G蛋白信号调节蛋白作为中枢神经系统药物新靶点研究进展

G蛋白偶联受体(G-prote in-coup led receptors,GPCR)是许多治疗药物的作用靶点。G蛋白信号调节蛋白(regu latorof G-prote in signaling,RGS)属一类新发现的蛋白家族,它们在GPCR信号传导中起重要作用。一般来说RGS可加速G蛋白失活进而终止GPCR信号传导,但也有些RGS同时具有效应分子和信号传递功能。兼具GPCR激动和RGS抑制功能的药物将大大增强信号传导,同时还能增加激动剂的区域特异性。由于RGS的多样性,组织分布特异性以及较强的调节活性,RGS很可能成为寻找新型中枢神经系统疾病治疗药物的新靶点。     

Regulators of G protein signaling (RGS proteins): Novel central nervous system drug targets

Abstract: Many drugs of abuse signal through receptors that couple to G proteins (GPCRs), so the factors that control GPCR signaling are likely to be important to the understanding of drug abuse. Contributions by the recently identified protein family, regulators of G protein signaling (RGS) to the control of GPCR function are just beginning to be understood. RGS proteins can accelerate the deactivation of G proteins by 1000‐fold and in cell systems they profoundly inhibit signaling by many receptors, including mu‐opioid receptors. Coupled with the known dynamic regulation of RGS protein expression and function, they are of obvious interest in understanding tolerance and dependence mechanisms. Furthermore, drugs that could inhibit their activity could be useful in preventing the development of or in treating drug dependence.     

Mitochondria as therapeutic targets of estrogen action in the central nervous system

Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca2+ homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased/enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca2+ sequestration. These effects are likely to be enhanced by antioxidant effects of estrogen, preventing the initiation of the deleterious "mitochondrial spiral". The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.     

Excitatory amino acid transporters as emerging targets for central nervous system therapeutics

In the mammalian central nervous system (CNS) the excitatory amino acid transporter (EAAT) family of proteins are responsible for the high-affinity sodium-dependent uptake of glutamate into both astroglial cells and neurones. Normal EAAT function is required both for the efficient termination of glutamatergic neurotransmission and for the maintenance of low extracellular glutamate concentrations, thereby preventing glutamate excitotoxicity. It is widely believed that a dysfunction of glutamate transmission participates in the aetiology of a number of neurodegenerative and neuropsychiatric disorders and diseases. This review introduces the EAATs as a new family of emerging therapeutic targets for CNS disorders by virtue of their central role in maintaining glutamate homeostasis. We examine recent findings on the modulation and regulation of EAATs and review the changes in both EAAT function and expression which have been described in a number of neuropathological conditions.     

Purinergic signalling and disorders of the central nervous system

Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathological conditions including brain trauma and ischaemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signalling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A(2A), P2X(4) and P2X(7), that might be therapeutically targeted for the treatment of these conditions.     

Section Review Central & Peripheral Nervous Systems: Mechanisms of apoptosis as drug targets in the central nervous system

Programmed cell death or apoptosis describes a process whereby cells actively commit to die. Under normal conditions, it is likely that apoptosis is required for embryogenesis, immune system function and tissue remodelling. Pathological conditions might lead to inappropriate inhibition or activation of apoptosis. The former is thought to occur in the development of cancers, while the latter might account for cellular degenerative disorders. Many central nervous system (CNS) disorders occur as a result of neurodegeneration but, while it is clear that cell death observed in these conditions is a result of both apoptosis and necrosis, it is not clear to what extent each contributes to the overiying pathology. If apoptosis plays a significant role in neuronal cell death there might be therapeutic potential in targeting the apoptotic mechanisms. This review discusses some of the more recent molecular mechanisms that might play a role in neuronal apoptosis. In addition, the in vitro and in vivo evidence for apoptosis in a range of central nervous system pathologies, as well as the experimental approaches used to define the mechanisms of cell death are critically examined.     

