Sulfur Metabolism and Sulfur-Containing Amino Acids Derivatives – II: Autism Spectrum Disorders, Schizophrenia and Fibromyalgia

The metabolism of sulfur (S) compounds concurs to the maintain of cell homeostasis and tissue integrity in the human body. Sulfur chemical species act in all cells as anti-oxidant/scavenging agents or regulators of membrane stability/excitability. At the same time, they also exert tissue-dependent functions behaving as protective molecules of the liver and cardiovascular system, as modulators of the immune response, gut activity and CNS neurotransmitter signaling. The involvement of S compounds in human complex, chronic, disabling diseases at multifaceted pathogenesis is actually under investigation: altered levels of S metabolites could be in fact bio-indicators of impaired oxidation state in the body and their unbalance could be risk factors for disease onset. By the present review, we will discuss data from the literature which unearth an altered S biochemistry in human complex illnesses, taking as an example highly invalidating neuropsychiatry and pain perception diseases as autism spectrum disorders (ASD), schizophrenia and fibromyalgia. As well, we will depict herein the utility at applying to this area of the clinical research high resolving -omics strategies in combination with methodological tools which specifically explore S metabolism in patients. The perspectives of these kind of analyses would be the adoption of more valuable, personalized therapeutics protocols and, possibly, an improved bio-monitoring of patients, also including their response to treatments

Parkinson’s Disease and Alpha-Synucleinopathies: from Arising Pathways to Therapeutic Challenge

Parkinson’s Disease (PD) and alpha synucleinopathies are multifactorial disorders, which manifest through motor symptoms and non-motor symptoms involving the Central Nervous System (CNS), the Peripheral Nervous System (PNS) and, recently, also the Enteric Nervous System (ENS). The typical hallmarks of alpha synucleinopathies are proteinaceous inclusions of alpha synuclein (αS). In PD they are known as Lewy Bodies (LBs) and Lewy Neurites (LNs), discovered in dopaminergic neurons of substantia nigra (pars compacta) as well as in other regions of the central and peripheral nervous systems. Despite the clear causes which lead to LBs/LNs are still unknown, according to Braak’s theory, these inclusions appear first in PNS to spread, following neuronal innervation, towards the CNS in a spatio- temporal dissemination described in a staging procedure. In line with these observations, several animal models have been used with the purpose to reproduce PD as well as to propose new therapeutic approaches. Different pathways can cooperate to neurodegeneration in PD such as genetic mutations of αS gene, mitochondrial dysfunctions, neuroinflammation. The present review highlights αS as the key-word for PD pathology and alpha synucleinopathies and a main target in PD research. Several therapeutic approaches can be proposed, however all of them are addressed in advanced stages of the pathology. Our focus will be the alteration of αS physiological pathway, which allows to address therapy in early stages at intracellular or extracellular level, such as the use of anti ER-stress compounds and innovative immunotherapy, which could be promising tools to reduce neuronal degeneration and to halt PD progression

Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans

L-Tryptophan is the unique protein amino acid (AA) bearing an indole ring: its biotransformation in living organisms contributes either to keeping this chemical group in cells and tissues or to breaking it, by generating in both cases a variety of bioactivemolecules. Investigations on the biology of Trp highlight the pleiotropic effects of its small derivatives on homeostasis processes. In addition to protein turn-over, in humans the pathways of Trp indole derivatives cover the synthesis of the neurotransmitter/hormone serotonin (5-HT), the pineal gland melatonin (MLT), and the trace amine tryptamine. The breakdown of the Trp indole ring defines instead the “kynurenine shunt” which produces cell-response adapters as L-kynurenine, kynurenic and quinolinic acids, or the coenzyme nicotinamide adenine dinucleotide (NAD+). This reviewaims therefore at tracing a “map” of themainmolecular effectors in human tryptophan (Trp) research, starting from the chemistry of this AA, dealing then with its biosphere distribution and nutritional value for humans, also focusing on some proteins responsible for its tissue-dependent uptake and biotransformation.We will thus underscore the role of Trp biochemistry in the pathogenesis of human complex diseases/syndromes primarily involving the gut, neuroimmunoendocrine/stress responses, and the CNS, supporting the use of -Omics approaches in this field

Brain-Derived Neurotrophic Factor (BDNF) and Serotonin Transporter (SERT) in Platelets of Patients with Mild Huntington’s Disease: Relationships with Social Cognition Symptoms

