Showing papers in "Annals of the New York Academy of Sciences in 2004"

Adolescent Brain Development: A Period of Vulnerabilities and Opportunities. Keynote Address

Abstract: This article introduces and summarizes the goals of the symposium. It also provides an overview of a conceptual framework for understanding adolescence, which emphasizes how the very nature of this developmental transition requires an interdisciplinary approach-one that focuses on brain/behavior/social-context interactions during this important maturational period. More specifically it describes a set of neurobehavioral changes that appear to be linked to pubertal development, which appear to have a significant effect on motivation and emotion, and considers these puberty-specific changes in affect in relation to a much larger set of developmental changes in adolescence. This framework is used to argue for the need for a transdisciplinary dialogue that brings together work in several areas of neuroscience (including animal models) and normal development with clinical and social policy research aimed at early intervention and prevention strategies.

Structural Magnetic Resonance Imaging of the Adolescent Brain

Abstract: Magnetic resonance imaging (MRI) provides accurate anatomical brain images without the use of ionizing radiation, allowing longitudinal studies of brain morphometry during adolescent development. Results from an ongoing brain imaging project being conducted at the Child Psychiatry Branch of the National Institute of Mental Health indicate dynamic changes in brain anatomy throughout adolescence. White matter increases in a roughly linear pattern, with minor differences in slope in the four major lobes (frontal, parietal, temporal, occipital). Cortical gray matter follows an inverted U-shape developmental course with greater regional variation than white matter. For instance, frontal gray matter volume peaks at about age 11.0 years in girls and 12.1 years in boys, whereas temporal gray matter volume peaks at about age at 16.7 years in girls and 16.2 years in boys. The dorsal lateral prefrontal cortex, important for controlling impulses, is among the latest brain regions to mature without reaching adult dimensions until the early 20s. The details of the relationships between anatomical changes and behavioral changes, and the forces that influence brain development, have not been well established and remain a prominent goal of ongoing investigations.

Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders.

Abstract: Stress promotes adaptation, but prolonged stress leads over time to wear-and-tear on the body (allostatic load). Neural changes mirror the pattern seen in other body systems, that is, short-term adaptation vs. long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesity, bone demineralization, and atrophy of nerve cells in the brain. Many of these processes are seen in major depressive illness and may be expressed also in other chronic anxiety disorders. The brain controls the physiological and behavioral coping responses to daily events and stressors. The hippocampal formation expresses high levels of adrenal steroid receptors and is a malleable brain structure that is important for certain types of learning and memory. It is also vulnerable to the effects of stress and trauma. The amygdala mediates physiological and behavioral responses associated with fear. The prefrontal cortex plays an important role in working memory and executive function and is also involved in extinction of learning. All three regions are targets of stress hormones. In animal models, neurons in the hippocampus and prefrontal cortex respond to repeated stress by showing atrophy, whereas neurons in amygdala show a growth response. Yet, these are not necessarily "damaged" and may be treatable with the right medications.

Risk Taking in Adolescence: What Changes, and Why?

Abstract: Extant studies of age differences in cognitive processes relevant to risk taking and decision making, such as risk perception and risk appraisal, indicate few significant age differences in factors that might explain why adolescents engage in more risk taking than adults The present analysis suggests that the greater propensity of adolescents to take risks is not due to age differences in risk perception or appraisal, but to age differences in psychosocial factors that influence self-regulation It is argued that adolescence is a period of heightened vulnerability to risk taking because of a disjunction between novelty and sensation seeking (both of which increase dramatically at puberty) and the development of self-regulatory competence (which does not fully mature until early adulthood) This disjunction is biologically driven, normative, and unlikely to be remedied through educational interventions designed to change adolescents' perception, appraisal, or understanding of risk Interventions should begin from the premise that adolescents are inherently more likely than adults to take risks, and should focus on reducing the harm associated with risk-taking behavior

The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification.

Abstract: Although well established in medical terminology, the term carcinoid is no longer adequate to cover the entire morphological and biological spectrum of neoplasms of the disseminated neuroendocrine cell system. Therefore, instead of carcinoid, the WHO classification published in 2000 uses the general terms neuroendocrine tumor and neuroendocrine carcinoma. In this review a classification of gastroenteropancreatic neuroendocrine tumors based on the WHO criteria is described. We also classify and comment on the most important tumor entities. On the basis of localization and of various morphological and biological criteria, we distinguish between benign neuroendocrine tumors, tumors with uncertain malignant potential, and tumors showing low-grade and high-grade malignancy.

