Glycans and glycan-binding proteins in brain: galectin-1-induced expression of neurotrophic factors in astrocytes

Astrocytes are a major cell type in the central nervous system (CNS). They are considered to act in cooperation with neurons and other glial cells and to participate in the development and maintenance of functions of the CNS. Immature astrocytes possess a polygonal shape and have no processes, and continue to proliferate, while mature astrocytes have a stellate cell morphology, increased glial fibrillary acidic protein expression, and proliferate slowly. Stellate astrocytes, which immediately appear at the site of brain lesions by ischemia or other brain injuries, are thought to produce several neurotrophic factors to protect neurons from delayed post-lesion death. Previously we reported that galectin-1, a member of the family of beta-galactoside-binding proteins, induced astrocyte differentiation, and the differentiated astrocytes greatly enhanced their production of brain-derived neurotrophic factor (BDNF). BDNF is known to promote neuronal survival, guide axonal pathfinding, and participate in activity-dependent synaptic plasticity during development. The effect of galectin-1 is astrocyte-specific and does not have any effect on neurons. Prevention of neuronal loss during CNS injuries is important to maintain brain function. Induction of neuroprotective factors in astrocytes by an endogenous mammalian lectin may be a new mechanism for preventing neuronal loss after brain injury, and may be useful for the treatment of neurodegenerative disorders.     

Microglia toxicity in preterm brain injury

Microglia are the resident phagocytic cells of the central nervous system. During brain development they are also imperative for apoptosis of excessive neurons, synaptic pruning, phagocytosis of debris and maintaining brain homeostasis. Brain damage results in a fast and dynamic microglia reaction, which can influence the extent and distribution of subsequent neuronal dysfunction. As a consequence, microglia responses can promote tissue protection and repair following brain injury, or become detrimental for the tissue integrity and functionality. In this review, we will describe microglia responses in the human developing brain in association with injury, with particular focus on the preterm infant. We also explore microglia responses and mechanisms of microglia toxicity in animal models of preterm white matter injury and in vitro primary microglia cell culture experiments.     

Revoking the privilege: targeting HER2 in the central nervous system

Pharmacologic agents developed for cancer therapy have traditionally relied on a therapeutic ratio of effects between tumors and normal tissue. Over the past decade, this concept has been refined through the development of agents that are intended to specifically target tumor cells. The epidermal growth factor receptor (EGFR) (ErbB) family of receptor tyrosine kinases is an intensely studied target in many cancer cell types, and several successful therapeutic agents have been developed to block the growth promoting functions of these receptors. However, with their success has come the evolution of novel clinical scenarios by which tumor cells can evade these targeted therapies. Trastuzumab, a monoclonal antibody to Her2/ErbB2 that is used in breast cancer, has been shown to provide a survival benefit for patients whose tumors express this receptor but it does not have activity in the central nervous system because of the blood-brain barrier. In this issue of Molecular Pharmacology, Emanuel et al. (p. 328) report on a tyrosine kinase inhibitor that targets Her2/neu and also crosses the blood-brain barrier. Efforts to improve current strategies of targeting this receptor may lead not only to benefits in the treatment of breast cancer but also to advances in the treatment of other central nervous system malignancies, such as gliomas and medulloblastoma.     

Gastric mucosal protection: from prostaglandins to gene-therapy

The maintenance of gastric mucosal function and integrity highly depends on the status of microcirculation. Vasoactive agents--prostaglandins, nitric oxide and sensory neuropeptides (e.g. calcitonin gene-related peptide)--play a crucial role in mucosal defensive processes. Beside the local release of vasoactive mediators the central nervous system is also involved in regulation of gastric functions. Cerebral lesions, stimulation of different brain areas can result in gastric mucosal injury. Noxious challenge of gastric mucosa alters the sodium currents in gastric sensory neurons and induces cfos mRNA expression in nucleus tractus solitarii and area postrema. Vagal nerve has long been established to play a permissive role in the development of gastric lesions. However, several lines of evidences suggest its physiological relevance in the enhancement of gastric mucosal resistance. It was concluded that gastroprotection can be induced by low level of central vagal stimulation and the consequent release of prostaglandins, nitric oxide, and calcitonin gene-related peptide. Prostaglandins, nitric oxide and sensory neuropeptides play a role also in ulcer healing by stimulating the formation of growth factors, the epithelial proliferation and angiogenesis. Both systemic and local administration of growth factors accelerated the ulcer healing. Local, single injection of plasmid-DNA encoding vascular endothelial growth factor (VEGF) was shown to stimulate the ulcer healing in the rat. The transient, local expression of VEGF in ulcerated tissue might be a new therapeutic strategy in the treatment of gastric ulcer disease.     

