Current Neuropharmacology (v.9, #2)

The paraventricular nucleus (PVN) of the hypothalamus has been described as the "autonomic master controller".It co-ordinates critical physiological responses through control of the hypothalamic-pituitary-adrenal (HPA)-axis, and bymodulation of the sympathetic and parasympathetic branches of the central nervous system. The PVN comprises severalanatomical subdivisions, including the parvocellular/ mediocellular subdivision, which contains neurones projecting to themedulla and spinal cord. Consensus indicates that output from spinally-projecting sympathetic pre-autonomic neurones(SPANs) increases blood pressure and heart rate, and dysfunction of these neurones has been directly linked to elevatedsympathetic activity during heart failure. The influence of spinally-projecting SPANs on cardiovascular function highlightstheir potential as targets for future therapeutic drug development. Recent studies have demonstrated pharmacologicalcontrol of these spinally-projecting SPANs with glutamate, GABA, nitric oxide, neuroactive steroids and a number ofneuropeptides (including angiotensin, substance P, and corticotrophin-releasing factor). The underlying mechanism ofcontrol appears to be a state of tonic inhibition by GABA, which is then strengthened or relieved by the action of othermodulators. The physiological function of spinally-projecting SPANs has been subject to some debate, and they may beinvolved in physiological stress responses, blood volume regulation, glucose regulation, thermoregulation and/or circadianrhythms. This review describes the pharmacology of PVN spinally-projecting SPANs and discusses their likely roles incardiovascular control.

The Dopaminergic System in Peripheral Blood Lymphocytes: From Physiology to Pharmacology and Potential Applications to Neuropsychiatric Disorders by Francesca R. Buttarelli, Alessandra Fanciulli, Clelia Pellicano, Francesco E. Pontieri (278-288).
Besides its action on the nervous system, dopamine (DA) plays a role on neural-immune interactions. Here wereview the current evidence on the dopaminergic system in human peripheral blood lymphocytes (PBL). PBL synthesizeDA through the tyrosine-hydroxylase/DOPA-decarboxylase pathway, and express DA receptors and DA transporter(DAT) on their plasma membrane. Stimulation of DA receptors on PBL membrane contributes to modulate the developmentand initiation of immune responses under physiological conditions and in immune system pathologies such asautoimmunity or immunodeficiency.The characterization of DA system in PBL gave rise to a further line of research investigating the feasibility of PBL as acellular model for studying DA derangement in neuropsychiatric disorders. Several reports showed changes of the expressionof DAT and/or DA receptors in PBL from patients suffering from several neuropsychiatric disorders, in particularparkinsonian syndromes, schizophrenia and drug- or alcohol-abuse. Despite some methodological and theoretical limitations,these findings suggest that PBL may prove a cellular tool with which to identify the derangement of DA transmissionin neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatments.

Here, we show that volume neurotransmission and the redox property of dopamine, as well as redox-regulatedprocesses at glutamate receptors, can contribute significantly to our understanding of schizophrenia. Namely, volumeneurotransmission may play a key role in the development of dysconnectivity between brain regions in schizophrenicpatients, which can cause abnormal modulation of NMDA-dependent synaptic plasticity and produce local paroxysmsin deafferented neural areas. During synaptic transmission, neuroredox regulations have fundamental functions, whichinvolve the excellent antioxidant properties and nonsynaptic neurotransmission of dopamine. It is possible that the effectof redox-linked volume neurotransmission (diffusion) of dopamine is not
Keywords: as exact as communication by the classicalsynaptic mechanism so approaching the study of complex schizophrenic mechanisms from this perspective maybe beneficial. However, knowledge of redox signal processes, including the sources and molecular targets of reactivespecies, is essential for understanding the physiological and pathophysiological signal pathways in cells and the brain, aswell as for pharmacological design of various types of new drugs.

Oxidative Stress in Schizophrenia by Marija Boskovic, Tomaz Vovk, Blanka Kores Plesnicar, Iztok Grabnar (301-312).
Increasing evidence indicates that oxidative damage exists in schizophrenia. Available literature about possiblemechanisms of oxidative stress induction was reviewed. Furthermore, possibilities of measuring biomarkers of schizophreniaoutside the central nervous system compartment, their specificity for different types of schizophrenia and potentialtherapeutic strategies to prevent oxidative injuries in schizophrenia were discussed. Data were extracted from publishedliterature found in Medline, Embase, Biosis, Cochrane and Web of Science, together with hand search of references.Search terms were: schizophrenia, oxidative stress, antipsychotics, antioxidants and fatty acids. Finding a sensitive,specific and non invasive biomarker of schizophrenia, which could be measured in peripheral tissue, still stays animportant task. Antioxidant enzymes, markers of lipid peroxidation, oxidatively modified proteins and DNA aremost commonly used. As it considers the supplemental therapy, according to our meta-analysis vitamin E couldpotentially improve tardive dyskinesia, while for the effect of therapy with polyunsaturated fatty acids there is noclear evidence. Oxidative stress is a part of the pathology in schizophrenia and appears as a promising field to developnew therapeutic strategies. There is a need for well designed, placebo controlled trials with supplementation therapy inschizophrenia.