Regulation of Adolescent Sleep: Implications for Behavior

Abstract: Adolescent development is accompanied by profound changes in the timing and amounts of sleep and wakefulness. Many aspects of these changes result from altered psychosocial and life-style circumstances that accompany adolescence. The maturation of biological processes regulating sleep/wake systems, however, may be strongly related to the sleep timing and amount during adolescence-either as "compelling" or "permissive" factors. The two-process model of sleep regulation posits a fundamental sleep-wake homeostatic process (process S) working in concert with the circadian biological timing system (process C) as the primary intrinsic regulatory factors. How do these systems change during adolescence? We present data from adolescent participants examining EEG markers of sleep homeostasis to evaluate whether process S shows maturational changes permissive of altered sleep patterns across puberty. Our data indicate that certain aspects of the homeostatic system are unchanged from late childhood to young adulthood, while other features change in a manner that is permissive of later bedtimes in older adolescents. We also show alterations of the circadian timing system indicating a possible circadian substrate for later adolescent sleep timing. The circadian parameters we have assessed include phase, period, melatonin secretory pattern, light sensitivity, and phase relationships, all of which show evidence of changes during pubertal development with potential to alter sleep patterns substantially. However the changes are mediated-whether through process S, process C, or by a combination-many adolescents have too little sleep at the wrong circadian phase. This pattern is associated with increased risks for excessive sleepiness, difficulty with mood regulation, impaired academic performance, learning difficulties, school tardiness and absenteeism, and accidents and injuries.

Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies.

Abstract: Research indicates that exposure to traumatic stressors and psychological trauma is widespread. The association of such exposures with posttraumatic stress disorder (PTSD) and other mental health conditions is well known. However, epidemiologic research increasingly suggests that exposure to these events is related to increased health care utilization, adverse health outcomes, the onset of specific diseases, and premature death. To date, studies have linked traumatic stress exposures and PTSD to such conditions as cardiovascular disease, diabetes, gastrointestinal disease, fibromyalgia, chronic fatigue syndrome, musculoskeletal disorders, and other diseases. Evidence linking cardiovascular disease and exposure to psychological trauma is particularly strong and has been found consistently across different populations and stressor events. In addition, clinical studies have suggested the biological pathways through which stressor-induced diseases may be pathologically expressed. In particular, recent studies have implicated the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) stress axes as key in this pathogenic process, although genetic and behavioral/psychological risk factors cannot be ruled out. Recent findings, indicating that victims of PTSD have higher circulating T-cell lymphocytes and lower cortisol levels, are intriguing and suggest that chronic sufferers of PTSD may be at risk for autoimmune diseases. To test this hypothesis, we assessed the association between chronic PTSD in a national sample of 2,490 Vietnam veterans and the prevalence of common autoimmune diseases, including rheumatoid arthritis, psoriasis, insulin-dependent diabetes, and thyroid disease. Our analyses suggest that chronic PTSD, particularly comorbid PTSD or complex PTSD, is associated with all of these conditions. In addition, veterans with comorbid PTSD were more likely to have clinically higher T-cell counts, hyperreactive immune responses on standardized delayed cutaneous hypersensitivity tests, clinically higher immunoglobulin-M levels, and clinically lower dehydroepiandrosterone levels. The latter clinical evidence confirms the presence of biological markers consistent with a broad range of inflammatory disorders, including both cardiovascular and autoimmune diseases.

Glucocorticoids and the Th1/Th2 balance.

Abstract: Evidence accumulated over the last 5-10 years indicates that glucocorticoids (GCs) inhibit the production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha, and tumor necrosis factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells. Through this mechanism increased levels of GCs may systemically cause a selective suppression of the Th1-cellular immunity axis, and a shift toward Th2-mediated humoral immunity, rather than generalized immunosuppression. During an immune response and inflammation, the activation of the stress system, and thus increased levels of systemic GCs through induction of a Th2 shift, may actually protect the organism from systemic "overshooting" with Th1/pro-inflammatory cytokines and other products of activated macrophages with tissue-damaging potential. However, conditions associated with significant changes of GCs levels, such as acute or chronic stress or cessation of chronic stress, severe exercise, and pregnancy and postpartum, through modulation of the Th1/Th2 balance may affect the susceptibility to or the course of infections as well as autoimmune and atopic/allergic diseases.