New advances on the functions of epidermal growth factor receptor and ceramides in skin cell differentiation, disorders and cancers

Recent advances in understanding of the biological functions of the epidermal growth factor and epidermal growth factor receptor (EGF-EGFR) system and ceramide production for the maintenance of skin integrity and barrier function are reported. In particular, the opposite roles of EGFR and ceramide cascades in epithelial keratinocyte proliferation, migration and terminal differentiation are described. Moreover, the functions of ceramides in the epidermal permeability barrier are reviewed. The alterations in EGFR signaling and ceramide metabolism, which might be involved in the etiopathogenesis of diverse skin disorders and cancers, are described. New progress in understanding of skin organization, which might provide the basis for the design of new transcutaneous drug delivery techniques as well as for the development of new therapies of skin disorders and cancers, are reported.     

促红细胞生成素及受体神经保护作用的研究进展

促红细胞生成素（EPO）是刺激红细胞造血的生长因子和细胞因子。最近几年,有报道显示EPO在神经系统中有重要的非造血功能,对神经系统的发生、维持、保护和修复有极为关键的作用。大量实验研究显示EPO及其受体在神经系统中有表达,在细胞培养和神经系统紊乱的动物模型中EPO发挥着显著的神经保护作用。本文对EPO的分子机制、神经营养和神经保护特性进行综述。     

Blood-brain barrier interfaces and brain tumors

In the developing brain, capillaries are differentiated and matured into the blood-brain barrier (BBB), which is composed of cerebral endothelial cells, astrocyte end-feet, and pericytes. Since the BBB regulates the homeostasis of central nervous system (CNS), the maintenance of the BBB is important for CNS function. The disruption of the BBB may result in many brain disorders including brain tumors. However, the molecular mechanism of BBB formation and maintenance is poorly understood. Here, we summarize recent advances in the role of oxygen tension and growth factors on BBB development and maintenance, and in BBB dysfunction related with brain tumors.     

The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications

Stress responses have been posited to be a key component of mental health and disease by playing essential roles both in normal adaptive processes and maladaptive physiological responses that in part underlie the pathogenesis of certain subtypes of mood and anxiety disorders. Early research focused on delineating the function of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently examined its role in mediating the mammalian stress responses and its hyperactivity in depression. Much evidence now supports an important function of the biological mediators of this system in relation to not only depression, but also anxiety, substance abuse, and psychotic disorders, and implicates several components of this system as areas of intervention for novel pharmacotherapy. Perhaps the best studied central nervous system (CNS) component of this system is corticotropin-releasing factor (CRF), and considerable research has focused on its role in the HPA axis, as well in extrahypothalamic brain regions.     

Activation of GABA(A) receptors by taurine and muscimol blocks the neurotoxicity of beta-amyloid in rat hippocampal and cortical neurons

The β-amyloid peptide (Aβ) is centrally related to the pathogenesis of Alzheimer's disease (AD) and is potently neurotoxic to central nervous system neurons. The neurotoxicity of Aβ has been partially related to the over activation of glutamatergic transmission and excitotoxicity. Taurine is a naturally occurring β-amino acid present in the mammalian brain. Due to its safety and tolerability, taurine has been clinically used in humans in the treatment of a number of non-neurological disorders. Here, we show that micromolar doses of taurine block the neurotoxicity of Aβ to rat hippocampal and cortical neurons in culture. Moreover, taurine also rescues central neurons from the excitotoxicity induced by high concentrations of extracellular glutamate. Neuroprotection by taurine is abrogated by picrotoxin, a GABA_A receptor antagonist. GABA and muscimol, an agonist of the GABA_A receptor, also block neuronal death induced by Aβ in rat hippocampal and cortical neurons. These results suggest that activation of GABA_A receptors protects neurons against Aβ toxicity in AD-affected regions of the mammalian brain and that taurine should be investigated as a novel therapeutic tool in the treatment of AD and of other neurological disorders in which excitotoxicity plays a relevant role.     

