Neurosteroids: a new brain function?

The biosynthesis of neurosteroids proceeds through cholesterol side-chain cleavage, and gives rise to pregnenolone (P) and dehydroepiandrosterone (D). These steroids accumulate in the rat brain independently of the supply by peripheral endocrine glands. This led to the discovery of a steroid biosynthesis pathway in rat brain oligodendrocytes based on enzyme immunocytochemistry and conversion of radioactive precursors to C-21 steroids. Several biological functions have been proposed for P and D. They may serve as precursors of other steroids (such as progesterone and testosterone and their metabolites). They are implicated in the control of some behavioural activities. They have excitatory effects on neurons, and they modulate the function of GABAA-receptors. These observations may apply to all mammalian species including the human, and the physiological significance of neurosteroid synthesis needs further investigation. The relationship between steroids and cerebral function may be reconsidered in the light of a new fact: the existence of a biosynthetic pathway of these compounds from cholesterol, assured in the brain by the oligodendrocytes, glial cells which synthesize myelin.     

Iron trafficking inside the brain

Iron, an essential element for all cells of the body, including those of the brain, is transported bound to transferrin in the blood and the general extracellular fluid of the body. The demonstration of transferrin receptors on brain capillary endothelial cells (BCECs) more than 20 years ago provided the evidence for the now accepted view that the first step in blood to brain transport of iron is receptor-mediated endocytosis of transferrin. Subsequent steps are less clear. However, recent investigations which form the basis of this review have shed some light on them and also indicate possible fruitful avenues for future research. They provide new evidence on how iron is released from transferrin on the abluminal surface of BCECs, including the role of astrocytes in this process, how iron is transported in brain extracellular fluid, and how iron is taken up by neurons and glial cells. We propose that the divalent metal transporter 1 is not involved in iron transport through the BCECs. Instead, iron is probably released from transferrin on the abluminal surface of these cells by the action of citrate and ATP that are released by astrocytes, which form a very close relationship with BCECs. Complexes of iron with citrate and ATP can then circulate in brain extracellular fluid and may be taken up in these low-molecular weight forms by all types of brain cells or be bound by transferrin and taken up by cells which express transferrin receptors. Some iron most likely also circulates bound to transferrin, as neurons contain both transferrin receptors and divalent metal transporter 1 and can take up transferrin-bound iron. The most likely source for transferrin in the brain interstitium derives from diffusion from the ventricles. Neurons express the iron exporting carrier, ferroportin, which probably allows them to excrete unneeded iron. Astrocytes lack transferrin receptors. Their source of iron is probably that released from transferrin on the abluminal surface of BCECs. They probably to export iron by a mechanism involving a membrane-bound form of the ferroxidase, ceruloplasmin. Oligodendrocytes also lack transferrin receptors. They probably take up non-transferrin bound iron that gets incorporated in newly synthesized transferrin, which may play an important role for intracellular iron transport.     

Models for the study of memory and neurosteroids]

The steroids dehydroepiandrosterone sulfate (DHEA-S) and pregnenolone sulfate (Preg-S) are naturally synthetized in the brain. They improve short term and long term memory performances in a variety of learning tasks and models of amnesia in rodents. DHEA-S and Preg-S modulate GABAergic and glutamatergic synaptic transmission through direct interactions with GABA-A, NMDA and/or sigma 1 membrane receptors. In addition, these two neurosteroids facilitate the release of acetylcholine and modulate synaptic plasticity phenomena in cerebral structures, such as the hippocampus, known to play a role in learning and memory processes. The possible links between these actions and the promnestic effects of DHEA-S and Preg-S are discussed in the present review.     

Prostanoid receptors: ontogeny and implications in vascular physiology

Prostanoids exert significant effects on circulatory beds. They play a role in the response of the vasculature to adjustments in perfusion pressure and oxygen and carbon dioxide tension, and they mediate the actions of numerous factors. The role of prostanoids in governing circulation of the perinate is suggested to surpass that in the adult. Prostanoids are abundantly generated in the perinate. They have been implicated in autoregulation of blood flow as studied in brain and eyes. Prostaglandins are also dominant regulators of ductus arteriosus tone. The effects of these autacoids are mediated through specific G protein-coupled receptors. In addition to the pharmacological characterization of the prostanoid receptors, important advances in understanding the biology of these receptors have been made in the last decade. Their cloning and the development of animals with disrupted genes of these receptors have been very informative. The involvement of prostanoid receptors in the developing subject, especially on brain and ocular vasculature and on ductus arteriosus, has also begun to be investigated; the expression of these receptors changes with development. Some but not all of the ontogenic changes in these receptors are attributed to homologous regulation. Interestingly, in the process of elucidating their effects, functional perinuclear prostaglandin E2 receptors have been uncovered. This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology.     