Cadherin switch in tumor progression.

Abstract: The loss of E-cadherin expression or function in epithelial carcinomas has long been thought as a primary reason for disruption of tight epithelial cell-cell contacts and release of invasive tumor cells from the primary tumor. Indeed, E-cadherin serves as a widely acting suppressor of invasion and growth of epithelial cancers, and its functional elimination represents a key step in the acquisition of the invasive phenotype for many tumors. Recent evidence indicates, however, that in addition to the loss of the "invasion-suppressor" E-cadherin, another adhesion molecule, N-cadherin, becomes upregulated in invasive tumor cell lines. N-cadherin was shown to be present in the most invasive and dedifferentiated breast cancer cell lines, and its exogenous expression in tumor cells induces a scattered morphology and heightened motility, invasion, and metastasis. N-cadherin cooperates with the FGF receptor, resulting in signals that lead to the up-modulation of MMP-9 and, hence, cellular invasion. In addition to a signaling function in metastasis, N-cadherin probably also supports the systemic dissemination of tumor cells by enabling circulating tumor cells to associate with the stroma and the endothelium at distant sites. Here, we summarize the various aspects of the E- to N-cadherin switching in epithelial carcinomas and its potential impact on metastatic progression.

Psychosocial stress-induced activation of salivary alpha-amylase: an indicator of sympathetic activity?

Abstract: Assessment of sympathoadrenal medullary system (SAM) activity is only possible to date via measurement of catecholamines in blood plasma or via electrophysiological methods. Both ways of measurement are restricted to endocrinological or psychophysiological laboratories, as both require either immediate freezing of blood samples or complex recording devices. Efforts have therefore been undertaken to find a method comparable to salivary cortisol measurements, in which noninvasive samples can be taken at any place and stored at room temperature for sufficient time before later analysis in the laboratory. Salivary alpha-amylase (sAA) is a candidate that may prove useful in this context. We show here that sAA activity is increased by acute psychosocial stress (Trier Social Stress Test) and that increases in sAA correlate with increases in norepinephrine. We further report that sAA exhibits a stable circadian pattern that mirrors that of salivary cortisol. In conclusion, the current data show that salivary alpha-amylase may serve as an easy-to-use index for SAM activity. However, some questions remain to be answered; for example, what impact does salivary flow rate exert on stress-induced sAA activity?

Inflammation and the Degenerative Diseases of Aging

Abstract: Chronic inflammation is associated with a broad spectrum of neurodegenerative diseases of aging. Included are such disorders as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, the Parkinson-dementia complex of Guam, all of the tauopathies, and age-related macular degeneration. Also included are such peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial infarction. Inflammation is a two-edged sword. In acute situations, or at low levels, it deals with the abnormality and promotes healing. When chronically sustained at high levels, it can seriously damage viable host tissue. We describe this latter phenomenon as autotoxicity to distinguish it from autoimmunity. The latter involves a lymphocyte-directed attack against self proteins. Autotoxicity, on the other hand, is determined by the concentration and degree of activation of tissue-based monocytic phagocytes. Microglial cells are the brain representatives of the monocyte phagocytic system. Biochemically, the intensity of their activation is related to a spectrum of inflammatory mediators generated by a variety of local cells. The known spectrum includes, but is not limited to, prostaglandins, pentraxins, complement components, anaphylotoxins, cytokines, chemokines, proteases, protease inhibitors, adhesion molecules, and free radicals. This spectrum offers a huge variety of targets for new anti-inflammatory agents. It has been suggested, largely on the basis of transgenic mouse models, that stimulating inflammation rather than inhibiting it can be beneficial in such diseases as AD. If this were the case, administration of NSAIDs, or other anti-inflammatory drugs, would be expected to exacerbate conditions such as AD, PD, and atherosclerosis. However, epidemiological evidence overwhelmingly demonstrates that the reverse is true. This indicates that, at least in these diseases, the inflammation is harmful. So far, advantage has not been taken of opportunities indicated by these epidemiological studies to treat AD and PD with appropriate anti-inflammatory agents. Based on this evidence, classical NSAIDs are the most logical choice. Dosage, though, must be sufficient to combat the inflammation. Analysis of mRNA levels of inflammatory mediators indicates that the intensity of inflammation is considerably higher in AD hippocampus and in PD substantia nigra than in osteoarthritic joints. Thus, full therapeutic doses of NSAIDs, or combinations of anti-inflammatory agents, are needed to achieve the suggested neurological benefits.

