bluuebunny/crossref_metadata_2025 huggingface dataset:
The risk and interval to malignancy of patients with laryngeal dysplasia; a systematic review of case series and meta‐analysis
Authors: Weller M.D. , Nankivell P.C. , McConkey C. , Paleri V. , Mehanna H.M.
Published: July 2010

Clin. Otolaryngol. 2010, 35, 364–372

Background:  Laryngeal dysplasia is a pre‐malignant condition with wide variability in rates of malignant transformation reported in the literature. The management and follow‐up strategies of these lesions vary widely.

Objectives:  To assess the risk of and interval to malignant transformation in patients with laryngeal dysplasia, the effect of different treatment modalities on malignant transformation and the effects that risk factors such as smoking, excessive alcohol intake and histological grade may have on this.

Type of review:  Systematic of observational studies with attempted meta‐analysis.

Search strategy:  A structured search of Medline (1966 to January 2010), EMBASE (1980 to January 2010), CINAHL (1981 to January 2010) and Cochrane databases (CENTRAL, Cochrane Library, 1995 to January 2010).

Results:  Nine hundred and forty cases from nine studies were included in the analysis. Overall malignant transformation rate was 14% (confidence interval 8, 22) and mean time to malignant transformation was 5.8 years. The malignant transformation rate is higher with increased severity of dysplasia grade – severe/CIS 30.4%versus mild/moderate 10.6% (P < 0.0002). Treatment modality did not show significant effects.

Conclusions:  Laryngeal dysplasia carries a significant risk of malignant transformation. This risk triples with increasing severity of dysplasia. Transformation often occurs late and is not related to the grade of dysplasia. There is little evidence, therefore, to support the early discharge of patients with mild/moderate dysplasia, which is practised by some clinicians.
Mitochondrial Membrane Permeabilization during the Apoptotic Process
Authors: JACOTOT ETIENNE , COSTANTINI PAOLA , LABOUREAU ERIC , ZAMZAMI NAOUFAL , SUSIN SANTOS A. , KROEMER GUIDO
Published: July 2010

Apoptosis may be viewed as a triphasic process. During the pre‐mitochondrial initiation phase, very different pro‐apoptotic signal transduction or damage pathways can be activated. These pathways then converge on the mitochondrion, where they cause the permeabilization of the inner and/or outer membranes with consequent release of soluble intermembrane proteins into the cytosol. The process of mitochondrial membrane permeabilization would constitute the decision/effector phase of the apoptotic process. During the post‐mitochondrial degradation phase downstream caspases and nucleases are acticated and the cell acquires an apoptotic morphology. Recently, a number of different second messengers (calcium, ceramide derivatives, nitric oxide, reactive oxygen species) and pro‐apoptotic proteins (Bax, Bak, Bid, and caspases) have been found to directly compromise the barrier function of mitochondrial membranes, when added to isolated mitochondria. The effects of several among these agents are mediated at least in part via the permeability transition pore complex (PTPC), a composite channel in which members of the Bcl‐2 family interact with sessile transmembrane proteins such as the adenine nucleotide translocator. These findings suggest that the PTPC may constitute a pharmacological targer for chemotherapy and cytoprotection.
Apoptosis‐related Functional Features of the DNaseI‐like Family of Nucleases
Authors: LIU QING Y. , RIBECCO MARIA , PANDEY SIYARAM , WALKER P. ROY , SIKORSKA MARIANNA
Published: July 2010

Rat DNaseY b and its human homolog DHP2 are members of a new family of DNaseI‐like endonucleases. They contain all the conserved amino acid residues to engage a DNaseI‐like catalytic activity and the same molecular mechanisms of DNA hydrolysis. The sequence similarity can be extended to other families of nucleases, such as FEN‐1, DNA polymerases, RNaseH and exonuclease III, involved in the ion‐dependent hydrolysis of nucleic acids. Their unique features include the NLS signals that place them in the nucleic and a high content of positively charged amino acid residues that results in their high affinity for the substrate. Their properties are consistent with a role in the early stage DNA degradation during apoptosis. The caspase‐DFF45/CIDE‐CPAN pathway is most likely involved in the second stage of internucleosomal DNA degradation. However, cells express constitutively multiple transcripts encoding DNA degrading enzymes and related molecules, hence they have the molecular diversity to engage the self‐destructive pathway appropriate to a given trigger.
The Molecular Mechanism of Programmed Cell Death in C. elegans
Authors: LIU QIONG A. , HENGARTNER MICHAEL O.
Published: July 2010

Programmed cell death or apoptosis plays a fundamental role during animal development, metamorphosis, and tissue homeostasis. It is a genetically controlled physiological process that comprises two distinct and sequential processes: the death of cells, and their subsequent removal by engulfing cells. In the nematode C. elegans, genetic studies led to the discovery of 15 genes that function in programmed cell death 1 (Fig. 1). These 15 genes have been divided into four groups based on the order of their activity during the process of programmed cell death: (1) those involved in the decision making (ces‐1 and ces‐2); (2) in the process of execution (ced‐3, ced‐4, ced‐9 and egl‐1); (3) in the engulfment of dying cells by engulfing cells (ced‐1, ced‐2, ced‐5, ced‐6, ced‐7, ced‐10, ced‐12); and (4) those in the degradation of cell corpses within engulfing cells (nuc‐1). In the last five years, several genes in the genetic pathway of programmed cell death have been shown to be conserved across a wide range of species; all genes involved in the step of execution in C. elegans have their corresponding mammalian homologs (Fig. 2). Furthermore, emerging evidence from molecular studies of engulfment genes in several species suggests that the signaling process from apoptotic cells to engulfing cells and the subsequent engulfment process might be also conserved across species (Table 1).