Potential therapeutic uses of BDNF in neurological and psychiatric disorders

The growth factor brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TRKB) are actively produced and trafficked in multiple regions in the adult brain, where they influence neuronal activity, function and survival throughout life. The diverse presence and activity of BDNF suggests a potential role for this molecule in the pathogenesis and treatment of both neurological and psychiatric disorders. This article reviews the current understanding and future directions in BDNF-related research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.     

Role of PPARgamma in the development of the central nervous system

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that plays a central role in adipocyte differentiation and insulin sensitivity. Recently, a diversity of the action of PPARgamma on many other cell types or organs is indicated. We summarize here the possible role of PPARgamma in the development of the murine central nervous system. Expressions of PPARgamma in newborn or adult mouse brain are extremely low, but high in embryo or fetal mouse brain. Furthermore, we investigated the role of PPARgamma in proliferation or differentiation of neural stem cells (NSCs) isolated from murine embryonic brains, because NSCs are considered to be a major source of neurons in developmental brains. Administrations of PPARgamma-specific ligands on the NSCs from wild-type mice resulted in the stimulation of cell growth. On the other hand, administration of PPARgamma-antagonist showed the cell death and apoptosis of NSCs. These results may indicate that PPARgamma plays an important role during the early stage of the development of the central nervous system.     

The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System

The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), α and β (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells. PDGF exerts essential roles from the gastrulation period to adult neuronal maintenance by contributing to the regulation of development of preplacodal progenitors, placodal ectoderm, and neural crest cells to adult neural progenitors, in coordinating with other factors. In adulthood, PDGF plays critical roles for maintenance of many specific cell types in the nervous system together with vascular cells through controlling the blood brain barrier homeostasis. At injury or various stresses, PDGF modulates neuronal excitability through adjusting various ion channels, and affecting synaptic plasticity and function. Furthermore, PDGF stimulates survival signals, majorly PI3-K/Akt pathway but also other ways, rescuing cells from apoptosis. Studies imply an involvement of PDGF in dendrite spine morphology, being critical for memory in the developing brain. Recent studies suggest association of PDGF genes with neuropsychiatric disorders. In this review, we will describe the roles of PDGF in the nervous system, from the discovery to recent findings, in order to understand the broad spectrum of PDGF in the nervous system. Recent development of pharmacological and replacement therapies targeting the PDGF system is discussed.     

Drug-associated mitochondrial toxicity and its detection

Mitochondrial dysfunction is a fundamental mechanism in the pathogenesis of several significant toxicities in mammals, especially those associated with the liver, skeletal and cardiac muscle, and the central nervous system. These changes can also occur as part of the natural aging process and have been linked to cellular mechanisms in several human disease states including Parkinson's and Alzheimer's, as well as ischemic perfusion injury and the effects of hyperglycemia in diabetes mellitus. Our knowledge of the effects of xenobiotics on mitochondrial function has expanded to the point that chemical structure and properties can guide the pharmaceutical scientist in anticipating mitochondrial toxicity. Recognition that maintenance of the mitochondrial membrane potential is essential for normal mitochondrial function has resulted in the development of predictive cell-based or isolated mitochondrial assay systems for detecting these effects with new chemical entities. The homeostatic role of some uncoupling proteins, differences in mitochondrial sensitivity to toxicity, and the pivotal role of mitochondrial permeability transition (MPT) as the determinant of apoptotic cell death are factors that underlie the adverse effects of some drugs in mammalian systems. In order to preserve mitochondrial integrity in potential target organs during therapeutic regimens, a basic understanding of mitochondrial function and its monitoring in the drug development program are essential. Toward this end, this review focuses on two topics, (1) the specific effects of xenobiotics on mitochondrial structure and function and (2) a summarization of current methods for quantifying these changes in a preclinical toxicology laboratory.     

