TRD) are treated with antidepressant combinations (ADs) or with second-generation antipsychotics plus AD (SGA+AD) augmentation; however, the clinical characteristics, the factors associated independently with response to SGA+AD, and the outcome trajectories have not yet been characterized. We performed a naturalistic study on the latest stable trial (medication unchanged for about 3 months) in 86 TRD patients with resistance to at least two ADs trials, who received ADs (n=36) or SGA+AD (n=50) treatments. Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton-Depression Rating Scale (HAM-D17), and other scales were administered before (T0) and after the latest 3-month stable trial (T3). Compared to ADs, the SGA+AD group showed increased percentage of depression with psychotic features, comorbidity for personality disorders and substance use disorders (SUD), higher number of failed ADs pharmacotherapies and depressive symptoms at T0 on all scales (P

Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.

Melatonin (MLT) is a neurohormone implicated in several physiological processes such as sleep. Contrasting results have been produced on whether or not it may act as a hypnotic agent, and the neurobiological mechanism through which it controls the vigilance states has not yet been elucidated. In this study we investigated the effect of MLT (40 mg/kg), a non-selective MT1/MT2 receptor agonist (UCM793, 40 mg/kg), and a selective MT2 partial agonist (UCM924, 40 mg/kg) on the 24-h vigilance states. EEG and EMG sleep-wake patterns were registered across the 24-h light-dark cycle in adult Sprague-Dawley male rats. MLT decreased (-37%) the latency to the first episode of non rapid eye movement sleep (NREMS), enhanced the power of NREMS delta band (+33%), but did not alter the duration of any of the three vigilance states. Differently, UCM793 increased the number of episodes (+52%) and decreased the length of the episodes (-38%) of wakefulness but did not alter the 24-h duration of wakefulness, NREMS and REMS. UCM924 instead reduced the latency (-56%) and increased (+31%) the duration of NREMS. Moreover, it raised the number of REMS episodes (+57%) but did not affect REMS duration. Taken together, these findings show that MLT and non-selective MT1/MT2 receptor agonists do not increase the quantity of sleep but differently influence the three vigilance states. In addition, they support the evidence that selective MT2 receptor agonists increase NREMS duration compared to MLT and non-selective MT1/MT2 agonists.

Background Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT1 (MEL1a) and MT2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT1 and MT2 receptors. Here we have reviewed current knowledge about the implications of MT2 receptors in brain functions.

The pharmacological potential of targeting selectively melatonin MT1 or MT2 receptors has not yet been exploited in medicine. Research using selective MT1/MT2 receptor ligands and MT1/MT2 receptor knockout mice has indicated that the activation of MT2 receptors selectively increases non-rapid eye movement (NREM) sleep whereas MT1 receptors seem mostly implicated in the regulation of REM sleep. Moreover, MT1 knockout mice show an increase in NREM sleep, while MT2 knockout a decrease, suggesting an opposite role of these two receptors. A recent paper in mice by Sharma et al (J Pineal Res, 2018, e12498) found that MT1 but not MT2 receptors are expressed on orexin neurons in the perifornical lateral hypothalamus (PFH). Moreover, after injecting melatonin or luzindole into the mouse PFH, the authors suggest that melatonin promotes NREM sleep because activates PFH MT1 receptors, which in turn inhibit orexin neurons that are important in promoting arousal and maintaining wakefulness. In this commentary, we have critically commented on some of these findings on the bases of previous literature. In addition, we highlighted the fact that no conclusions could be drawn on the melatonin receptor subtype mediating the effects of melatonin on sleep because the authors used the non-selective MT1/MT2 receptors antagonist luzindole. More solid research should further characterize the pharmacological function of these two melatonin receptors in sleep.

Melatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G-protein coupled receptors, MT1 and MT2. In this review, we present the analgesic properties of MLT in preclinical and clinical studies, giving particular emphasis to the effects mediated by MT2 receptors and to recent investigations demonstrating the analgesic effects of MT2 receptor partial agonists in chronic and acute/inflammatory pain conditions. MT2 receptors are localized in specific brain areas, including the reticular and the ventromedial nuclei of the thalamus (part of the ascending nociceptive pathway) and the ventrolateral periaqueductal grey matter (vlPAG) (part of the descending antinociceptive pathway). MLT displays analgesic properties in several animal paradigms of chronic, acute, inflammatory and neuropathic pain; importantly, these effects are mediated by MT2 receptors since they are blocked by selective MT2 antagonists. In different pain paradigms, UCM924 and UCM765, two selective MT2 receptor partial agonists, produce analgesic effects with higher potency than MLT, thus confirming the involvement of MT2 receptors in pain. Notably, these compounds do not induce sedation and motor impairments. Although their analgesic mechanism of action is not yet completely elucidated, they act on antinociceptive descending pathways by stimulating MT2 receptors on glutamatergic neurons of the vlPAG, which in turn activate OFF cells and inhibit ON cells of the rostral ventromedial medulla (RVM). Collectively, there is strong preclinical evidence suggesting the pharmacological potential of MT2 receptor partial agonists, which also have a favorable toxicological profile. These compounds may be further developed as novel analgesic drugs.

OBJECTIVE: The pathogenesis of hot flushes involves several brain neurotransmitter systems, and changes in serotonin turnover have been hypothesized. Veralipride is an anti-dopaminergic agent that relieves hot flushes and putatively also modulates serotonergic neurons. To further elucidate this relationship, in the present study we evaluated whether administration of veralipride for relief of hot flushes is able to affect serum levels of the serotonin precursor tryptophan in postmenopausal women.METHODS: Twenty-four postmenopausal women were randomly assigned to receive veralipride (100 mg/day) or similar placebo tablets for 3 months (n = 12 per group). Free tryptophan and total tryptophan (free + protein-bound) levels were assayed before and monthly by high pressure liquid chromatography. Data were analyzed with repeated measures ANOVA and Student-Newman-Keuls post hoc test.RESULTS: Relief of hot-flushes was achieved with complete suppression of symptoms after veralipride, but not placebo, treatment. In the veralipride group, total tryptophan levels significantly (p < 0.05) decreased from baseline (11.2 +/- 0.4 microg/ml) to 3 months (8.0 +/- 0.3 microg/ml), as well as free tryptophan concentrations (baseline 2.1 +/- 0.1 microg/ml; after 3 months 1.3 +/- 0.1 microg/ml; p < 0.05). No changes were recorded in the placebo group.CONCLUSION: Women treated with veralipride for relief of menopausal symptoms show a decrease in serum levels of serotonin precursors, suggesting that the brain serotonergic system may be involved in the pathogenesis of postmenopausal vasomotor symptoms.

The most effective treatment of chronic hepatitis C (HCV) available to date is represented by interferon-α (IFN-α), alone or in combination with ribavirin. However, the therapy presents adverse effects, including depressive symptoms. As IFN-α can cause an alteration of the tryptophan metabolism and a consequent reduced synthesis of serotonin, we have designed a study aimed to investigate the effect of IFN-α therapy on the serum levels of tryptophan and on the development of depression in patients affected by the hepatitis C virus. Nine patients with HCV were enrolled while treated with IFN-α2a (3 MU thrice/week) plus ribavirin (15 mg/kg/day) for six months. All patients were evaluated by a hepatologist and received two self-administered scales [Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS)]. Blood samples were collected before treatment and at one month and six months of therapy. Tryptophan, 5-hydroxytryptophan and serotonin were analysed by HPLC with a spectrofluorometric detector. In all cases, a significant decrease of serum tryptophan concentrations from baseline (17.60 ± 1.08 mg/ml) to one month (13.94 ± 1.18 mg/ml) and six months (12.68 ± 0.64 mg/ml) with an increase of symptoms of depression was obtained, whereas 5-hydroxytryptophan and serotonin levels did not show any variation during the therapy from baseline values. The preliminary results suggest that IFN-α plays a role in serum tryptophan reduction and the development of depressive symptoms.

The contents of protein and non-protein (free and protein-bound) tryptophan and of proteins in the flours of nine legume seeds were determined. Lupins and soybeans showed the highest protein concentrations, followed by groundnuts, beans, broad beans, lentils, vetches, chick-peas, and peas. Protein tryptophan content is higher in soybeans and lower in peas (502 and 192 mg/100 g of dry flour, respectively) than in the other legumes, which also contain non-protein tryptophan. Chick-peas show the highest value of free tryptophan and groundnuts the lowest (58.2 and 2.24 mg/100 g of dry flour, respectively). Tryptophan appears to be bound to water-soluble proteins and to proteins soluble at pH 8.9. In particular, chick-peas contain a high amount of tryptophan bound to water-soluble proteins, followed by beans. The results are evaluated, considering the importance, not only of protein, but also non-protein tryptophan, for assessing the nutritive value of a protein in foods.