Learned birdsong and the neurobiology of human language.

Abstract: Vocal learning, the substrate for human language, is a rare trait found to date in only three distantly related groups of mammals (humans, bats, and cetaceans) and three distantly related groups of birds (parrots, hummingbirds, and songbirds). Brain pathways for vocal learning have been studied in the three bird groups and in humans. Here I present a hypothesis on the relationships and evolution of brain pathways for vocal learning among birds and humans. The three vocal learning bird groups each appear to have seven similar but not identical cerebral vocal nuclei distributed into two vocal pathways, one posterior and one anterior. Humans also appear to have a posterior vocal pathway, which includes projections from the face motor cortex to brainstem vocal lower motor neurons, and an anterior vocal pathway, which includes a strip of premotor cortex, the anterior basal ganglia, and the anterior thalamus. These vocal pathways are not found in vocal non-learning birds or mammals, but are similar to brain pathways used for other types of learning. Thus, I argue that if vocal learning evolved independently among birds and humans, then it did so under strong genetic constraints of a pre-existing basic neural network of the vertebrate brain.

The Emergence of Collaborative Brain Function: fMRI Studies of the Development of Response Inhibition

Abstract: Adolescence marks the beginning of adult-level cognitive control of behavior supported by the brain maturation processes of synaptic pruning and myelination. Cognitive development studies on adolescence indicate that this period is characterized by improvements in the performance of existing abilities including speed and capacity of information processing and the ability to have consistent cognitive control of behavior. Although adolescents can behave at adult levels in some ways, brain imaging studies indicate that the functional organization of brain systems that support higher-cognitive processes are not fully mature. Synaptic pruning allows for more efficient local computations, enhancing the ability of discrete brain regions to support high-level cognitive control of behavior including working memory. Myelination increases the speed of neuronal transmission supporting the collaboration of a widely distributed circuitry, integrating regions that support top-down cognitive control of behavior. Functional brain imaging methods allow for the characterization of the relationship between cognitive development and brain maturation as we can map progressions in the establishment of distributed brain circuitry and its relation to enhanced cognitive control of behavior. We present a review on the maturation (as distinct from “development” in emphasizing the transition to maturity and stabilization) of response inhibition, brain structure, and brain function through adolescence. We also propose a model for brain-behavior maturation that allows for the qualitative changes in cognitive processes that occur during adolescence.

Mechanism of Telomere Shortening by Oxidative Stress

Abstract: We investigated whether oxidative stress, which contributes to aging, accelerates the telomere shortening in human cultured cells. The terminal restriction fragment (TRF) from WI-38 fibroblasts irradiated with UVA (365-nm light) decreased with increasing of the irradiation dose. Furthermore, UVA irradiation dose-dependently increased the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in both WI-38 fibroblasts and HL-60 cells. In order to clarify the mechanism of the acceleration of telomere shortening, we investigated site-specific DNA damage induced by UVA irradiation in the presence of endogenous photosensitizers using (32)P 5' end-labeled DNA fragments containing telomeric oligonucleotide (TTAGGG)(4). UVA irradiation with riboflavin induced 8-oxodG formation in the DNA fragments containing telomeric sequence, and Fpg protein treatment led to chain cleavages at the central guanine of 5'-GGG-3' in telomere sequence. Human 8-oxodG-DNA glycosylase introduces a chain break in a double-stranded oligonucleotide specifically at an 8-oxodG residue. The amount of 8-oxodG formation in DNA fragment containing telomere sequence [5'-CGC(TTAGGG)(7)CGC-3'] was approximately five times more than that in the DNA fragment containing nontelomere sequence [5'-CGC(TGTGAG)(7)CGC-3']. Furthermore, H(2)O(2) plus Cu(II) caused DNA damage, including 8-oxodG formation, specifically at the GGG sequence in the telomere sequence (5'-TTAGGG-3'). It is concluded that the formation of 8-oxodG at the GGG triplet in telomere sequence induced by oxidative stress could participate in acceleration of telomere shortening.