The genetic pathway for programmed cell death in C. elegans. In the nematode C. elegans, genetic studies led to the discovery of 15 genes related to programmed cell death. These 15 genes have been divided into four groups based on the order of their activity during the process of programmed cell death: ces‐1 and ces‐2 are involved in the decision making, ced‐3, ced‐4, ced‐8, ced‐9, and egl‐1 in the process of execution, ced‐1, ced‐2, ced‐5, ced‐6, ced‐7, and ced‐10 in the engulfinent of dying cells by engulfing cells, and nuc‐1 in the degradation of cell corpses within engulfing cells. Adapted from reference 1.

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Conservation of the execution step in the genetic pathway for programmed cell death. In C. elegans, the execution step in the genetic pathway for programmed cell death comprises four genes, ced‐3, ced‐4, ced‐9, and egl‐1. All of these genes have their corresponding mammalian homologs: CED‐9 is a member of the Bcl‐2 family, CED‐3 is a caspase family member, CED‐4 is homologous to the Apaf‐ 1 protein, and EGL‐1 is similar in structure to Bid and other BH3 domain only‐containing proteins. In Drosophila, reaper, hid, and grim are required for the apoptotic cell death and might act upstream of the Drosophila caspases, drICE, DREDD, and DCP‐1. The homologs of reaper, hid, and grim in other species have not been identified. Similarly, the homologs of EGL‐1, CED‐4 and CED‐9 in Drosophila have not been found.

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Evolutionary conservation of engulfment genesa

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Hyperoxia‐induced Cell Death in the Lung‐the Correlation of Apoptosis, Necrosis, and Inflammation
Authors: MANTELL LIN L. , HOROWITZ STUART , DAVIS JONATHAN M. , KAZZAZ JEFFREY A.
Published: July 2010

Prolonged exposure to hyperoxia causes tissue damage in many organs and tissues. Since the entire surface area of lung epithelium is directly exposed to O2and other inhaled agents, hyperoxia leads to the development of both acute and chronic lung injuries. These pathologic changes in the lung can also be seen in acute lung injury (ALI) in response to other agents. Simple strategies to mitigate hyperoxia‐induced ALI might not be effective by virtue of merely reducing or augmenting the extent of apoptosis of pulmonary cells. Identification of the specific cell types undergoing apoptosis and further understanding of the precise timing of the onset of apoptosis may be necessary in order to gain a greater understanding of the connection between apoptosis and tolerance to hyperoxia and ALI. Attention should also be focused on other forms of non‐apoptotic programmed cell death.
Programmed Cell Death as a Mechanism of CD4 and CD8 T Cell Deletion in AIDS: Molecular Control and Effect of Highly Active Anti‐retroviral Therapy
Authors: GOUGEON MARIE‐LISE , MONTAGNIER LUC
Published: July 2010

Infection with human immunodeficiency virus (HIV) results in the progressive destruction of CD4 T lymphocytes, generally associated with progression of the disease. The progressive disappearance of CD4 T lymphocytes leads to the lack of control of HIV replication and to the development of severe immune deficiency responsible for the occurrence of opportunistic infections associated with AIDS. In this review we discuss premature lymphocyte apoptosis in the context of HIV infection as the consequence of the continuous production of viral proteins, leading to an unbalanced immune activation and to the triggering of apoptotic programs. The chronic immune activation induces the continuous expression of death factors which could turn lymphocytes, including CD4 T cells, CD8 CTL or APC, into effectors of apoptosis, leading to the destruction of healthy activated non‐infected cells. Thus, programmed cell death would significantly contribute to peripheral T cell depletion in AIDS, particularly if the Th cell renewal is impaired. Under potent anti‐retroviral therapies, a complete normalization of lymphocyte apoptosis is observed, concomitant with a partial restoration of the number and the functions of the immune system.
The Proopiomelanocortin System
Authors: HADLEY MAC E. , HASKELL‐LUEVANO CARRIE
Published: July 2010

ABSTRACT: POMC (31,000 MW) is localized to the pituitary, brain, skin, and other peripheral sites. The particular enzyme profile present within a cell dictates the nature of the hormonal ligand (melanocortin) synthesized and secreted: melanotropic peptides (α‐MSH β‐lipotropin, λ‐MSH), corticotropin (ACTH), several endorphins (e.g., met‐enkephalin). These POMC‐derived peptides mediate their actions through typical seven‐spanning membrane receptors (MCRs; MCR1, 2, 3, 4, and 5). A specific melanocortin acting on a specific MCR regulates a particular biological response; for example, α‐MSH on MCR1 increases melanogenesis within melanocytes, ACTH on MCR2 increases cortisol production within adrenal zona fasciculata cells. Within the brain melanocortins regulate satiety (MCR4) and erectile activity (MCR?). MCRs have been localized by melanocortin macromolecular probes, for example, fluorescent to human epidermal melanocytes and also to keratinocytes, suggesting that systemic melanocortins or localized POMC products might regulate these integumental cellular elements in synchrony to enhance skin pigmentation and/or immunological responses. Superpotent, prolonged acting melanotropic peptides have been synthesized and their application in clinical medicine has been demonstrated. MCR antagonists have been used to discover and further delineate other roles of melanocortin ligands. For example, melanocortin‐induced satiety can be antagonized by a melanocortin antagonist. Defects in melanocortin ligand biosynthesis, secretion, and melanocortin receptor function can lead to a diverse number of pathological states.
POMC‐Derived Peptides and Their Biological Action
Authors: SOLOMON SAMUEL
Published: July 2010