Peripheral biological correlates of early-stage Huntington’s disease (HD) are currently attracting much interest given their possible use as prognostic predictors of later neurodegeneration. Since deficits in social-cognition processing are present among the initial disease symptoms, aim of this work was to appraise, in blood platelets, Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HT) transporter (SERT), two proteins involved in human adaptive behavior as potential biochemical correlates of such disabilities in mild-HD. Thirteen gene positive and symptomatic patients (9M/4W, HD-stage II, age> 40y) together 11 gender/age matched controls without a concurrent diagnosis of psychiatric disorders, underwent a blood test to determine BDNF storage and membrane-bound SERT in platelets by ELISA immune-enzyme and [3H]-paroxetine ([3H]-PAR) binding assays, respectively. Concomitantly, all subjects were examined through a battery of socio-cognitive and emotion recognition questionnaires. Results showed moderately increased intra-platelet BDNF amounts (+20-22%) in patients versus controls, whereas [3H]-PAR binding parameters, maximum density (Bmax) and dissociation constant (KD), did not appreciably vary between the two groups. While patients displaying significantly reduced cognitive/emotion abilities, biochemical parameters and clinical features or psychosocial scores did not correlate each other, except for platelet BDNF and the illness duration, positively correlated, or for SERT KDs and angry voice recognition ability, negatively correlated in both controls and patients. Therefore, in this pilot investigation, platelet BDNF and SERT did not specifically underlie psychosocial deficits in stage II-HD. Higher platelet BDNF storage in patients showing lasting-mild symptoms would derive from compensatory mechanisms. Thus, supplementary investigations are warranted by also comparing patients in other illness’s phases

Region-dependent effects of flibanserin and buspirone on adenylyl cyclase activity in the human brain

The mode of action of antidepressant drugs may be related to mechanisms of receptor adaptation, involving overall the serotonin 1A (5-HT1A) receptor subtype. However, so far, the clinical effectiveness of selective compounds acting at this level has proved disappointing. This could be explained by the heterogeneity of 5-HT1A receptors within the central nervous system. In animals, two 5-HT1A agonists, flibanserin and buspirone, have shown different pharmacological properties, depending on the brain region. Since no evidence supports this observation in humans, this study sought to investigate whether these two drugs exert different effects on 5-HT1A receptor activation in three different human brain areas: the prefrontal cortex, hippocampus and raphe nuclei. 5-HT1A-mediated inhibition of forskolin-stimulated adenylyl cyclase (AC) was taken as an index of 5-HT1A receptor activation. Flibanserin significantly reduced the activity of AC post-synaptically, i.e. in the prefrontal cortex [EC50 (mean +/- S.E.M.), 28 +/- 10.2 nM; Emax, 18 +/- 2.3%] and in the hippocampus (EC50, 3.5 +/- 3.1 nM; Emax, 20 +/- 4.0%), but had no effect in the raphe nuclei, i.e. at pre-synaptic level. Vice versa, buspirone was only slightly but significantly effective in the raphe (EC50, 3.0 +/- 2.8 nM; Emax, 12 +/- 1.9%). Agonist effects were sensitive to the 5-HT1A antagonists WAY-100135 and pindobind 5-HT1A in the cortex and raphe nuclei, whereas buspirone antagonized flibanserin in the hippocampus. These findings suggest a region-related action of flibanserin and buspirone on forskolin-stimulated AC activity in human brain

Melatonin and pro-hypnotic effectiveness of the antidepressant Trazodone: A preliminary evaluation in insomniac mood-disorder patients

Objective To preliminary investigate the link between the darkness hormone melatonin (MLT) and the pro-hypnotic effectiveness of the atypical antidepressant Trazodone (TRZ) in a group of mood disorder patients suffering of insomnia. Design and methods The study's design comprised: i) the enrolment of insomniac outpatients, ii) baseline (t0) psychiatric and biochemical examinations; iii) the subsequent patients' introduction into a treatment with TRZ for 3–4 weeks, followed by post-therapy re-evaluations (t1). The MLT function was investigated by t0/t1 ELISA determinations of 6-hydroxy-MLT sulfate (6-OH-MLTs) levels in early-morning urines and HPLC analysis of morning MLT serum amount. Concomitantly, TRZ and its metabolite m-chloro-phenylpiperazine (m-CPP) were measured by HPLC in serum to monitor patients' compliance/metabolism. Results Seventeen insomniac outpatients, displaying mild symptoms of depression/anxiety resistant to antidepressants, completed TRZ therapy (dose:10–20 mg/day, bedtime). Serum TRZ levels (127 ± 57 ng ml− 1, mean ± SD) confirmed patients' compliance, while the anxiogenic metabolite m-CPP resulting almost undetectable. Moreover, the 6-OH-MLTs output was found increased at t1 vs. baseline values (t1: 58.4 ± 45.02 ng ml− 1; t0: 28.6 ± 15.8 ng ml− 1; mean ± SD, P < 0.05) in 9 patients who recovered both insomnia and depression/anxiety (P < 0.01). Unresponsive subjects showed instead no post-therapy 6-OH-MLTs variation (t1: 48.53 ± 50.70 ng ml− 1; t0: 49.80 ± 66.53 ng ml− 1). Morning MLT in serum slightly diminished at t1 without reaching the statistical significance, not allowing therefore to define the patients' outcome. Conclusions This initial investigation encourages to explore MLT networks as possible correlates of TRZ pro-hypnotic responses