During the past decades Neural Stem Cells have been considered as an alternative source of cells to replacelost neurons and NSC transplantation has been indicated as a promising treatment for neurodegenerative disorders. Nevertheless,the current understanding of NSC biology suggests that, far from being mere spare parts for cell replacementtherapies, NSCs could play a key role in the pharmacology of neuroprotection and become protagonists of innovativetreatments for neurodegenerative diseases. Here, we review this new emerging concept of NSC biology.

Context: Currently, the keyword ‘BDNF’ retrieves 7388 publications in Pubmed, which point to many directions.Objective: This paper aims to uncover patterns that are hidden under this huge mass of studies and then to review the mostprominent sub-topics in ‘BDNF and mental health’.Method: Several semi-automatic tools employed, in order to present: 1. A visual representation of BDNF’s main molecularpathways; 2. A table with all the components of this pathway that are known to be associated with human diseases; 3. Aconceptual map of the whole literature; 4. A histogram of the mental disorders that are known to be associated withBDNF, as well as a review of the literature on each one of these topics.Results: The conceptual map suggests that the field is divided in two major sections: BDNF molecular pathways, receptors,other neurotrophins and neurotransmitters; and BDNF-related disorders. Among the latter, the mental disorders thatare mostly related to BDNF are: depression, schizophrenia, Parkinson disease, Alzheimer disease, and bipolar disorder.

Circadian disruptions are common in modern society, and there is an urgent need for effective treatmentstrategies. According to standard diagnostic criteria, most adolescents showing both insomnia and daytime sleepiness arediagnosed as having behavioral-induced sleep efficiency syndrome resulting from insomnia due to inadequate sleephygiene. However, a simple intervention of adequate sleep hygiene often fails to treat them. As a solution to this clinicalproblem, the present review first overviews the basic neurochemical and neuropharmachological aspects of sleep andcircadian rhythm regulation, then explains several circadian disruptions from similar viewpoints, and finally introducesthe clinical notion of asynchronization. Asynchronization is designated to explain the pathophysiology/pathogenesis ofexhibition of both insomnia and hypersomnia in adolescents, which comprises disturbances in various aspects of biologicalrhythms. The major triggers for asynchronization are considered to be a combination of light exposure during thenight, which disturbs the biological clock and decreases melatonin secretion, as well as a lack of light exposure in themorning, which prohibits normal synchronization of the biological clock to the 24-hour cycle of the earth and decreasesthe activity of serotonin. In the chronic phase of asynchronization, involvement of both wake- and sleep-promotingsystems is suggested. Both conventional and alternative therapeutic approaches for potential treatment of asynchronizationare suggested.

Nuclear Factor κB and Adenosine Receptors: Biochemical and Behavioral Profiling by Vickram Ramkumar, Krishna A. Jhaveri, Xiaobin Xie, Sarvesh Jajoo, Linda A. Toth (342-349).
Adenosine is produced primarily by the metabolism of ATP and mediates its physiological actions by interactingprimarily with adenosine receptors (ARs) on the plasma membranes of different cell types in the body. Activationof these G protein-coupled receptors promotes activation of diverse cellular signaling pathways that define their tissuespecificfunctions. One of the major actions of adenosine is cytoprotection, mediated primarily via two ARs - A1 (A1AR)and A3 (A3AR). These ARs protect cells exposed to oxidative stress and are also regulated by oxidative stress. Stressmediatedregulation of ARs involves two prominent transcription factors - activator protein-1 (AP-1) and nuclear factor(NF)-κB - that mediate the induction of genes important in cell survival. Mice that are genetically deficient in thep50 subunit of NF-κB (i.e., p50 knock-out mice) exhibit altered expression of A1AR and A2AAR and demonstrate distinctbehavioral phenotypes under normal conditions or after drug challenges. These effects suggest an important role forNF-κB in dictating the level of expression of ARs in vivo, in regulating the cellular responses to stress, and in modifyingbehavior.