ABSTRACT:It has long been known that a large number of POMC‐related peptides are found in skin. In this introduction I describe the formation of POMC‐derived peptides in various tissues to indicate that processing is largely tissue‐dependent. I focus on the peptides from the N‐terminal fragment, such as γ‐MSH, ACTH and α‐MSH, and β‐lipopropin as well as β‐endorphin. I touch on the factors that control the synthesis of the various peptides, which are now numerous and varied, and again are tissue specific. The biologic activity of the peptides generated from POMC are described in relation to their possible action in skin. In addition, I describe a new class of peptides induced in skin following injury and which are of great interest.
Synthetic Melanocortin Receptor Agonists and Antagonists
Authors: LERNER MICHAEL R.
Published: July 2010

ABSTRACT: Multiple melanocortin receptor subtypes with distinct cell and tissue distribution patterns have recently been identified, thereby presenting numerous opportunities for biological investigation. Many of these studies could benefit from the availability of subtype selective or specific agonists and antagonists. The purpose of this report is to summarize the state of available melanocortin receptor agonists and antagonists.
Proopiomelanocortin and the Immune‐Neuroendocrine Connection
Authors: BLALOCK J. EDWIN
Published: July 2010

ABSTRACT:This presentation will cover the history, recent developments in, and implications of the ability of both the immune and neuroendocrine systems to produce POMC. The discovery of POMC in immune cells was one of the events that heralded a molecular understanding of neuroimmunomodulation. This, together with the presence of opiate and ACTH receptors on lymphocytes and macrophages, provided the first biochemical circuit for which the same signal molecules and receptors could be used for intrasystem regulation, as well as bidirectional communication between the immune and neuroendocrine systems. Today we have a quite good understanding of the regulation and processing of POMC in immune cells, as well as the interaction of its product peptides with other cytokines. For instance, IL‐1 causes POMC production by immune cells, and the POMC product, α‐MSH, in turn, acts functionally as an IL‐1 antagonist. In the past year, the expression of full‐length POMC mRNA has been reported and this solved one of the paradoxes with respect to POMC production, processing, and secretion. We provide data on these developments together with quite startling findings on the physiologic function of POMC peptides in the immune system. Among these are the local antinociceptive effects of immune cell‐derived β‐endorphin, altered hematopoiesis in opiate receptor‐deficient animals, and the diagnosis of ACTH insensitivity by a deficiency of ACTH receptors on lymphocytes.
Human Peripheral Blood‐Derived Dendritic Cells Express Functional Melanocortin Receptor MC‐1R
Authors: BECHER E. , MAHNKE K. , BRZOSKA T. , KALDEN D.‐H. , GRABBE S. , LUGER T. A.
Published: July 2010

ABSTRACT: The neuropeptide, α‐melanocyte‐stimulating hormone (α‐MSH) is well known for its immunomodulating capabilities. α‐MSH antagonizes the activity of numerous proinflammatory mediators; for example, Interleukin‐1 (IL‐1), IL‐6, tumor necrosis factor α (TNFα), and bacterial endotoxin. In vivoα‐MSH has been shown to suppress a contact hypersensitivity reaction in mice, and to induce hapten‐specific tolerance. Since antigen presenting cells (APC) represent key elements for tolerance induction, the effect of α‐MSH, and the expression of its receptor‐melanocortin receptor‐1 (MC‐1R), on human peripheral blood‐derived monocytes and dendritic cells (DC), was investigated. Semiquantitative RT‐PCR demonstrated that monocytes and DC express MC‐1R, but none of the other members of the MC‐receptor family. Moreover, the extent of MC‐1R expression correlated with the state of activation of these cells. Since the major ligand of MC‐1R is α‐MSH the question of whether α‐MSH affects the function of monocyte derived DC was further investigated. We found that the expression of the costimulatory molecules CD 86 and CD 40 was downregulated on DC in the presence of α‐MSH. Thus, α‐MSH may exert its immunosuppressive effects by altering the function of APC.
Neural Influences on Induction of Contact Hypersensitivity
Authors: STREILEIN J. WAYNE , ALARD PASCALE , NIIZEKI HIRONORI
Published: July 2010

ABSTRACT: Contact hypersensitivity (CH)‐induction begins when cutaneous antigen‐presenting cells (APC) capture hapten that has been applied epicutaneously, and the process prepares hapten for presentation to T‐cells. APCs are functionally plastic, are influenced by the microenvironment in which they reside, and their functional properties have a profound effect on the phenotype of the hapten‐specific T‐cells that they activate. Ultraviolet B radiation (UVR) distorts the cutaneous microenvironment, thereby altering local APC function, and changing the immune outcome from sensitization to unresponsiveness. Although UVR induces keratinocytes to produce TNFα and IL‐10 (cytokines that have been implicated in failed CH‐induction and tolerance, respectively, after UVR), dermal mast cells turn out to be the source of these immunomodulatory cytokines. Mast cell degranulation is triggered by CGRP released from UVR‐exposed cutaneous nerve termini. Even in normal skin, cutaneous nerves influence the immune response to haptens. Substance P released from cutaneous nerves acts as an adjuvant, raising the immunogenicity of epicutaneously applied haptens. Thus, the nerves and the neuropeptides that these processes release contribute to the cutaneous microenvironment. By altering APC function, cutaneous nerves can dictate the quality and the quantity of immune responses to antigens of the skin.
Alpha‐Melanocyte‐Stimulating Hormone Modulates Activation of NF‐κB and AP‐1 and Secretion of Interleukin‐8 in Human Dermal Fibroblasts
Authors: BÖHM MARKUS , SCHULTE URSULA , KALDEN HENNER , LUGER T. A.
Published: July 2010