Cytokines and acute neurodegeneration

Cytokines have been implicated as mediators and inhibitors of diverse forms of neurodegeneration. They are induced in response to brain injury and have diverse actions that can cause, exacerbate, mediate and/or inhibit cellular injury and repair. Here we review evidence for the contribution of cytokines to acute neurodegeneration, focusing primarily on interleukin 1 (IL-1), tumour necrosis factor-alpha (TNFalpha) and transforming growth factor-beta (TGFbeta). TGFbeta seems to exert primarily neuroprotective actions, whereas TNFalpha might contribute to neuronal injury and exert protective effects. IL-1 mediates ischaemic, excitotoxic and traumatic brain injury, probably through multiple actions on glia, neurons and the vasculature. Understanding cytokine action in acute neurodegeneration could lead to novel and effective therapeutic strategies, some of which are already in clinical trials.     

Estrogen and microglia: A regulatory system that affects the brain.

Sex hormones are involved in the physiological regulation of several aspects of behavior and neuroendocrine events. It has been accepted that such effects are mediated directly by steroid actions on neurons; however, new studies have shown that the glial cells are also affected by gonadal steroids. The microglia are one specialized brain glial cell type, which is a target for estrogen actions. In fact, we believe that many of the immune and nonimmune regulatory functions of microglia in the brain are influenced directly by estrogen via expression and secretion of cytokines, and growth factors by the microglia. The present review details only a section of the known aspects of microglial function, focusing mainly on nonimmune regulatory actions in the brain and their functional relationship with sex hormones. Moreover, we present evidence for the presence of estrogen receptor-beta (ERbeta) in rat microglial cells.     

Steroid hormones as mediators of neural plasticity

Steroid and thyroid hormone receptors are expressed in the developing brain and persist throughout adult life. They mediate a variety of effects on the brain, ranging from developmental effects of thyroid hormone and the process of sexual differentiation to the cyclic changes during reproductive cycles in adult female animals. This review summarizes data from the author's laboratory on three topics: (1) actions of extradiol and progesterone on the ventromedial nucleus of the hypothalamus in adult female and male rats, showing both the cyclicity and the consequences of brain sexual differentiation; (2) actions of estradiol on the cholinergic neurons of the basal forebrain of the female and male rat, reflecting the plasticity of the adult cholinergic system as well as sex differences which are developmentally programmed; and (3) diverse actions of estrogens, thyroid hormone and glucocorticoids on the morphology of hippocampal neurons. The review concludes by discussing the interactions between "organizational" (i.e. developmental) effects and the "activational" effects of steroids on the mature nervous system in relation to the environmental control of brain gene expression.     

Extra-nuclear signaling of ERα to the actin cytoskeleton in the central nervous system

Cell morphology is controlled by a complex and redundant array of intracellular signaling pathways devoted to the regulation of the actin cytoskeleton and of its relationship with the cell membrane and the extracellular matrix. Sex steroids are effective regulators of cell morphology and tissue organization, and recent evidence indicates that this is obtained through the regulation of the cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through rapid, non-classical signaling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis. The identification of the mechanistic basis for these rapid actions on cell cytoskeleton has special relevance for the characterization of the effects of sex steroids in physiological conditions, such as their role in the control of brain cell remodeling. Brain cell morphology is controlled by estrogens that regulate the development of neuron/neuron interconnections and dendritic spine density. This is thought to be critical for gender-specific differences in brain function and dysfunction. The recent advancements in the characterization of the molecular basis of the extra-nuclear signaling of estrogen helps to understand the role of estrogen in the brain, and may in the future turn out to be of relevance for clinical purposes. This review highlights the regulatory effects on the cytoskeleton and cell morphology of estrogens as well as the recent advances in the characterization of these mechanisms, providing insights and working hypotheses on possible clinical applications for the modulation of these pathways in the central nervous system.     