The possible role of melatonin in melanogenesis was investigated by performing reactions of melatonin with peroxidase + H2O2 or H2O2 only, in the presence or absence of UV irradiation. Samples of the reaction mixtures were drawn at different times (from 15 to 480 min), the enzyme (when present) was removed by ultrafiltration and the samples so obtained were analyzed by MALDI/MS. The results show that melatonin undergoes oligomerization reaction with peroxidase + H2O2, leading to heptameric species. For high reaction times the MALDI/MS data do not show the formation of larger oligomers, but UV-vis spectroscopy indicates that the oligomerization processes proceed. The failure of MALDI-TOF in the identification of larger oligomers was related to the chemical-physical and morphological behavior of melanins. In the case of UV irradiation, the formation of species originating from the O- and O2 addition to melatonin, which activate new oligomerization channels, has been observed.

In order to investigate the role of tryptophan and its metabolites in biogenesis of melanins, a study on the enzymatic reaction of 3-hydroxykynurenine with tyrosinase and peroxidase was performed. The reaction at different pH values was monitored by sampling at different times, with ultrafiltration used before analysis by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The data obtained in this way showed that oligomerization processes take place with both enzymes, but with different behaviour, also depending on pH. 3-Hydroxykynurenine in the presence of tyrosinase at pH 6.0 leads to formation of xanthommatin, and at pH 8.0 hydroxanthommatin is formed in the first step of the reaction followed by formation of black-brown pigments. In contrast, the formation of oligomerization products by peroxidase action is observed in high yields under both acidic and basic conditions; however, at pH 6.0, a more extensive oligomerization process is observed. Thus peroxidase is able to activate oligomerization analogous to that observed in the case of tyrosinase without depending on the variation of pH. Due to the early formation of decarboxylated hydroxykynurenine, hydroxanthommatin and decarboxylated hydroxanthommatin, the enzymatic reaction leads to mixed oligomers, which can be considered as precursors of new pathways in pigment production.

Patients experiencing mental disorders are at an elevated risk for developing aggressive behavior. In the past 10 years, the psychopharmacological treatment of aggression has changed dramatically owing to the introduction of atypical antipsychotics on the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients.This review (second of 2 parts) uses a translational medicine approach to examine the neurobiology of aggression, discussing the major neurotransmitter systems implicated in its pathogenesis (serotonin, glutamate, norepinephrine, dopamine, and γ-aminobutyric acid) and the neuropharmacological rationale for using atypical antipsychotics, anticonvulsants, and lithium in the therapeutics of aggressive behavior. A critical review of all clinical trials using atypical antipsychotics (aripiprazole, clozapine, loxapine, olanzapine, quetiapine, risperidone, ziprasidone, and amisulpride), anticonvulsants (topiramate, valproate, lamotrigine, and gabapentin), and lithium are presented. Given the complex, multifaceted nature of aggression, a multifunctional combined therapy, targeting different receptors, seems to be the best strategy for treating aggressive behavior. This therapeutic strategy is supported by translational studies and a few human studies, even if additional randomized, double-blind, clinical trials are needed to confirm the clinical efficacy of this framework.