ABSTRACT: Alpha‐melanocyte‐stimulating hormone (α‐MSH) has evolved as a mediator of diverse biological activities in an ever‐growing number of non‐melanocytic cell types. One mechanism by which α‐MSH exerts its effects is modulation of AP‐1 and NF‐κB. These two transcription factors also play an important role in fibroblasts, in extracellular matrix composition, and in cytokine expression. By use of electric mobility shift assays, we demonstrate that α‐MSH (10−6 to 10−14 M) activates AP‐1 in human dermal fibroblasts, whereas coincubation with interleukin‐1β (IL‐1β) results in suppression of its activation. α‐MSH also induces activation of NF‐κB but does not modulate DNA binding on costimulation with IL‐1β. Since AP‐1 and NF‐κB are key elements in controlling interleukin‐8 (IL‐8) transcription, human fibroblasts were treated with α‐MSH and IL‐1β for 24 hours, and cytokine levels in the supernatants were measured by ELISA. α‐MSH alone had little effect, whereas coincubation with IL‐1β led to marked downregulation of IL‐8 secretion (at most 288 ± 152 ng/mL) when compared to treatment with IL‐1β alone (919 ± 157 ng/mL). Our results indicate that α‐MSH exerts modulatory effects on the activation of NF‐κB and AP‐1, and that it can regulate chemokine secretion in human dermal fibroblasts. These effects of α‐MSH may have important regulatory functions in extracellular matrix composition, wound healing, or angiogenesis.
Melanocortins and the Treatment of Nervous System Disease: Potential Relevance to the Skin?
Authors: GISPEN WILLEM HENDRIK , ADAN ROGER A.H.
Published: July 2010

ABSTRACT:For several decades melanocortins have been implicated in the modulation of brain function. More recently, this idea has been supported by the identification and cloning of melanocortin (MC) receptors in the nervous system. MCs stimulate axonal growth in fetal neural tissue or in neural cell lines in culture. This feature was utilized in screening their neurotrophic or neuroprotection potential in animal studies of nervous system disease (peripheral nerve and spinal cord trauma, toxic and metabolic neuropathies, EAN, EAE, etc.). Some of these effects may be mediated by MC4 receptor activation, although as yet unknown receptors may also be involved (for instance, protection by Org 2766). To what extent MC‐nervous system effects are related to known effects of MCs in skin‐ and neuro‐immune systems, remains to be discovered. Nevertheless, it is of interest to note that activation of brain MC4 receptors profoundly affects care behavior for the body surface (skin and fur). The excessive grooming response in rodents exhibits a remarkable functional correlation with MSH activity in a brain‐skin axis.
The Skin POMC System (SPS): Leads and Lessons from the Hair Follicle
Authors: PAUS RALF , BOTCHKAREV VLADIMIR A. , BOTCHKAREVA NATALIA V. , MECKLENBURG LARS , LUGER THOMAS , SLOMINSKI ANDRZEJ
Published: July 2010

ABSTRACT: Human and murine skin are prominent extrapituitary sources and targets for POMC products. The expression of, for example, ACTH, α‐MSH, β‐endorphin, and MC‐1‐receptors fluctuates during synchronized hair follicle cycling in C57BL/6 mice. Since hair growth can be induced by ACTH injections in mice and mink, and since high doses of MSH peptides modulate epidermal and/or follicle keratinocyte proliferation in murine skin organ culture, some POMC products may operate as locally generated growth modulators, in addition to their roles in cutaneous pigment and immunobiology. Intrafollicularly generated ACTH and α‐MSH as well as their cognate receptors may assist in the maintenance of the peculiar immune privilege of the anagen hair bulb. Possibly, they are also involved in the development of the follicle pigmentary unit, with whose generation their expression coincides. Given that murine skin also expresses (in a hair‐cycle‐dependent way) CRH and CRH‐R, which control pituitary POMC expression and in view of the fact that CRH arrests follicles in telogen, this suggests the existence of a local skin POMC system (SPS). This may be an integral component of cutaneous stress response‐systems, and may most instructively be studied using the murine hair cycle as a model.
Two Inbred Strains of Rats, Fischer 344 and Lewis, Showed Differential Behavior and Brain Expression of Corticosterone Receptor mRNA Induced by Methamphetamine
Authors: NUMACHI YOHTARO , YOSHIDA SUMIKO , TODA SHIGENOBU , MATSUOKA HIROO , SATO MITSUMOTO
Published: July 2010

Recently, a role of the hypothalamo‐pituitary‐adrenocortical (HPA) axis in facilitating the behavioral and neurochemical effects of psychostimulants has been proposed. Two inbred strains of rats, Fischer 344/N (F344) and Lewis/N (LEW), have markedly different HPA axes as well as behavioral responses to psychostimulants: F344 rats show hyperresponsive HPA axis and no significant sensitization to cocaine, whereas LEW rats display blunted response in HPA axis and develop cocaine‐induced locomotor sensitization. Corticosterone exerts its biological effects via intracellular receptors, termed type I (mineralocorticoid receptor: MR) and type II (glucocorticoid receptor: GR). The present study examines the development of stereotypy sensitization and the brain expression of mRNAs for MR, GR, and heat shock protein 90 (HSP90) in methamphetamine (MAP)‐treated F344 and LEW rats. Animals received i.p. injections with chronic saline (SAL: once daily for 21 days), chronic saline and acute MAP (AM: saline for 20 days and 4 mg/kg MAP on the 21st day), or chronic MAP (CM: 4 mg/kg MAP for 21 days) and were sacrificed three hours after the last injections. Striatum, hippocampus, and cerebellum were quickly dissected on ice and total RNA was isolated for northern analyses. LEW rats developed stereotypy sensitization significantly earlier than F344 rats. AM significantly decreased GR and MR mRNA expression in hippocampus of LEW, compared to SAL. CM significantly increased GR and MR mRNA expression in striatum of F344 compared to SAL and AM, while it decreased GR mRNA in striatum of LEW and MR mRNA in hippocampus, compared to SAL. AM significantly increased HSP90 mRNA in all brain regions examined, without the hippocampus in LEW. CM significantly increased the expression of HSP90 mRNA in the striatum and cerebellum of F344, but significantly decreased in the striatum and hippocampus of LEW. These contrasting differences between F344 and LEW, in their susceptibility to stereotypy sensitization and striatal expression of GR mRNA by chronic MAP, suggest that some striatal genes, whose transcription is regulated by GR, play a crucial role in the development of MAP‐induced behavioral sensitization.
Comparison between the Role of the Neuronal and Inducible Nitric Oxide Synthase in Methamphetamine‐induced Neurotoxicity and Sensitization
Authors: ITZHAK YOSSEF , MARTIN JULIO L. , ALI SYED F.
Published: July 2010