Iron metabolism and the IRE/IRP regulatory system: an update

Abstract: Cellular iron homeostasis is accomplished by the coordinated regulated expression of the transferrin receptor and ferritin, which mediate iron uptake and storage, respectively. The mechanism is posttranscriptional and involves two cytoplasmic iron regulatory proteins, IRP1 and IRP2. Under conditions of iron starvation, IRPs stabilize the transferrin receptor and inhibit the translation of ferritin mRNAs by binding to "iron responsive elements" (IREs) within their untranslated regions. The IRE/IRP system also controls the expression of additional IRE-containing mRNAs, encoding proteins of iron and energy metabolism. The activities of IRP1 and IRP2 are regulated by distinct posttranslational mechanisms in response to cellular iron levels. Thus, in iron-replete cells, IRP1 assembles a cubane iron-sulfur cluster, which prevents IRE binding, while IRP2 undergoes proteasomal degradation. IRP1 and IRP2 also respond, albeit differentially, to iron-independent signals, such as hydrogen peroxide, hypoxia, or nitric oxide. Basic principles of the IRE/IRP system and recent advances in understanding the regulation and the function of IRP1 and IRP2 are discussed.

Manganese-induced parkinsonism and Parkinson's disease.

Abstract: It has long been appreciated that manganese exposure can cause neurotoxicity and a neurologic syndrome that resembles Parkinson's disease (PD). Current evidence indicates that manganese-induced parkinsonism can be differentiated from PD because of its predilection to accumulate in and damage the pallidum and striatum rather than the SNc. The clinical syndrome, response to levodopa, imaging studies with MRI and PET, and pathologic features all help to distinguish these two conditions and permit the correct diagnosis to be established. This is of particular relevance in differentiating patients with parkinsonism due to manganese intoxication from patients with idiopathic PD who have incidental manganese exposure.

Redox-active metals, oxidative stress, and Alzheimer's disease pathology.

Abstract: Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principal component of beta-amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH*). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H(2)O(2) mediates Abeta cellular toxicity and increases the production of both Abeta and amyloid precursor protein (APP). Third, the 5' untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is consistent with biochemical evidence that APP is a redox-active metalloprotein. Hence, the redox interactions between Abeta, APP, and metals may be at the heart of a pathological positive feedback system wherein Abeta amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease.

Suppression of the nuclear factor-κB activation pathway by spice-derived phytochemicals: Reasoning for seasoning

Abstract: A BSTRACT : The activation of nuclear transcription factor k B has now been linked with a variety of inflammatory diseases, including cancer, atherosclerosis, myocardial infarction, diabetes, allergy, asthma, arthritis, Crohn’s disease, multiple sclerosis, Alzheimer’s disease, osteoporosis, psoriasis, septic shock, and AIDS. Extensive research in the last few years has shown that the pathway that activates this transcription factor can be interrupted by phytochemicals derived from spices such as turmeric (curcumin), red pepper (capsaicin), cloves (eugenol), ginger (gingerol), cumin, anise, and fennel (anethol), basil and rosemary (ursolic acid), garlic (diallyl sulfide, S -allylmercaptocysteine, ajoene), and pomegranate (ellagic acid). For the first time, therefore, research provides “reasoning for seasoning.”

Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies.

Abstract: Glucocorticoids have been used for over 50 years in the treatment of inflammatory and autoimmune diseases and in preventing graft rejection. Today, knowledge of their molecular, cellular, and pharmacological properties allows a better understanding of glucocorticoid-mediated immunosuppression. Glucocorticoids exert both negative and positive effects with a dynamic and bi-directional spectrum of activities on various limbs and components of the immune response. They modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular (Th1) immunity and promote humoral (Th2) immunity. Interestingly, glucocorticoids can also induce tolerance to specific antigens by influencing dendritic cell maturation and function and promoting the development of regulatory high IL-10-producing T cells. The ex vivo therapeutic use of glucocorticoids could therefore represent an adjuvant treatment to cell therapy in autoimmune diseases, avoiding the long-term deleterious adverse effects of glucocorticoids. Thus, the panoramic view of glucocorticoid actions on the immune system provides an interesting model for characterizing important biological pathways of immunosuppression.