Medical Management of Parkinson’s Disease: Focus on Neuroprotection by Marie-Catherine Boll, Mireya Alcaraz-Zubeldia, Camilo Rios (350-359).
Neuroprotection refers to the protection of neurons from excitotoxicity, oxidative stress and apoptosis asprincipal mechanisms of cell loss in a variety of diseases of the central nervous system. Our interest in Parkinson’s disease(PD) treatment is focused on drugs with neuroprotective properties in preclinical experiments and evidence-based efficacyin human subjects. To this date, neuroprotection has never been solidly proven in clinical trials but recent adequate markersand/or strategies to study and promote this important goal are described. A myriad of compounds with protectiveproperties in cell cultures and animal models yield to few treatments in clinical practice. At present, markers of neuronalvitality, disease modifying effects and long term clinical stability are the elements searched for in clinical trials. This reviewhighlights new strategies to monitor patients with PD. Currently, neuroprotection in subjects has not been solidlyachieved for selegiline and pramipexole; however, a recent rasagiline trial design is showing new indications of diseasecourse modifying effects. In neurological practice, it is of utmost importance to take into account the potential neuroprotectionexerted by a treatment in conjunction with its symptomatic efficacy.

There is growing evidence that the env genes of two or more human endogenous retroviruses (HERVs) ofthe W family are contributing to the inflammatory processes, and thus to the pathogenesis, of multiple sclerosis (MS).Increasing understanding of the human endogenous retroviral locus, ERVWE1, and the putative multiple sclerosisassociated retrovirus, or MSRV, and in particular of the HERV-W env sequences associated with these, offers thepotential of new lines of pharmacological research that might assist diagnosis, prognosis and therapy of multiple sclerosis.

Evidence links dopamine release in the mid-brain to the pathophysiology of psychosis, addiction and reward.Repeated ingestion of refined carbohydrate may stimulate the same mesolimbic dopaminergic pathway, rewarding sucheating behaviour and resulting in excessive food intake along with obesity. In this paper, we explore the role of dopaminein reward and psychosis, and discuss how reward pathways may contribute to the weight gain that commonly followsantipsychotic drug use, in people with psychotic illness. Our theory also explains the frequent co-occurrence of substanceabuse and psychosis. From our hypothesis, we discuss the use of carbohydrate modified diets as an adjunctive treatmentfor people with psychosis.

Kynurenine Metabolites and Migraine: Experimental Studies and Therapeutic Perspectives by Annamaria Fejes, Arpad Pardutz, Jozsef Toldi, Laszlo Vecsei (376-387).
Migraine is one of the commonest neurological disorders. Despite intensive research, its exact pathomechanismis still not fully understood and effective therapy is not always available. One of the key molecules involved in migraineis glutamate, whose receptors are found on the first-, second- and third-order trigeminal neurones and are also present inthe migraine generators, including the dorsal raphe nucleus, nucleus raphe magnus, locus coeruleus and periaqueductalgrey matter. Glutamate receptors are important in cortical spreading depression, which may be the electrophysiologicalcorrelate of migraine aura.The kynurenine metabolites, endogenous tryptophan metabolites, include kynurenic acid (KYNA), which exerts ablocking effect on ionotropic glutamate and 7-nicotinic acetylcholine receptors. Thus, KYNA and its derivatives mayact as modulators at various levels of the pathomechanism of migraine. They can give rise to antinociceptive effects at theperiphery, in the trigeminal nucleus caudalis, and may also act on migraine generators and cortical spreading depression.The experimental data suggest that KYNA or its derivatives might offer a novel approach to migraine therapy.

Glutamate excitotoxicity contributes to a variety of disorders in the central nervous system, which is triggeredprimarily by excessive Ca2+ influx arising from overstimulation of glutamate receptors, followed by disintegration of theendoplasmic reticulum (ER) membrane and ER stress, the generation and detoxification of reactive oxygen species as wellas mitochondrial dysfunction, leading to neuronal apoptosis and necrosis. Kainic acid (KA), a potent agonist to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate class of glutamate receptors, is 30-fold more potent in neurotoxicitythan glutamate. In rodents, KA injection resulted in recurrent seizures, behavioral changes and subsequent degenerationof selective populations of neurons in the brain, which has been widely used as a model to study the mechanisms of neurodegenerativepathways induced by excitatory neurotransmitter. Microglial activation and astrocytes proliferation arethe other characteristics of KA-induced neurodegeneration. The cytokines and other inflammatory molecules secreted byactivated glia cells can modify the outcome of disease progression. Thus, anti-oxidant and anti-inflammatory treatmentcould attenuate or prevent KA-induced neurodegeneration. In this review, we summarized updated experimental data withregard to the KA-induced neurotoxicity in the brain and emphasized glial responses and glia-oriented cytokines, tumornecrosis factor-α, interleukin (IL)-1, IL-12 and IL-18.