The involvement of the neuronal and inducible nitric oxide synthase (nNOS and iNOS, respectively) in methamphetamine (METH)‐induced dopaminergic neurotoxicity and behavioral sensitization was investigated. To determine METH‐induced neurotoxicity, mice deficient in the nNOS and iNOS genes, nNOS(‐/‐) and iNOS(‐/‐) mice, and wild‐type controls received either saline or METH (5 mg/kg × 3). After 72 h the level of striatal dopaminergic markers were measured. Administration of METH to nNOS(‐/‐) mice had no significant effect on the level of striatal dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), or dopamine transporter (DAT) binding sites. However, METH caused 25‐40% depletion of dopaminergic markers in iNOS(‐/‐) mice and 63‐69% depletion in the wild‐type mice. METH‐induced locomotor activity was measured following the administration of a low dose (1 mg/kg) on day 1. Subsequently animals received the high dose of METH (5 mg/kg × 3). On day 4, after a 68‐72 h drug free period, animals were challenged with 1 mg/kg METH, and locomotor activity was recorded. The intensity of METH‐induced locomotion in nNOS(‐/‐) mice on day 1 and 4 was similar, suggesting that locomotor sensitization did not develop. However, the intensity of METH‐induced locomotion in the iNOS(‐/‐) and wild‐type mice on day 4 was doubled compared to day 1, suggesting the development of sensitization. The present findings indicate that nNOS(‐/‐) mice are more resistant to METH‐induced neurotoxicity and behavioral sensitization than iNOS(‐/‐) mice. These results suggest a major role for nNOS rather than iNOS in the effects of METH.
Serotonin Transporters, Serotonin Release, and the Mechanism of Fenfluramine Neurotoxicity
Authors: BAUMANN MICHAEL H. , AYESTAS MARIO A. , DERSCH CHRISTINA M. , PARTILLA JOHN S. , ROTHMAN RICHARD B.
Published: July 2010

Administration ofd,l‐fenfluramine (FEN), or the more active isomerd‐fenfluramine (dFEN), causes long‐term depletion of forebrain serotonin (5‐HT) in animals. The mechanism underlying FEN‐induced 5‐HT depletion is not known, but appears to involve 5‐HT transporters (SERTs) in the brain. Some investigators have postulated that 5‐HT release evoked by FEN is responsible for the deleterious effects of the drug. In the present work, we sought to examine the relationship between drug‐induced 5‐HT release and long‐term 5‐HT depletion. The acute 5‐HT‐releasing effects of dFEN and the non‐amphetamine 5‐HT agonist 1‐(m‐chlorophenyl)piperazine (mCPP) were evaluated usingin vivomicrodialysis in rat nucleus accumbens. The ability of dFEN and mCPP to interact with SERTs was assessed usingin vitroassays for [3H]‐transmitter uptake and release in rat forebrain synaptosomes. Drugs were subsequently tested for potential long‐lasting effects on brain tissue 5‐HT after repeated dosing (2.7 or 8.1 mg/kg, ip × 4). dFEN and mCPP were essentially equipotent in their ability to stimulate acute 5‐HT releasein vivoandin vitro. Both drugs produced very selective effects on 5‐HT with minimal effects on dopamine. Interestingly, when dFEN or mCPP was administered repeatedly, only dFEN caused long‐term 5‐HT depletion in the forebrain at 2 weeks later. These data suggest that acute 5‐HT release per se does not mediate the long‐term 5‐HT depletion associated with dFEN. We hypothesize that dFEN and other amphetamine‐type releasers gain entrance into 5‐HT neurons via interaction with SERTs. Once internalized in nerve terminals, drugs accumulate to high concentrations, causing damage to cells. The relevance of this hypothesis for explaining clinical side effects of FEN and dFEN, such as cardiac valvulopathy and primary pulmonary hypertension, warrants further study.
Correlation between 5‐HT Content and Uptake Site Density following (S)‐MDMA and Dexfenfluramine‐induced Depletion, and with Neuroprotection by the Glycine Site‐specific NMDA Antagonist ACEA 1021
Authors: RUSSELL B. R. , LAVERTY R.
Published: July 2010

3,4‐Methylenedioxymethamphetamine (MDMA) and fenfluramine are amphetamine analogues that both cause long‐term depletion of serotonin (5‐HT) and 5‐HT uptake sites in brain tissue. Depletion caused by these amphetamines is commonly measured by labeling 5‐HT uptake sites using3H‐paroxetine combined with autoradiography or, alternatively measuring the concentration of 5‐HT in tissue using high‐performance liquid chromatography (HPLC). A close correlation between the 5‐HT concentration measured in micropunch samples and the density of3H‐paroxetine‐labeled 5‐HT uptake sites measured in corresponding 20 μm coronal slices was determined (R2= 0.92). These methods combined demonstrated that the glycine‐site specific NMDA antagonist ACEA 1021 (4 × 30 mg/kg, i.p., 2 hourly) given 30 minutes before (S)‐MDMA (4 × 10 mg/kg, i.p., 2 hourly) was able to prevent the depletion of both 5‐HT content and uptake site density but unable to prevent the depletion of 5‐HT content and uptake site density caused dexfenfluramine (4 × 15 mg/kg, i.p., 2 hourly).
Immunomodulating Activity of MDMA
Authors: PACIFICI R. , ZUCCARO P. , FARRÉ M. , PICHINI S. , DI CARLO S. , ROSET P. N. , LÓPEZ C. HERNADEZ , ORTUÑO J. , SEGURA J. , CAMÍ J. , DE LA TORRE R.
Published: July 2010

MDMA (3,4‐methylenedioxymethamphetamine) use can cause neurochemical, behavioral and endocrine alterations, similar to those produced by exposure to acute stress, suggesting its potential as a “chemical stressor.” It is known that stressful stimuli can produce a depression of immune function and an alteration in immune cells distribution.In vitroexposure to MDMA resulted in a modulation of several immune functional parameters such as T‐cell regulatory function, cytotoxic T‐lymphocyte activity, natural killer cell activity and macrophage function.