The expression of platelet serotonin transporter (SERT) in human obesity

Serotonin (5-HT) is a well-known modulator of eating behavior. However, the molecular mechanisms linking its action to body weight balance have been only partially elucidated. Since platelets are a suitable peripheral model to study 5-HT transport, metabolism and release, we herein evaluated the expression of the platelet 5-HT re-uptake system (SERT) by [3H]-paroxetine binding assay. A cohort of 114 unrelated individuals (34 males, 80 females; age, mean +/- SD: 38.57 +/- 12.47 years) without major psychiatric disorders, was recruited following a naturalistic design regarding age or gender and classified accordingly to their body mass index (BMI). Subjects were divided into 5 groups: normal-weight (NW), overweight (OW) and grade I-III obese (OB) individuals. For gender analyses, data were transformed into [3H]-paroxetine density (Bmax)/BMI ratios to overcome both the disparity of women vs. men number and anthropometric differences between sexes.[3H]-paroxetine Bmax (SERT density, fmol/mg proteins) was reduced in platelet membranes of grade II (p &lt; 0.01) and III (p &lt; 0.001) obese subjects vs. controls and in overweight subjects (p &lt; 0.05) vs. grade III obese individuals. Considering all patients together, a strong negative correlation between Bmax and BMI (r = -0.449; P &lt; 0.0001) was demonstrated. Conversely, [3H]-paroxetine KD (dissociation constant, nM) did not differ among groups. No gender-related variation concerning Bmax/BMI ratios was observed in this cohort of subjects.The down-regulation of SERT in platelet membranes of severe human obesity (BMI &gt; 35 Kg/m2) confirms the involvement of 5-HT system in body weight gain. Moreover, this findings may help to elucidate those monoamine-endocrine networks acting on fat storage, adipocyte signaling and energy balance. Targeting 5-HT/5-HT-related markers will possibly uncover the existence of human obesity subtypes

Serotonin transporter (SERT) and translocator protein (TSPO) expression in the obese ob/ob mouse

Background: An ever growing body of evidences is emerging concerning metabolism hormones, neurotransmitters or stress-related biomarkers as effective modulators of eating behavior and body weight in mammals. The present study sought at examining the density and affinity of two proteins related to neurotransmission and cell metabolism, the serotonin transporter SERT and the cholesterol import-benzodiazepine site TSPO (translocator protein), in a rodent leptin-lacking mutant, the obese ob/ob mouse. Binding studies were thus carried out in brain or peripheral tissues, blood platelets (SERT) and kidneys (TSPO), of ob/ob and WT mice supplied with a standard diet, using the selective radiochemical ligands [(3)H]-paroxetine and [(3)H]-PK11195. Results: We observed comparable SERT number or affinity in brain and platelets of ob/ob and WT mice, whilst a significantly higher [(3)H]-PK11195 density was reported in the brain of ob/ob animals. TSPO binding parameters were similar in the kidneys of all tested mice. By [(3)H]-PK11195 autoradiography of coronal hypothalamic-hippocampal sections, an increased TSPO signal was detected in the dentate gyrus (hippocampus) and choroids plexus of ob/ob mice, without appreciable changes in the cortex or hypothalamic-thalamic regions. Conclusions: These findings show that TSPO expression is up-regulated in cerebral regions of ob/ob leptin-deficient mice, suggesting a role of the translocator protein in leptin-dependent CNS trophism and metabolism. Unchanged SERT in mutant mice is discussed herein in the context of previous literature as the forerunner to a deeper biochemical investigation

Depression, Insomnia and Atypical Antidepressants

A high incidence of people suffering from depression displays a disrupted sleep and, in particular, insomnia. Persistent loss of sleep can significantly worsen the quality of life and prognosis of patients, by even increasing their risk of relapses and suicidality. Moreover, an ever emerging issue in the management of depressed patients is the possible arise of poor sleep during an antidepressant treatment. This is essentially due to the complex interweave between mood and sleep physiology, which can make considerably difficult to apply suitable diagnoses and interventions for psychiatrists and physicians. Beside behavioral/psychotherapy approaches, pro-hypnotic drugs are considered preferential overall for treating geriatric depressive patients with insomnia or cases showing refractory poor-quality sleep. Among elective pro-hypnotic compounds, some second generation and atypical antidepressants, acting on multiple pharmacological targets, have been found the most effective and better tolerated for these patients. In this book chapter, we will thus present some aspects of the neurobiology of sleep, its interlace with mood tonus, as well as sleep disruptions present in depression subtypes, also in respect to their onset as an antidepressant side-effect. Afterwards, we will discuss the effectiveness and advantages of atypical antidepressants on hypnotic and antidepressant responses, overall on those acting on the serotonin and melatonin systems, together our specific aims in this search field. A deeper knowledge of the mechanisms of action of these drugs could indeed elucidate, on the one hand, the physiopathology of sleep, while, on the other, would better define their targeted uses in the clinical practice