The bark of several coniferous species, a waste product of the timber industry, contains significant amounts of natural antioxidants. In our ongoing studies of Nepalese medicinal plants, we examined the bark from Abies spectabilis as the starting material for extracting antioxidant compounds. In vitro antioxidant activity evaluated by means of three antioxidant methods, namely 2,2-diphenyl-1-picrylhydrazyl (DPPH), Briggs-Rauscher oscillating reaction (BR) and Trolox Equivalent Antioxidant Capacity (TEAC) and total phenol contents with the Folin-Ciocalteau reagent; the ferrous iron chelating capacity was also assessed. The methanol extract of A. spectabilis showed significant antioxidant activity and polyphenol contents (IC 50 4.13 µg/mL, 0.20 μg/mL eq. resorcinol, 4.22 mM eq. Trolox, 3.9 µg/g eq. gallic Acid in the DPPH, BR, TEAC and Folin-Ciocalteau tests, respectively) and weak Fe 2+ chelating capacity. Phytochemical studies were also carried out with 1D- and 2D NMR experiments and DI-ESI-MS, HPLC-DAD and LC-MSn measurements. Oligomeric C-type proanthocyanidins, mainly trimeric gallocatechin derivatives, were the most abundant compounds (16% of extract expressed as procyanindin B1). Gallocatechin oligomers (up to six units) and prodelphynidin-gallocatechin polymers were also identified in the extract. Prodelphynidin B4, cyclograndisolide and trans-docosanil ferulate were also isolated and characterized by NMR and MS spectroscopy.

The water-soluble protein profile of the seeds of green, red, and yellow Theobroma cacao L. fruits has been determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS). The seeds were powdered under liquid nitrogen and defatted. The residues were dialyzed and lyophilized. The obtained samples were suspended in the matrix solution of sinapinic acid. The obtained MALDI mass spectra showed the presence of a wide number of proteins with molecular weight ranging from 8000 to 13 000 Da and a cluster of peaks centered at 21 000 Da that were attributed to albumin. The abundance of this peak was found to depend on the different portion of the seed (husk, apical and cortical parts); however, the MALDI mass spectra obtained from the different varieties of cocoa were practically superimposable. Changes in the protein profiles were also observed after the cocoa seeds were treated by fermentation and roasting, which are processes usually employed for the commercial production of cocoa.

The currently recommended therapy for chronic hepatitis C (HCV) is a combination of pegylated interferon-alpha (PEG-IFN alpha) and ribavirin. Psychiatric disorders, including depression, are frequent in HCV patients under therapy. We investigated the effect of the antiviral treatment on tryptophan (Trp) metabolism along both serotonin pathway (via 5-hydroxytryptophan, 5-HTP) and kynurenine (Kyn) pathway and on the onset of depressive symptoms in patients with HCV. The key enzyme of the Kyn pathway is indoleamine 2,3-dioxygenase (IDO), an intracellular haem protein enzyme expressed in several tissues. It was also investigated the influence of the therapy with PEG-IFN-alpha-2a or PEG-IFN-alpha-2b plus oral ribavirin and possible differences between genders. Free and total Trp, 5-hydroxytryptophan (5-HTP) and Kyn serum concentrations and the presence of depressive symptoms [Beck Depression Inventory (BDI) scores] were evaluated in 45 patients with HCV infection treated with PEG-IFN alpha-2a or -2b at four different times: baseline (before treatment), 1 and 6 months during therapy, and 3 months after the end of therapy. The concentration of serum total TRP (free + protein bound) as well as that of 5-HTP significantly decreased after 1 and 6 months of therapy, and then returned to baseline values 3 months after the end of therapy, while the levels of free TRP did not vary significantly during and after the therapy. On the contrary, the time course of Kyn markedly arose during treatment, paralleled by a significant increase of [Kyn/Trp] × 10 3 ratio, an index used to measure IDO activity. No significant difference was detected between males and females neither between PEG-IFN-alpha-2a or -2b treatment. The BDI scores significantly increased during therapy, and returned to baseline values 3 months after the end of therapy. Our results support the hypothesis that the increased IDO-mediated tryptophan metabolism along the Kyn pathway, leading to plasma Trp depletion and a decline of serotonin pathway, concurs to the development of depressive symptoms observed in HCV patients undergoing IFN-alpha therapy. © 2010 Elsevier Masson SAS. All rights reserved.

Centella asiatica (L.) Urban is widely used in traditional medicine in many countries and in the formulation of drugs and cosmetics, and is therefore suitable as a trade item for the development of medicinal plants for the population of Nepal. The aim of this work was to select plant populations of C. asiatica with high contents of secondary metabolites growing in various localities in Nepal, and to enhance knowledge of the cultivation of this plant. Quali-quantitative analysis of bioactive triterpenes (asiaticoside and asiatic acid) and phenol derivatives (flavonoids and caffeoyl esters) was performed by HPLC-DAD-ELSD. The highest quantities of triterpenes and phenols were found in samples from the Gorkha and Chitwan districts. Regarding cultivated plants, soil fertilisation is critical, since over-rich soils affect secondary metabolite content. Plants growing in sand-rich soils produce more terpenes. This work provides indications on how to select high-terpene producing germplasm and recommendations for plant cultivation.