Administration of MDMA in rats produced a rapid and sustained suppression of induced lymphocytes proliferation and a significant decrease in circulating lymphocytes. These alterations in rat immune function were accompanied by a significant rapid increase in plasma corticosterone concentrations. It was postulated that the result of altered induced proliferation response of lymphocytes could have been due to a combined effect of direct action of MDMA on lymphocytes and to the activation of the hypothalamic pituitary adrenal axis (HPA axis) and/or the sympathetic nervous system (SNS) via central mechanisms.

In humans, acute MDMA treatment produced a time‐dependent immune dysfunction associated with MDMA plasma concentrations. Although total leukocyte count remained unchanged, there was a decrease in CD4+T‐cells and functional responsiveness of lymphocytes to mitogenic stimulation, while percentage of natural killer cells significantly increased. A rise of cortisol plasma concentrations similar to that observed in the rat model supported the hypothesis of MDMA‐induced release of corticotrophin‐releasing factor from the median eminence of the hypothalamus and subsequent HPA axis and SNS activation. The present findings indicate that MDMA ingestion may represent a potential health hazard for an increased risk of immune system‐related diseases.
Protein Phosphorylation Cascades Associated with Methamphetamine‐induced Glial Activation
Authors: HEBERT MELEIK A. , O'CALLAGHAN JAMES P.
Published: July 2010

Reactive gliosis is the most prominent response to diverse forms of central nervous system (CNS) injury. The signaling events that mediate this characteristic response to neural injury are under intense investigation. Several studies have demonstrated the activation of phosphoproteins within the mitogen‐activated protein kinase (MAPK) and Janus kinase (JAK) pathways following neural insult. These signaling pathways may be involved or responsible for the glial response following injury, by virtue of their ability to phosphorylate and dynamically regulate the activity of various transcription factors. This study sought to delineate,in vivo, the relative contribution of MAPK‐ and JAK‐signaling components to reactive gliosis as measured by induction of glial‐fibrillary acidic protein (GFAP), following chemical‐induced neural damage. At time points (6, 24, and 48 h) following methamphetamine (METH, 10 mg/kg × 4, s.c.) administration, female C57BL/6J mice were sacrificed by focused microwave irradiation, a technique that preserves steady‐state phosphorylation. Striatal (target) and nontarget (hippocampus) homogenates were assayed for METH‐induced changes in markers of dopamine (DA) neuron integrity as well as differences in the levels of activated phosphoproteins. GFAP upregulation occurred as early as 6 h, reaching a threefold induction 48 h following METH exposure. Neurotoxicant‐induced reductions in striatal levels of DA and tyrosine hydroxylase (TH) paralleled the temporal profile of GFAP induction. Blots of striatal homogenates, probed with phosphorylation‐state specific antibodies, demonstrated significant changes in activated forms of extracellular‐regulated kinase 1/2 (ERK 1/2),c‐junN‐terminal kinase/stress‐activated protein kinase (JNK/SAPK), MAPK/ERK kinase (MEK1/2), 70‐kDa ribosomal S6 kinase (p70 S6), cAMP responsive element binding protein (CREB), and signal transducer and activator of transcription 3 (STAT3). MAPK‐related phosphoproteins exhibited an activation profile that peaked at 6 h, remained significantly increased at 24, and fell to baseline levels 48 h following neurotoxicant treatment. The ribosomal S6 kinase was enhanced over 60% for all time points examined. Immunoreactivity profiles for the transcription factors CREB and STAT3 indicated maximal increases in phosphorylation occurring at 24 h, and measuring greater than 2‐ or 17‐fold, respectively. Specific signaling events were found to occur with a time course suggestive of their involvement in the gliotic response. The toxicant‐induced activation of these growth‐associated signaling cascades suggests that these pathways could be obligatory for the triggering and/or persistence of reactive gliosis and may therefore serve as potential targets for modulation of glial response to neural damage.
Effect of Acute and Chronic Administration of Methamphetamine on Calcium‐Calmodulin Dependent Protein Kinase II Activity in the Rat Brain
Authors: AKIYAMA KAZUFUMI , SUEMARU JUNKO
Published: July 2010