瞬时受体电位6型通道在重大中枢神经系统疾病中病理生理机制及其作为药物靶点的前景

经典瞬时受体电位6型(TRPC6)通道是一类非选择性阳离子通道,参与神经元轴突生长锥导向、促进树突生长和兴奋性突触形成等生理过程。近年研究亦表明,TRPC6参与了诸多中枢神经系统(CNS)疾病的病理过程。本文主要介绍了TRPC6在神经系统中的生理功能及在CNS疾病如脑卒中、阿尔茨海默病和癫痫中的病理机制,及以其作为药物靶点的相关研究。总结和讨论了进一步研究中需要解决的问题,展望了以TRPC6作为靶点进行药物开发的前景。     

Melatonin receptors: potential targets for central nervous system disorders

The pineal hormone melatonin has become the subject of considerable speculation in both the scientific and lay press. Media coverage, coupled with scientific interest fuelled by the recent molecular cloning of a family of melatonin receptors, has led to a renaissance in melatonin research. While numerous physiological effects have been attributed to melatonin, the lack of selective agonists and antagonists for individual melatonin receptor subtypes has hampered progress towards the elucidation of the roles of these receptors. This review focuses on the molecular and pharmacological characterisation of melatonin receptors, the possible clinical utility of melatonin receptor ligands, and the progress towards the identification of selective ligands for these receptors.     

3-Aminotetrahydrocarbazoles as a new series of central nervous system agents.

3-Dimethylamino-1,2,3,4-tetrahydrocarbazole, a structurally modified tryptamine, prevented amphetamine-induced stereotyped behavior in rats and prevented reserpine-induced ptosis in mice. Further study of this compound and a number of substituted derivatives indicated that either imipramine-like or chlorpromazine-like profiles were obtainable by changing substituents and their positions.     

Toll-like receptors as targets for inflammation, development and repair in the central nervous system

Toll-like receptors (TLRs) that play key roles in inflammation are also widely expressed in the CNS. While they are well known to activate inflammatory responses to microbial products, TLRs fulfill additional roles in the absence of infection. Emerging evidence suggests that several TLRs play a role in CNS development during fetal life and in repair during adult life. This review discusses the available data on the expression and function of individual TLR family members in the CNS and clarifies why TLRs deserve close scrutiny as a novel group of therapeutic targets for CNS disorders.     

Blood-brain barrier drug discovery for central nervous system infections

Central nervous system (CNS) infections are formidable diseases with high rates of morbidity and mortality. Since the majority of antimicrobial agents discovered so far do not cross the blood-brain barrier (BBB), the treatment of CNS infections is a major challenge issue. The development of drugs to treat those diseases requires consideration of achievable brain concentrations by targeting the following question. How can the chemistry and biology of the BBB, and infectomics be exploited for the development of drugs against CNS infections? To date drug targeting approaches, such as chemistry-based, biology-based, and infectomics-based, have been implicated in the development of drugs for treatment of CNS infections. The chemistry-based strategies rely on lipid-mediated BBB drug transport as substances that readily permeate the BBB. These usually include small molecular weight of lipophilic or hydrophobic molecules. The biology-based strategies depend on endogenous BBB transport systems, including carrier-mediated transport (CMT), active efflux transport (AET), and receptor-mediated transport (RMT). These transporters play important roles in the influxes and/or effluxes of drugs including antimicrobial agents in brain capillary endothelial cells that form the BBB. Both microbial and host signatures of infectomes, which can be dissected by infectomics, provide invaluable fountains in the search for novel antimicrobial therapies. Key markers associated with the mechanisms of neuronal injury may be identified, and thus, provide important targets for the prevention and treatment of CNS infections. This review focuses on the major BBB drug targeting strategies in the development of therapeutics for CNS infections. A combination of these strategies will ultimately lead to improved treatments.     