The composition of the essential oil of Lindera neesiana Kurz fruit was examined by GC-MS, (1)H, (13)C and bidimensional NMR techniques (HMQC, HMBC, COSY, TOCSY). Forty compounds were identified, representing approximately 86% of the oil: Z-citral (15.08%), E-citral (11.89%), eucalyptol (8.75%), citronellal (6.72%), alpha-pinene (6.63%) and beta-pinene (5.61%) were the major components. The essential oil of L. neesiana fruit showed significant antimicrobial activity against Staphylococcus aureus and Candida albicans at non-cytotoxic doses in human keratinocytes, suggesting possible topical applications. GRAPHICAL ABSTRACT: The essential oil of Lindera neesiana was investigated by GC-MS and NMR techniques. Its biological activities suggest possible topical applications.

One new glycoside derivative from syringic acid and one new phenol glycoside, curculigoside E (1) and orchioside D (2), were isolated and characterized from the rootstock of Curculigo orchioides collected in the Nawalparasi District (Nepal). The structures of the new isolated compounds were elucidated by means of spectroscopic methods such as 1D, 2D NMR and MS.

In this paper we report the study of tryptophan metabolism via serotonin in ventricular CSF in HIV-1 infection in order to investigate the origin of tryptophan metabolites in the human brain. The patients (n=4) were affected with non-communicating hydrocephalus. One of these also was suffering from HIV-1 infection. The CSF was withdrawn from different sites of the cerebral cavity with a neuroendoscopic procedure which allows an accurate exploration of all the cerebral ventricles. The measurement of tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin was carried out by HPLC with fluorometric detection. In HIV-1 infection the highest concentration of tryptophan is present in the CSF of the choroid plexus; however, the levels are markedly lower than those in hydrocephalic individuals (control group). 5-Hydroxytryptophan CSF content is higher in HIV-1 infection than in hydrocephalic controls in all districts examined. Regarding serotonin, a great difference appears in the choroid plexus and in the pituitary recess between the HIV-1 infected patient and the control group. The values of 5-hydroxyindoleacetic acid are much lower in the CSF of the HIV-1 infected patient than in hydrocephalic controls. Melatonin levels appear to fluctuate largely but, in the HIV-1 infection, a great variability is present among the sites of CSF withdrawal. The third ventricle contains the highest concentration of melatonin and the choroid plexus and the pituitary recess the lowest. All the melatonin concentrations in HIV-1 infection are largely different than in hydrocephalic controls. This is the first report on the measurement of tryptophan metabolites via serotonin in ventricular CSF in HIV-1 infection.

Background: Melancholic depression, described also as endogenous depression, is a mood disorder with distinctive specific psychopathological features and biological homogeneity, including anhedonia, circadian variation of mood, psychomotor activation, weight loss, diurnal cortisol changes, and sleep disturbances. Although several hypotheses have been proposed, the etiology of this disorder is still unknown. Methods: Behavioral, electrophysiological and biochemical approaches were used to characterize the emotional phenotype, serotonergic and noradrenergic electrical activity, and corticosterone in melatonin MT1 receptor knockout mice and their wild type counterparts, during both light and dark phases. Results: Melatonin MT1 receptor knockout mice have decreased mobility in the forced swim and tail suspension tests as well as decreased sucrose consumption, mostly during the dark/inactive phase. These mood variations are reversed by chronic treatment with the tricyclic antidepressant desipramine. In addition, MT1 receptor knockout mice exhibit psychomotor disturbances, higher serum levels of corticosterone the dark phase, and a blunted circadian variation of corticosterone levels. In vivo electrophysiological recordings show a decreased burst-firing activity of locus coeruleus norepinephrine neurons during the dark phase. The circadian physiological variation in the spontaneous firing activity of high-firing neuronal subpopulations of both norepinephrine neurons and dorsal raphe serotonin neurons are abolished in MT1 knockout mice. Conclusions: These data demonstrate that melatonin MT1 receptor knockout mice recapitulate several behavioral and neurobiological circadian changes of human melancholic depression and, for the first time, suggest that the MT1 receptor may be implicated in the pathogenesis of melancholic depression and is a potential pharmacological target for this mental condition.