Astrocytes: targets for neuroprotection in stroke

In the past two decades, over 1000 clinical trials have failed to demonstrate a benefit in treating stroke, with the exception of thrombolytics. Although many targets have been pursued, including antioxidants, calcium channel blockers, glutamate receptor blockers, and neurotrophic factors, often the focus has been on neuronal mechanisms of injury. Broader attention to loss and dysfunction of non-neuronal cell types is now required to increase the chance of success. Of the several glial cell types, this review will focus on astrocytes. Astrocytes are the most abundant cell type in the higher mammalian nervous system, and they play key roles in normal CNS physiology and in central nervous system injury and pathology. In the setting of ischemia astrocytes perform multiple functions, some beneficial and some potentially detrimental, making them excellent candidates as therapeutic targets to improve outcome following stroke and in other central nervous system injuries. The older neurocentric view of the central nervous system has changed radically with the growing understanding of the many essential functions of astrocytes. These include K+ buffering, glutamate clearance, brain antioxidant defense, close metabolic coupling with neurons, and modulation of neuronal excitability. In this review, we will focus on those functions of astrocytes that can both protect and endanger neurons, and discuss how manipulating these functions provides a novel and important strategy to enhance neuronal survival and improve outcome following cerebral ischemia.     

The glutamatergic neurotransmission in the central nervous system

Glutamate is one of the major neurotrasmitters in mammalian brain and changes in its concentration have been associated with a number of neurological disorders, including neurodegenerative, cerebrovascular diseases and epilepsy. Moreover, recently a possible role for glutamatergic system dysfunction has been suggested also in the peripheral nervous system. This chapter will revise the current knowledge in the distribution of glutamate and of its receptors and transporters in the central nervous system.     

Targeting mTOR as a novel therapeutic strategy for traumatic CNS injuries

The adult central nervous system (CNS) has a remarkable ability to repair itself. However, severe brain and spinal cord injuries (SCIs) cause lasting disability and there are only a few therapies that can prevent or restore function in such cases. In this review, we provide an overview of traumatic CNS injuries and discuss several emerging pharmacological options that have shown promise in preclinical and early clinical studies. We highlight therapies that modulate mammalian target of rapamycin (mTOR) signaling, a pathway that is well known for its roles in cell growth, metabolism and cancer. Interestingly, this pathway is also gaining newfound attention for its role in CNS repair and regeneration.     

The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia.

The pathogenesis of schizophrenia may be ascribed to early maldevelopment of brain tissue. Neurotrophins are a group of dimeric proteins that affect the development of the nervous system in all vertebrates' species. Since neurotrophins, as well as other growth factors, play a crucial role in neurodevelopment, they are plausible candidates of taking part in the pathophysiology of schizophrenia. In line with this hypothesis, accumulating preclinical and clinical data indicate that dysfunctions of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may contribute to impaired brain development, neuroplasticity and synaptic "dysconnectivity" leading to the schizophrenic syndrome, or at least some of its presentations. This article reviews the functions of neurotrophins in the complex process of normal brain development, and their possible relevance to the neuropathology and neuropharmacology of schizophrenia. Further research in this area may bring about novel pharmacological therapeutic strategies to this chronic debilitating disorder.     

Erythropoietin in the brain: can the promise to protect be fulfilled?

Erythropoietin (EPO) has emerged as a versatile growth factor that has transcended its traditional role as a mediator of erythroid maturation to one that modulates stem cell development, cellular protection and angiogenesis in the brain. As a possible candidate for nervous system disorders, it becomes crucial to understand the cellular mechanisms that foster cytoprotection rather than cytotoxicity for EPO. EPO offers novel neuronal and vascular protection not only through the maintenance of cellular integrity, but also through the prevention of cellular inflammation. The protective and anti-inflammatory capacities of EPO originate with the Janus tyrosine kinase 2 protein and protein kinase B (Akt). Downstream cellular pathways include FOXO3a, GSK-3beta, Bad, Bcl-xL, NF-kappaB, mitochondrial membrane permeability, APAF-1 and caspases. Further understanding of the cellular pathways that are susceptible to modulation by EPO will be crucial to foster the development of this agent as a robust and efficacious therapy for the brain.