Infant vitamin D supplementation and allergic conditions in adulthood: Northern Finland Birth Cohort 1966

Abstract: Allergen-induced secretion of Th2-type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)(2)D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all individuals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n = 7,648), and atopy determined by skin-prick test in a sub-sample still living in northern Finland or the Helsinki area (n = 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4-2.0, and OR 1.66, 95%CI 1.1-1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99-1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P = 0.01 for atopy, P = 0.001 for allergic rhinitis, and P = 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long-term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation.

Kinetics, Pharmacokinetics, and Regulation of l-Carnitine and Acetyl-l-carnitine Metabolism

Abstract: In mammals, the carnitine pool consists of nonesterified L-carnitine and many acylcarnitine esters. Of these esters, acetyl-L-carnitine is quantitatively and functionally the most significant. Carnitine homeostasis is maintained by absorption from diet, a modest rate of synthesis, and efficient renal reabsorption. Dietary L-carnitine is absorbed by active and passive transfer across enterocyte membranes. Bioavailability of dietary L-carnitine is 54-87% and is dependent on the amount of L-carnitine in the meal. Absorption of L-carnitine dietary supplements (0.5-6 g) is primarily passive; bioavailability is 14-18% of dose. Unabsorbed L-carnitine is mostly degraded by microorganisms in the large intestine. Circulating L-carnitine is distributed to two kinetically defined compartments: one large and slow-turnover (presumably muscle), and another relatively small and rapid-turnover (presumably liver, kidney, and other tissues). At normal dietary L-carnitine intake, whole-body turnover time in humans is 38-119 h. In vitro experiments suggest that acetyl-L-carnitine is partially hydrolyzed in enterocytes during absorption. In vivo, circulating acetyl-L-carnitine concentration was increased 43% after oral acetyl-L-carnitine supplements of 2 g/day, indicating that acetyl-L-carnitine is absorbed at least partially without hydrolysis. After single-dose intravenous administration (0.5 g), acetyl-L-carnitine is rapidly, but not completely hydrolyzed, and acetyl-L-carnitine and L-carnitine concentrations return to baseline within 12 h. At normal circulating l-carnitine concentrations, renal l-carnitine reabsorption is highly efficient (90-99% of filtered load; clearance, 1-3 mL/min), but displays saturation kinetics. Thus, as circulating L-carnitine concentration increases (as after high-dose intravenous or oral administration of L-carnitine), efficiency of reabsorption decreases and clearance increases, resulting in rapid decline of circulating L-carnitine concentration to baseline. Elimination kinetics for acetyl-L-carnitine are similar to those for L-carnitine. There is evidence for renal tubular secretion of both L-carnitine and acetyl-L-carnitine. Future research should address the correlation of supplement dosage, changes and maintenance of tissue L-carnitine and acetyl-L-carnitine concentrations, and metabolic and functional changes and outcomes.

Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites.

Abstract: Environmental conditions in early life permanently alter the development of glucocorticoid receptor gene expression in the hippocampus and hypothalamic-pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive glucocorticoid receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets within the chromatin structure of the promoter region of the rat hippocampal glucocorticoid receptor gene.

Modulation of glucocorticoid receptor function via phosphorylation.

Abstract: The glucocorticoid receptor (GR) is phosphorylated at multiple serine residues in a hormone-dependent manner. It has been suggested that GR phosphorylation affects turnover, subcellular trafficking, or the transcriptional regulatory functions of the receptor, yet the contribution of individual GR phosphorylation sites to the modulation of GR activity remains enigmatic. This review critically evaluates the literature on GR phosphorylation and presents more recent work on the mechanism of GR phosphorylation from studies using antibodies that recognize GR only when it is phosphorylated. In addition, we present support for the notion that GR phosphorylation modifies protein-protein interactions, which can stabilize the hypophosphorylated form of the receptor in the absence of ligand, as well as facilitate transcriptional activation by the hyperphosphorylation of GR via cofactor recruitment upon ligand binding. Finally, we propose that GR phosphorylation also participates in the nongenomic activation of cytoplasmic signaling pathways evoked by GR. Thus, GR phosphorylation is a versatile mechanism for modulating and integrating multiple receptor functions.