Several lines of evidence have implicated Ca2+/calmodulin (CaM)‐dependent protein kinase II (CaM‐kinase II), a multifunctional protein kinase, in the regulation of signal transduction after chronic administration of psycho‐stimulants. CaM‐Kinase II activities were decreased in discrete brain regions after a single methamphetamine (METH) injection to rats. Pretreatment with either SCH 23390 (a dopamine D1 receptor antagonist) or MK‐801 (anN‐methyl‐D‐aspartate receptor antagonist) prevented the acute METH‐induced decrease in CaM‐kinase II activity in the parietal cortex, nucleus accumbens, and substantia nigra/ventral tegmental area (SN/VTA). Striatal CaM‐kinase II activity was significantly lower than that of the chronic saline‐treated controls after a one‐week, but not a four‐week, abstinence from chronic administration of METH. A METH challenge after a four‐week abstinence period decreased CaM‐kinase II activity in rats chronically injected with METH to a greater extent than in rats chronically injected with saline. Western blot analysis revealed that protein amount of CaM‐kinase II was not altered after a single METH injection or after chronic METH injections, as compared with saline‐treated controls. However, amounts of phosphorylated (Thr286) CaM‐kinase II in the parietal cortex, striatum, and SN/VTA were significantly decreased at 3 h after an acute METH injection compared with saline‐treated controls. It is suggested that dephosphorylation of CaM‐kinase II may contribute to the decreased enzyme activities induced by acute METH administration, and that chronic treatment with METH leads to an enhanced capacity of METH to decrease CaM‐kinase II activity after an extended withdrawal period.
Calpain Upregulation in Spinal Cords of Mice with 1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced Parkinson's Disease
Authors: RAY SWAPAN K. , WILFORD GLORIA G. , ALI SYED F. , BANIK NAREN L.
Published: July 2010

1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), a heroin analogue, is a neurotoxin that undergoesin vivooxidation by monoamine oxidase‐B (MAO‐B) to 1‐methyl‐4‐phenylpyridinium ion (MPP+) which preferentially exerts its toxic effects on the dopaminergic neurons of the substantia nigra in brain. Spinal interneuronal pathways are also likely to be affected in the course of MPP+neurotoxicity. The primary effect of MPP+is mediated by irreversible inhibition of mitochondrial complex I, releasing free radicals. MPP+may also activateN‐methyl‐d‐aspartate (NMDA) receptors, increasing the cytosolic concentration of free Ca2+. Intracellular free radicals indirectly and free Ca2+directly can activate Ca2+‐dependent proteases such as calpain. We investigated involvement of calpain in spinal cord degeneration due to neurotoxin by subjecting male C57BL/6N mice (17 months old) to MPTP administration (12.5 mg/kg for 0.5 h; 25 mg/kg for 0.25 h; and 50 mg/kg for 0.25, 0.5, 1, 2, and 24 h). RT‐PCR and Western blot analysis were performed using the thoracic segment of spinal cords from control and MPTP‐administered mice. The administration of MPTP caused calpain upregulation at the mRNA and protein levels to various extents, compared to control mice. Calpain activity was measured by 68 kDa neurofilament protein (NFP) degradation, which was increased in MPTP‐induced PD mice. These results suggest that calpain may play a role in spinal cord degeneration in mice with MPTP‐induced PD.
The Effects of DCG‐IV and L‐CCG‐1 upon Phencyclidine (PCP)‐induced Locomotion and Behavioral Changes in Mice
Authors: TOMITA NAOKI , MURATA MASAMI , WATANABE HIROMI , ICHIKAWA TOMIO , WASHIYAMA KAZUO , KUMANISHI TOSHIRO , TAKAHASHI YASUO
Published: July 2010

The behavioral changes of mice induced by acute and repeated ip injection of phencyclidine (PCP) were observed by measuring locomotor activity and stereotyped behavior. Then, the effects of metabotropic glutamate receptor (mGluR) agonists, DCG‐IV and L‐CCG‐1, on the above behavioral changes induced by PCP were found. The effects of DCG‐IV were very strong and completely depressed the PCP‐induced hyperlocomotion. The effects of L‐CCG‐1 were not so strong. Repeated injection of PCP for 20 days into mice induced lower locomotor activity than that in acutely injected mice. These behavioral changes may be related with the negative symptoms of schizophrenia. In order to examine some molecular mechanisms of PCP‐induced behavioral changes, Northern blot analysis of total RNA from prefrontal cortical tissues of mice treated with PCP, DCG‐IV, and L‐CCG‐1 was carried out.
Noribogaine (12‐Hydroxyibogamine): A Biologically Active Metabolite of the Antiaddictive Drug Ibogaine
Authors: BAUMANN M. H. , PABLO J. P. , ALI S. F. , ROTHMAN R. B. , MASH D. C.
Published: July 2010

Ibogaine (IBO) is a plant‐derived alkaloid that is being evaluated as a possible medication for substance use disorders. When administered peripherally to monkeys and humans, IBO is rapidly converted to ano‐demethylated metabolite, 12‐hydroxyibogamine (NORIBO). We have found in rats that peak blood levels of NORIBO can exceed those of the parent compound, and NORIBO persists in the bloodstream for at least 24 h. Surprisingly few studies have examined thein vivobiological activity of NORIBO. In the present series of experiments, we compared the effects of intravenous (iv) administration of IBO and NORIBO (1 and 10 mg/kg) on unconditioned behaviors, circulating stress hormones, and extracellular levels of dopamine (DA) and serotonin (5‐HT) in the nucleus accumbens of male rats. IBO caused dose‐related increases in tremors and forepaw treading, whereas NORIBO did not. Both IBO and NORIBO produced significant elevations in plasma corticosterone and prolactin, but IBO was more potent as a stimulator of corticosterone secretion. Neither drug affected extracellular DA levels in the nucleus accumbens. However, both IBO and NORIBO increased extracellular 5‐HT levels, and NORIBO was more potent in this regard. The present data demonstrate that NORIBO is biologically active and undoubtedly contributes to thein vivopharmacological profile of IBO in rats. Most importantly, NORIBO appears less likely to produce the adverse effects associated with IBO (i.e., tremors and stress‐axis activation), suggesting that the metabolite may be a safer alternative for medication development.
18‐Methoxycoronaridine (18‐MC) and Ibogaine: Comparison of Antiaddictive Efficacy, Toxicity, and Mechanisms of Action
Authors: GLICK STANLEY D. , MAISONNEUVE ISABELLE M. , SZUMLINSKI KAREN K.
Published: July 2010