Innovations in drug delivery to the central nervous system

The theoretical goal of the ideal drug - to localize specifically and directly to its intended target, have a high therapeutic index and achieve therapeutic efficacy without side effects - is becoming feasible through improved drug delivery and targeting. The clinical advantages of improved drug delivery include continuously therapeutic drug levels, decreased drug dose, improved patient compliance, increased viability of short-lived pharmaceuticals like peptides and proteins, less invasive routes of administration, reduced drug side effects and simplified dosing. Innovative techniques include antibody-mediated drug release, feedback-responsive delivery systems, manipulation of carrier-mediated transport, microspheres composed of polymers and liposomes, permeabilizers, selective delivery to localized sites and vectors to penetrate the blood-brain barrier. Several delivery systems have been approved and more are in clinical trials. Drug delivery system research has greatly influenced the management of brain tumors, central nervous system infections, chronic pain, drug addiction, epileptic disorders, migraine headaches, neurodegenerative diseases, schizophrenia, spasticity and stroke. For many disorders, optimization of drug delivery will continue to be the therapeutic focus for a long while.     

Current approaches for drug delivery to central nervous system

Brain, the center of the nervous system in all vertebrate, plays the most vital role in every function of human body. However, many neurodegenerative diseases, cancer and infections of the brain become more prevalent as populations become older. In spite of the major advances in neuroscience, many potential therapeutics are still unable to reach the central nervous system (CNS) due to the blood-brain barrier (BBB) which is formed by the tight junctions within the capillary endothelium of the vertebrate brain. This results in the capillary wall behaving as a continuous lipid bilayer and preventing the passage of polar and lipid insoluble substances. Several approaches for delivering drugs to the CNS have been developed to enhance the capacity of therapeutic molecules to cross the BBB by modifying the drug itself, or by coupling it to a vector for receptor-mediated, carrier mediated or adsorption-mediated transcytosis. The current challenge is to develop drug delivery systems that ensure the safe and effective passage of drugs across the BBB. This review focuses on the strategies and approaches developed to enhance drug delivery to the CNS.     

Cytokines in the central nervous system: targets for therapeutic intervention

Accumulating evidence implicates inflammatory processes in the development of a number of neurodegenerative diseases and demonstrates that neurons and microglia can be a source for various cytokines, which are believed to be involved in neuropathology, and therefore can serve as targets for therapeutic treatment. Moreover, it is now established that many of these pro-inflammatory molecules, commonly associated with the peripheral immune system, are also produced within the central nervous system (CNS). The term 'cytokine network' has been widely used to describe cytokine biology in the brain. However, the function of this network has not been well-characterised. It is believed that understanding the function of this network might have important clinical applications. This article reviews recent and current developments in cytokine research that pertain to the development of new strategies targeting cytokines in the brain, thus opening up new avenues for novel therapeutic approaches for the treatment of various pathological conditions and diseases of the CNS.     

Regulators of G protein signalling: potential targets for treatment of allergic inflammatory diseases such as asthma

Asthma, a disease that affects nearly 15% of the world’s population, is characterised by lung inflammation and reversible airway obstruction, which leads to wheezing and dyspnoea. Asthma is a prototype for allergic processes initiated by tissue inflammatory leukocytes, such as mast cells, whose secreted mediators recruit lymphocytes and eosinophils to the lung parenchyma. Signals transmitted through G-protein-coupled receptors (GPCRs) contribute to both the development and perpetuation of allergic processes, and pharmacological agents that block or stimulate GPCR action have been a mainstay of allergic disease therapy. Despite the widespread use of GPCR-targeted agents, little is understood about intracellular regulation of G protein pathways in immune cells. Regulators of G protein signalling (RGS proteins) enhance G protein deactivation and may contribute to the specificity and precision characteristic of GPCR signalling pathways. This review discusses the emerging functions of RGS proteins in immune processes and inflammatory states such as asthma, and their potential value as therapeutic targets for the treatment of allergic disease.