Risk taking and novelty seeking in adolescence: introduction to part I.

Abstract: Risk taking and novelty seeking are hallmarks of typical adolescent behavior. Adolescents seek new experiences and higher levels of rewarding stimulation, and often engage in risky behaviors, without considering future outcomes or consequences. These behaviors can have adaptive benefits with regard to the development of independence and survival without parental protection, but also render the adolescent more vulnerable to harm. Indeed, the risk of injury or death is higher during the adolescent period than in childhood or adulthood, and the incidence of depression, anxiety, drug use and addiction, and eating disorders increases. Brain pathways that play a key role in emotional regulation and cognitive function undergo distinct maturational changes during this transition period. It is clear that adolescents think and act differently from adults, yet relatively little is known about the precise mechanisms underlying neural, behavioral, and cognitive events during this period. Increased investigation of these dynamic alterations, particularly in prefrontal and related corticolimbic circuitry, may aid this understanding. Moreover, the investigation of mammalian animal models of adolescence-such as those examining impulsivity, reward sensitivity, and decision making-may also provide new opportunities for addressing the problem of adolescent vulnerability.

The relevance of iron in the pathogenesis of Parkinson's disease.

Abstract: Investigations that revealed increased levels of iron in postmortem brains from patients with Parkinson's disease (PD) as compared to those from individuals not suffering from neurological disorders are reported. The chemical natures in which iron predominates in the brain and the relevance of neuromelanin for neuronal iron binding are discussed. Major findings have been that iron levels increase with the severity of neuropathological changes in PD, presumably due to increased transport through the blood-brain barrier in late stages of parkinsonism. Glial iron is mainly stored as ferric iron in ferritin, while neuronal iron is predominantly bound to neuromelanin. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of reactive biological intermediates, including reactive oxygen species, and the formation of cytotoxic protein aggregates. There are indications that iron-mediated neuronal death in PD proceeds retrogradely. These results are also discussed with respect to their relevance for disease progression in relation to cytotoxic alpha-synuclein protofibril formation.

Hormones and the Stressed Brain

Abstract: The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action-in concert-is crucial for individual differences in coping with other individuals, which in turn depend on genetic- and experience-related factors. The actions exerted by cortisol and corticosterone have an enormous diversity. They include the regulation of rapid molecular aggregations, membrane processes, and gene transcription. In the latter transcriptional regulation, the corticosteroid hormones have two modes of operation. One mode is mediated by high-affinity mineralocorticoid receptors (MRs), which control gene networks underlying stabilization of neuronal activity as determinant for the sensitivity to trigger immediate responses to stress organized by corticotrophin-releasing hormone (CRH)-1 receptor. Whereas disturbance of homeostasis is prevented by MR-mediated processes, its recovery is facilitated via the low-affinity glucocorticoid receptors (GRs) that require stress levels of cortisol. GRs promote in coordination with CRH-2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance, and health. Imbalance induced by genetic modification or stressors changes specific neural signaling pathways underlying cognition and emotion. This yin-yang concept in stress regulation is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid-induced stress-related disorders such as severe forms of depression.

The "normal" endocrine cell of the gut: changing concepts and new evidences.

Abstract: The endocrine cells of the gut are a highly specialized mucosal cell subpopulation. Within the gastrointestinal tract at least 14 different cell types produce a wide range of hormones with a specific regional distribution. The gut endocrine cells belong to the diffuse endocrine system. These cells present two regulated pathways of secretion characterized by large dense core vesicles (LDCV) and synaptic-like microvesicles (SLMV). Gut endocrine cells are recognized by the expression of several “general” markers, including the LDCV marker chromogranin A and the SLMV marker synaptophysin, in addition to the cytosolic markers neuron-specific enolase and protein gene product 9.5. The expression of different hormones identifies specific cell types. The gut endocrine cells are reputed to be terminally differentiated and incapable of proliferation. However, some data suggest that the number of gut endocrine cells may adapt in response to tissue-specific physiological stimuli. Gut endocrine cell differentiation appears to follow a “constitutive” tissue-specific pathway, which may be disrupted and investigated by genetic manipulation in mice. It is suggested that endocrine cell homeostasis is maintained by the entry of new endocrine-committed cells along the differentiation pathway and that such intermediate cells may be sensitive to physiological stimuli as well as transforming agents.