The activity of tyrosinase and peroxidase +H(2)O(2) in promoting melanogenesis from tryptophan (Trp) and 7-hydroxytryptophan (7-HTP) has been investigated. The reaction samples have been drawn at different reaction times and analysed by MALDI mass spectrometry.The data obtained showed that tryptophan undergoes, under tyrosinase and peroxidase action, an oligomerization process mainly due to the reaction of anthranilic acid (AA) and Trp. However, analysing the UV and fluorescence data, it is seen that the oligomers cannot belong to the melanin pattern, but their possible role in melanogenesis is not to be excluded. Once it reacts with the two enzymes, 7-hydroxytryptophan leads to dark brown products, indicating its possible role in melanin production. In contrast to what was observed in the case of 5-hydroxytryptophan, for which oligomers were constituted by 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) units, the MALDI data indicate a sharply different behaviour for 7-HTP. In fact, in the case of 5-hydroxytryptophan, oligomerization takes place through the formation of 5-hydroxytryptamine and the oligomerization products are due to mixed 5-HTP-5-HT oligomers. In the case of 7-hydroxytryptophan, the formation of 7-hydroxytryptamine (7-HT) is also observed, but it does not seem to play any role; the only oligomerization products formed are due to the reaction of 7-hydroxytryptophan and AA. The data so obtained indicate that 7-hydroxytryptophan acts like an effective melanin precursor in the presence of both tyrosinase and peroxidase +H(2)O(2).

The aim of this study was to investigate in vitro the variations with age of the activities of the two antioxidant enzymes Cu/Zn-superoxide dismutase (SOD) and indole 2,3-dioxygenase (IDO) in metabolically active tissues of rats of various ages. In rats aged one week and 2-3 months the highest Cu/Zn-SOD activity was found in the liver and the lowest in the small intestine. At 12 and 18 months of age, the activity was higher in the brain and kidneys, when compared to the small intestine, lungs and liver. Cu/Zn-SOD activity decreased significantly after 2-3 months of age with advancing age in all tissues examined. In newborn rats IDO activity was present only in the small intestine. In the group of rats aged 2-3 months, the highest specific activity was observed in the small intestine and the lowest in the lungs and kidneys, whereas at 12 months of age, the highest IDO activity was found in the brain, with kidneys presenting the lowest activity. At 18 months, IDO returned to be more elevated in the small intestine. At 12 months of age the values of IDO in the tissues varied slightly, while at 18 months similar activities were found between the lungs and brain and between the small intestine and kidneys. In relation to age, IDO specific activity declined in the small intestine, after 2-3 months of age. In the lungs, the activity remained unchanged; in the brain and in the kidneys activity decreased significantly from 2-3 to 18 months of age. In conclusion, this study demonstrates an age-related decline in Cu/Zn-SOD and IDO activities, the two enzymes responsible for scavenging O2*-.

Neuroendoscopy has achieved extensive acceptance among neurosurgeons as a minimally invasive technique for the treatment of patients affected by blocked hydrocephalus. During endoscopic procedures minimal CSF amounts from selected anatomic sites of the ventricles can be withdrawn. Steerable endoscopes are used and their flexibility facilitates the aspiration of CSF during the preliminary inspection through the ventricular cavities, without any interference with the surgical actions or additional risks for the patients. In this preliminary study the concentrations of melatonin and other related metabolites in the lateral ventricles, third ventricle, pineal recess and infundibular recess were examined. The data obtained from a patient affected by blocked hydrocephalus confirmed a constant and significant difference of concentration of these substances, for instance, melatonin levels were found to be much higher in the third ventricle (542 pg/mL in its centre) than in the lateral ventricle (172 pg/mL in the right ventricle). Nevertheless, instead of what we would expect, the highest melatonin concentrations were not found in the pineal recess (438 pg/mL). In the future, neuroendoscopy, beside its evident therapeutic efficacy, could open new perspectives in the study of both CSF biochemistry and physiology, allowing a highly selective approach to the various substances which are released and float in it.