Cyclic GMP-Dependent Protein Kinase and Cellular Signaling in the Nervous System

Abstract: Nitric oxide (NO) and natriuretic peptide hormones play key roles in a surprising number of neuronal functions, including learning and memory. Most data suggest that they exert converging actions by elevation of intracellular cyclic GMP (cGMP) levels through activation of soluble and particulate guanylyl cyclases. However, cGMP is only the starting point for multiple signaling cascades, which are now beginning to be defined. A primary action of elevated cGMP levels is the stimulation of cGMP-dependent protein kinase (PKG), the major intracellular receptor protein for cGMP, which phosphorylates substrate proteins to exert its actions. It has become increasingly clear that PKG mediates some of the neuronal effects of cGMP, but how is not yet clear. One clear illustration of this pathway has been reported in striatonigral nerve terminals, where NO mediates phosphorylation of the protein phosphatase regulator dopamine- and cyclic AMP-regulated phosphoprotein having a molecular mass of 32,000 (DARPP-32) by PKG. There are remarkably few PKG substrates in brain whose identities are known. A survey of these proteins and those known from other tissues that might also be found in the nervous system reveals the key molecular sites where cGMP and PKG signaling is likely to be regulating neural function. These potential substrates are critically placed to have profound effects on the protein phosphorylation network through regulation of protein phosphatases, intracellular calcium levels, and the function of many ion channels and neurotransmitter receptors. The brain also contains a rich diversity of specific PKG substrates whose identities are not yet known. Their future identification will provide exciting new leads that will permit better understanding of the role of PKG signaling in both basic and higher orders of brain function.     

Ketone body synthesis in the brain: possible neuroprotective effects

Ketone bodies make an important contribution to brain energy production and biosynthetic processes when glucose becomes scarce. Although it is generally assumed that the liver supplies the brain with ketone bodies, recent evidence shows that cultured astrocytes are also ketogenic cells. Moreover, astrocyte ketogenesis might participate in the control of the survival/death decision of neural cells in at least two manners: first, by scavenging non-esterified fatty acids the ketogenic pathway would prevent the detrimental actions of these compounds and their derivatives (e.g. ceramide) on brain structure and function. Second, ketone bodies may exert pro-survival actions per se by acting as cellular substrates, thereby preserving neuronal synaptic function and structural stability. These findings support the notion that ketone bodies produced by astrocytes may be used in situ as substrates for neuronal metabolism, and raise the possibility that astrocyte ketogenesis is a neuroprotective pathway.     

Sensory circumventricular organs: central roles in integrated autonomic regulation

Circumventricular organs (CVO) play a critical role as transducers of information between the blood, neurons and the cerebral spinal fluid (CSF). They permit both the release and sensing of hormones without disrupting the blood-brain barrier (BBB) and as a consequence of such abilities the CVOs are now well established to have essential regulatory actions in diverse physiological functions. The sensory CVOs are essential signal transducers located at the blood-brain interface regulating autonomic function. They have a proven role in the control of cardiovascular function and body fluid regulation, and have significant involvement in central immune response, feeding behavior and reproduction, the extent of which is still to be determined. This review will attempt to summarize the research on these topics to date. The complexities associated with sensory CVO exploration are intense, but should continue to result in valuable contributions to our understanding of brain function.     

Peptides as regulators of the immune system: emphasis on somatostatin

Study of the communication between nervous and immune systems culminated in the understanding that cytokines, formerly considered exclusively as immune system-derived peptides, are endogenous to the brain and display central actions. More recently, immune cells have been recognized as a peripheral source of “brain-specific” peptides with immunomodulatory actions. This article reviews studies concerning reciprocal effects of selected cytokines and neuropeptides in the nervous and immune systems, respectively. The functional equivalence of these two categories of communicators is discussed with reference to the example of the actions of neuropeptide somatostatin in the immune system.     

DNA topoisomerase II, genotoxicity, and cancer

Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under- and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destabilize the genome. This article discusses both aspects of human type II topoisomerases.     