18‐MC, a novelibogaalkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18‐MC (40 mg/kg) decreases the intravenous self‐administration of morphine and cocaine and the oral self‐administration of ethanol and nicotine in rats; unlike ibogaine, 18‐MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18‐MC ameliorate opioid withdrawal signs. Both ibogaine and 18‐MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18‐MC block morphine‐induced and nicotine‐induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine‐induced increases in accumbal dopamine. Both ibogaine and 18‐MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18‐MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine‐induced locomotion in morphine‐experienced rats. Ibogaine produces whole body tremors and, at high doses (≥100 mg/kg), cerebellar damage; 18‐MC does not produce these effects. Ibogaine, but not 18‐MC, decreases heart rate at high doses. While 18‐MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18‐MC has much lower affinities than ibogaine for NMDA and sigma‐2 receptors, sodium channels, and the 5‐HT transporter. Both 18‐MC and ibogaine are sequestered in fat and, like ibogaine, 18‐MC probably has an active metabolite. The data suggest that 18‐MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.
Application of Electrophysiological Method to Study Interactions between Ibogaine and Cocaine
Authors: BINIENDA ZBIGNIEW , BEAUDOIN MICHAEL A. , THORN BRETT T. , SADOVOVA NATALYA , SKINNER ROBERT D. , SLIKKER WILLIAM , ALI SYED F.
Published: July 2010

The psychoactive indole alkaloid, ibogaine (IBO), has been investigated for over a decade concerning its reported anti‐addictive properties for opioids as well as psychomotor stimulants. The mechanism for the anti‐addictive action of IBO is still unclear. IBO interactions with opioid, NMDA, nicotinic, adrenergic, and serotonergic receptor sites have been suggested. The involvement of the dopaminergic system in IBO action is well documented. Increased or decreased levels of dopamine (DA) in specific brain regions following IBO pretreatment have been seen concomitantly with increased or decreased motor activity after subsequent amphetamine or cocaine administration. In this report,in vivoelectrophysiological measures were monitored in awake adult male rats in order to investigate alterations of the electrocorticogram (ECoG) resulting from interactions between IBO and cocaine (COC). Rats were implanted bilaterally with bipolar ECoG electrodes. They were either injected with saline, COC alone (20 mg/kg, i.p.) or IBO (50 mg/kg, i.p.) and COC 1 hr later. The concentrations of DA, 5‐HT, and their metabolites DOPAC, HVA, and 5‐HIAA were assessed in the caudate nucleus in separate groups of saline‐, COC‐, and IBO/COC‐treated rats. An alpha1power increase was observed within 10 min after COC injection, which lasted for less than 20 min. A desynchronization over alpha2and both beta power bands was observed throughout the recording. In IBO/COC‐treated rats, a significant increase in delta, theta, and alpha1power occurred within 20 min after COC injection (p<0.05). This effect lasted for up to an hour. DA levels significantly increased after COC only and decreased after IBO administration. A further decrease in levels of DA was observed in IBO/COC‐treated rats. DA turnover increased significantly after IBO alone but was not observed after IBO/COC treatment. The alterations in ECoG and neurotransmitter levels suggest a decreased response to COC following IBO pretreatment.
Neonatal Methamphetamine in the Rat: Evidence for Gender‐specific Differences upon Tyrosine Hydroxylase Enzyme in the Dopaminergic Nigrostriatal System
Authors: GOMES‐DA‐SILVA JOANA , PÉREZ‐ROSADO ALBERTO , DE MIGUEL ROSARIO , FERNÁNDEZ‐RUIZ JAVIER , SILVA M. CAROLINA , TAVARES M. AMÉLIA
Published: July 2010

Methamphetamine (Meth) neurotoxicity upon the mesencephalic dopaminergic systems was demonstrated in the adult, both in humans and in experimental models. In the rat, the development and maturation of the dopaminergic systems is accomplished during the first month of postnatal life, a period of particular vulnerability to environmental influences. In this study, the effect of Meth exposure during the first month of life was assessed in the nigrostriatal dopaminergic system of the rat. For this purpose, Wistar rat litters were culled to 8 pups, retaining preferentially 4 males and 4 females, which, in the day following birth (postnatal day 1, PND1), were randomly attributed to either the Meth or control group. Meth‐groups were administered 10 mg of (+)‐methamphetamine hydrochloride/kg body weight/day, subcutaneously, twice daily, from PND1 until PND29; control groups received isovolumetric doses of saline. Animals were sacrificed at PND30. Males exposed to Meth during the first month of life had increased tyrosine hydroxylase (TH) activity both in the caudate‐putamen and substantia nigra. Males also had increased nigral TH mRNA levels, as assessed by in situ hybridization. These effects did not exist in females. These results support the evidence that Meth exposure during the first month of life in the rat has a gender‐specific stimulatory effect upon the maturation of TH, the key enzyme for dopamine biosynthesis in the nigrostriatal dopaminergic system.
Regulation of Chloride Secretion: Novel Pathways and Messengers
Authors: KEELY STEPHEN J. , BARRETT KIM E.
Published: July 2010

Abstract: The capacity for active chloride secretion, thereby driving the secretion of fluid, is an important property of the intestinal epithelium. Chloride secretion is stimulated by mechanisms involving increases in either cyclic nucleotide or cytoplasmic calcium concentrations. The calcium‐dependent response is transient and limited in its magnitude, implying that negative signaling events may restrict the overall extent of this mode of chloride transport. We have uncovered a number of negative signaling mechanisms intrinsic to the epithelium that uncouple increases in calcium from the downstream response of chloride secretion. These involve various kinase cascades, the generation of messengers derived from membrane phospholipids, and interactions of G protein‐coupled receptors with those for peptide growth factors such as epidermal growth factor. This chapter will review emerging information on the details of these negative signaling mechanisms, as well as points of convergence and divergence. The possible physiological and pathophysiological significance of such signaling will also be discussed.