Limbic corticostriatal systems and delayed reinforcement.

Abstract: Impulsive choice, one aspect of impulsivity, is characterized by an abnormally high preference for small, immediate rewards over larger delayed rewards, and can be a feature of adolescence, but also attention-deficit/hyperactivity disorder (ADHD), addiction, and other neuropsychiatric disorders. Both the serotonin and dopamine neuromodulator systems are implicated in impulsivity; manipulations of these systems affect animal models of impulsive choice, though these effects may depend on the receptor subtype and whether or not the reward is signaled. These systems project to limbic cortical and striatal structures shown to be abnormal in animal models of ADHD. Damage to the nucleus accumbens core (AcbC) causes rats to exhibit impulsive choice. These rats are also hyperactive, but are unimpaired in tests of visuospatial attention; they may therefore represent an animal model of the hyperactive-impulsive subtype of ADHD. Lesions to the anterior cingulate or medial prefrontal cortex, two afferents to the AcbC, do not induce impulsive choice, but lesions of the basolateral amygdala do, while lesions to the orbitofrontal cortex have had opposite effects in different tasks measuring impulsive choice. In theory, impulsive choice may emerge as a result of abnormal processing of the magnitude of rewards, or as a result of a deficit in the effects of delayed reinforcement. Recent evidence suggests that AcbC-lesioned rats perceive reward magnitude normally, but exhibit a selective deficit in learning instrumental responses using delayed reinforcement, suggesting that the AcbC is a reinforcement learning system that mediates the effects of delayed rewards.

Role of Oxidative Stress in Pancreatic β-Cell Dysfunction

Abstract: Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic β-cell dysfunction found in diabetes. Possibly caused by low levels of antioxidant enzyme expressions, pancreatic β-cells are vulnerable to oxidative stress. When β-cell-derived HIT-T15 cells or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. To investigate the significance of oxidative stress in the progression of pancreatic β-cell dysfunction in type 2 diabetes, we evaluated the effects of antioxidants in diabetic C57BIL/KsJ-db/db mice. According to an intraperitoneal glucose tolerance test, the treatment with antioxidants retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Histological analyses of the pancreata revealed that the β-cell mass was significantly larger in the mice treated with the antioxidants, and the antioxidant treatment suppressed apoptosis in β-cells without changing the rate of β-cell proliferation. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident As possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (also known as IDX-l/STF-1/ IPF1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Under diabetic conditions, JNK is activated by oxidative stress and involved in the suppression of insulin gene expression. This JNK effect appears to be mediated in part by nucleocytoplasmic translocation of PDX-1, which is also downstream of JNK activation. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of β-cell dysfunction found in diabetes. Antioxidants may serve as a novel mechanism-based therapy for type 2 diabetes.

Anatomic and functional topography of the dorsal raphe nucleus.

Abstract: Serotonergic systems play an important and generalized role in regulation of sleep-wake states and behavioral arousal. Recent in vivo electrophysiologic recording studies in animals suggest that several different subtypes of serotonergic neurons with unique behavioral correlates exist within the brainstem raphe nuclei, raising the possibility that topographically organized subpopulations of serotonergic neurons may have unique behavioral or physiologic correlates and unique functional properties. We have shown that the stress-related and anxiogenic neuropeptide corticotropin-releasing factor can stimulate the in vitro neuronal firing rates of topographically organized subpopulations of serotonergic neurons within the dorsal raphe nucleus (DR). These findings are consistent with a wealth of behavioral studies suggesting that serotonergic systems within the DR are involved in the modulation of ongoing anxiety-related behavior and in behavioral sensitization, a process whereby anxiety- and fear-related behavioral responses are sensitized for a period of up to 24 to 48 h. The dorsomedial subdivision of the DR, particularly its middle and caudal aspects, has attracted considerable attention as a region that may play a critical role in the regulation of acute and chronic anxiety states. Future studies aimed at characterization of the molecular and cellular properties of topographically organized subpopulations of serotonergic neurons are likely to lead to major advances in our understanding of the role of serotonergic systems in stress-related physiology and behavior.