Brain Peptides and Obesity: Pharmacologic Treatment

Obesity results from an imbalance between nutrient ingestion and metabolism, with more calories being ingested than utilized. The brain plays an important role in coordinating these complex behavioral and physiological functions, operating through multiple neurochemical systems with distinct properties. This review focuses on two hypothalamic peptide systems, neuropeptide Y (NPY) and galanin (GAL), that illustrate how the brain operates through different mechanisms to control the body's nutrient stores, in different states or conditions. These peptides have different behavioral and physiological effects and are, themselves, differentially responsive to feedback signals from circulating steroids, peptides, and nutrients. They can be distinguished by their relation to natural feeding patterns and endogenous hormones and by their specificity of action in relation to natural biological rhythms. The neuroanatomical substrates involved in these actions of NPY and GAL are also distinct. The neurocircuit mediating NPY's actions originates in the arcuate nucleus and terminates in the medial portion of the paraventricular nucleus; the GAL-containing neurons, in contrast, are concentrated in the lateral portion of the paraventricular nucleus, in addition to the medial preoptic area, which contribute to local GAL innervation as well as projections to the median eminence. Regarding their distinct functions, the evidence suggests that the NPY system is more closely related to patterns of carbohydrate ingestion and carbohydrate utilization, channeling nutrients towards the synthesis of fat. It is most strongly activated at the start of the active feeding cycle or after weaning, in close association with the adrenal steroid, corticosterone. The GAL system, in contrast, is more closely associated with patterns of fat consumption and signals related to fat oxidation. This peptide system is most active during the middle of the feeding cycle or immediately after puberty, in close association with the gonadal steroids. The gene expression and synthesis of these peptides in their respective neuronal cell groups is inhibited by circulating insulin and altered by dietary nutrients. Disturbances in sensitivity to insulin and steroid feedback regulation in the brain are believed to be involved in producing abnormal patterns of peptide function that result in overeating and body weight gain.     

Minocycline attenuates neuronal apoptosis and improves motor function after traumatic brain injury in rats

Minocycline is a type of tetracycline antibiotic with broad-spectrum antibacterial activity that has been demonstrated to protect the brain against a series of central nervous system diseases. However, the precise mechanisms of these neuroprotective actions remain unknown. In the present study, we found that minocycline treatment significantly reduced HT22 cell apoptosis in a mechanical cell injury model. In addition, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining confirmed the neuroprotective effects of minocycline in vivo through the inhibition of apoptosis in a rat model of controlled cortical impact (CCI) brain injury. The western blotting analysis revealed that minocycline treatment significantly downregulated the pro-apoptotic proteins BAX and cleaved caspase-3 and upregulated the anti-apoptotic protein BCL-2. Furthermore, the beam-walking test showed that the administration of minocycline ameliorated traumatic brain injury (TBI)-induced deficits in motor function. Taken together, these findings suggested that minocycline attenuated neuronal apoptosis and improved motor function following TBI.     

Corticosteroid actions from neuronal membrane to behavior: neurophysiological mechanisms underlying rapid behavioral effects of corticosterone.

Investigation of the rapid suppression of male courtship clasping behavior by corticosterone in roughskin newts (Taricha granulosa) has led to the identification of a specific neuronal membrane receptor for this stress steroid. This paper describes studies of the neurophysiological effects of the rapid, membrane receptor mediated action of corticosterone on neurons that are involved in the control of clasping. In freely behaving newts, medullary neurons, including reticulospinal neurons, process clasp-triggering sensory signals and participate in control of clasping movements. Corticosterone injection causes these brainstem neurons to show selective depression of clasping-related sensorimotor function. These corticosterone effects appear in 3-10 min and are closely associated with the simultaneous depression of clasping. In addition to these functionally specific effects, corticosterone simultaneously causes widespread, primarily depressive effects on neuronal activity and excitability in the medulla and elsewhere in the brain. Thus, the membrane actions of corticosterone lead to diverse neural effects, including changes in membrane excitability as well as specific, network-level actions that are apparent only during behavior. These rapid corticosterone effects strongly interact with actions of the neuropeptides vasotocin and corticotropin-releasing factor, such that the form and magnitude of the steroid's effects depend on the prevailing neuroendocrine state of the brain.