Several new aspects of bubble-induced central nervous system injury

Ischaemia is a major mechanism underlying central nervous system (c.n.s.) damage in decompression sickness. Some recent experimental observations on the effect of bubble-induced ischaemia on c.n.s. tissue sharpen and extend our understanding of the pathophysiology of decompression sickness. After bubble-induced brain ischaemia, a measurable increase in 111In-labelled leucocytes occurs in the injured hemisphere. By 4 h into the recovery period the cells are concentrated in zones of low blood flow, as measured by the [14C]iodoantipyrine technique. The presence of these cells during the critical early hours of c.n.s. ischaemia suggests that they may contribute to the evolution of neuronal damage. Oedema is often cited as the cause of clinical deterioration after c.n.s. ischaemia or trauma. Recent evidence indicates that the presence and degree of circumscribed brain oedema is not a good predictor of the amount of nerve cell recovery (by using cortical sensory evoked response) after bubble-induced brain ischaemia. This brings into question the role of circumscribed oedema of the c.n.s. in dysfunction of post-ischemic nerve cells.     

ADAMTS expression and function in central nervous system injury and disorders

The components of the adult extracellular matrix in the central nervous system form a lattice-like structure that is deposited as perineuronal nets, around axon initial segments and as synapse-associated matrix. An abundant component of this matrix is the lecticans, chondroitin sulfate-bearing proteoglycans that are the major substrate for several members of the ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) family. Since lecticans are key regulators of neural plasticity, ADAMTS cleavage of lecticans would likely also contribute to neuroplasticity. Indeed, many studies have examined the neuroplastic contribution of the ADAMTSs to damage and recovery after injury and in central nervous system disease. Much of this data supports a role for the ADAMTSs in recovery and repair following spinal cord injury by stimulating axonal outgrowth after degradation of a glial scar and improving synaptic plasticity following seizure-induced neural damage in the brain. The action of the ADAMTSs in chronic diseases of the central nervous system appears to be more complex and less well-defined. Increasing evidence indicates that lecticans participate in synaptic plasticity in neurodegenerative disease states. It will be interesting to examine how ADAMTS expression and action would affect the progression of these diseases.     

Apoptotic cell death following traumatic injury to the central nervous system

Apoptotic cell death is a fundamental and highly regulated biological process in which a cell is instructed to actively participate in its own demise. This process of cellular suicide is activated by developmental and environmental cues and normally plays an essential role in eliminating superfluous, damaged, and senescent cells of many tissue types. In recent years, a number of experimental studies have provided evidence of widespread neuronal and glial apoptosis following injury to the central nervous system (CNS). These studies indicate that injury-induced apoptosis can be detected from hours to days following injury and may contribute to neurological dysfunction. Given these findings, understanding the biochemical signaling events controlling apoptosis is a first step towards developing therapeutic agents that target this cell death process. This review will focus on molecular cell death pathways that are responsible for generating the apoptotic phenotype. It will also summarize what is currently known about the apoptotic signals that are activated in the injured CNS, and what potential strategies might be pursued to reduce this cell death process as a means to promote functional recovery.     

Neuroplasticity. Key to recovery after central nervous system injury.

After an injury to the central nervous system, physical and cognitive impairments and disabilities often abate. These gains may be partly mediated by mechanisms that allow reorganizing of the structure and function within gray and white matter. The potential to enhance neurologic recovery by manipulating the brain and spinal cord must now be considered in clinical practice. Today''s rehabilitation routines may not encourage maximum recovery. Indeed, some commonly used physical and pharmacologic methods could inhibit the restoration of motor activities such as walking. On the other hand, therapies that use our expanding knowledge of neuroplasticity could lead to better results for patients.     

LPA receptor expression in the central nervous system in health and following injury

Lysophosphatidic acid (LPA) is released from platelets following injury and also plays a role in neural development but little is known about its effects in the adult central nervous system (CNS). We have examined the expression of LPA receptors 1-3 (LPA_1–3) in intact mouse spinal cord and cortical tissues and following injury. In intact and injured tissues, LPA₁ was expressed by ependymal cells in the central canal of the spinal cord and was upregulated in reactive astrocytes following spinal cord injury. LPA₂ showed low expression in intact CNS tissue, on grey matter astrocytes in spinal cord and in ependymal cells lining the lateral ventricle. Following injury, its expression was upregulated on astrocytes in both cortex and spinal cord. LPA₃ showed low expression in intact CNS tissue, viz. on cortical neurons and motor neurons in the spinal cord, and was upregulated on neurons in both regions after injury. Therefore, LPA_1–3 are differentially expressed in the CNS and their expression is upregulated in response to injury. LPA release following CNS injury may have different consequences for each cell type because of this differential expression in the adult nervous system.     

Regional differences in viral growth and central nervous system injury correlate with apoptosis

Infection of neonatal mice with reovirus T3 Dearing (T3D), the prototypic neurotropic reovirus, causes fatal encephalitis associated with neuronal injury and virus-induced apoptosis throughout the brain. T3D variant K (VarK) is an antigenic variant that has a nearly 1 million-fold reduction in neurovirulence following intracerebral (i.c.) inoculation compared to T3D and a restricted pattern of central nervous system injury with damage limited to the hippocampus, sparing other brain regions. We wished to determine whether the restricted pattern of VarK-induced injury was due to a reduced capacity to replicate in or injure cortical, as opposed to hippocampal, tissue. We found that following i.c. inoculation, VarK grew to similar titers as T3D in the hippocampus but had significantly lower titers in the cortex. Both viruses grew to identical titers and infected the same percentage of cells in mouse primary hippocampal cultures (MHC). In mouse primary cortical cultures (MCC) both the number of infected cells and the viral yield per infected cell were significantly lower for VarK than T3D. VarK-induced apoptosis was limited to the hippocampus in vivo, and in vitro both viruses induced apoptosis equally in MHC but VarK induced significantly less apoptosis than T3D in MCC. Growth of T3D in MCC was reduced to levels comparable to those of VarK following treatment of MCC with caspase inhibitors. Conversely, induction of apoptosis in VarK-infected MCC with fatty acid synthase-activating antibody significantly enhanced viral yield. These results suggest that the decreased neurovirulence of VarK may be due to its failure to efficiently induce apoptosis in cortical neurons.     

Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury

Mitochondrial dysfunction, resulting from the disruption of calcium homeostasis and the generation of toxic reactive oxygen species, is a central process leading to neuronal injury and death following acute CNS insults. Interventions aimed at preventing disturbances in mitochondrial function have therefore become targets of intense investigation. Mitochondrial uncoupling is a condition in which electron transport is disconnected from the production of ATP. As a consequence, there is a decrease in the mitochondrial membrane potential, which can temporarily decrease calcium influx and attenuate free radical formation. The potential use of pharmacological agents with uncoupling properties may provide a novel therapeutic approach for the treatment of acute neuronal injury.     

中枢神经系统内神经元信号处理(英文)

一种新颖的轴突断端(axon bleb)膜片钳记录方法大力促进了中枢神经系统轴突功能的研究。我们的工作应用这一方法揭示了大脑皮层锥体神经元的数码信号(具全或无特性的动作电位)的爆发和传播机制。在轴突始段(axon initial segment,AIS)远端高密度聚集的低阈值Na+通道亚型Nav1.6决定动作电位的爆发;而在AIS近端高密度聚集的高阈值Na+通道亚型Nav1.2促进动作电位向胞体和树突的反向传播。应用胞体和轴突的同时记录,我们发现胞体阈下膜电位的变化可以在轴突上传播较长的距离并可到达那些离胞体较近的突触前终末。进一步的研究证明了胞体膜电位的变化调控动作电位触发的突触传递,该膜电位依赖的突触传递是一种模拟式的信号传递。轴突上一类特殊K+通道(Kv1)的活动调制动作电位的波形,特别是其波宽,从而调控各种突触前膜电位水平下突触强度的变化。突触前终末的背景Ca2+浓度也可能参与模拟信号的传递。这些发现深化了我们对中枢神经系统内神经信号处理基本原理的认识,进而帮助我们理解脑如何工作。     

Endocannabinoids in the central nervous system

The major psychoactive component of cannabis derivatives, delta9-THC, activates two G-protein coupled receptors: CB1 and CB2. Soon after the discovery of these receptors, their endogenous ligands were identified: lipid metabolites of arachidonic acid, named endocannabinoids. The two major main and most studied endocannabinoids are anandamide and 2-arachidonyl-glycerol. The CB1 receptor is massively expressed through-out the central nervous system whereas CB2 expression seems restricted to immune cells. Following endocannabinoid binding, CB1 receptors modulate second messenger cascades (inhibition of adenylate cyclase, activation of mitogen-activated protein kinases and of focal-adhesion kinases) as well as ionic conductances (inhibition of voltage-dependent calcium channels, activation of several potassium channels). Endocannabinoids transiently silence synapses by decreasing neurotransmitter release, play major parts in various forms of synaptic plasticity because of their ability to behave as retrograde messengers and activate non-cannabinoid receptors (such as vanilloid receptor type-1), illustrating the complexity of the endocannabinoid system. The diverse cellular targets of endocannabinoids are at the origin of the promising therapeutic potentials of the endocannabinoid system.     

中枢神经系统谷氨酸转运体的研究进展

在中枢神经系统,谷氨酸转运体在谷氨酸一谷氨酰胺循环中发挥着重要作用。谷氨酸转运体有高亲和力转运体,即兴奋性氨基酸转运体（excitatory amino acid transporters,EAATs）和低亲和力转运体,即囊泡谷氨酸转运体（vesicular glutamate transporters,VGLUTs）两种类型。其中,VGLUTs的功能是特异地将突触囊泡外的谷氨酸转运进入突触囊泡内,它包括三个成员,分别是VGLUT1、VGLUT2和VGLUT3。一方面,VGLUT1和VGLUT2标记了所有的谷氨酸能神经元,是谷氦酸能神经元和它们轴突末端高度特异的标志;另一方面,VGLUT1标志着皮质一皮质投射,而VGLUT2则标志着丘脑一皮层投射,VGLUT3则位于抑制性突触末端。     

Emergence in the central nervous system

“Emergence” is an idea that has received much attention in consciousness literature, but it is difficult to find characterizations of that concept which are both specific and useful. I will precisely define and characterize a type of epistemic (“weak”) emergence and show that it is a property of some neural circuits throughout the CNS, on micro-, meso- and macroscopic levels. I will argue that possession of this property can result in profoundly altered neural dynamics on multiple levels in cortex and other systems. I will first describe emergent neural entities (ENEs) abstractly. I will then show how ENEs function specifically and concretely, and demonstrate some implications of this type of emergence for the CNS.     

Chondroitin sulphate proteoglycans in the central nervous system: changes and synthesis after injury

Chondroitin sulphate proteoglycans (CSPGs) are up-regulated in the central nervous system after injury, specifically around the lesion site where the glial scar forms. This structure contains astrocytes, oligodendrocyte precursor cells, microglia and meningeal cells, and forms an inhibitory substrate for axon re-growth. CSPGs have been shown to be closely involved in this neuronal growth inhibition, specifically through their sugar chains. These chains are composed of repeats of the same disaccharide unit carrying sulphate groups in different positions. The sulphation pattern directly influences the CSPG binding properties and function; the specific sulphation pattern required for the inhibitory activity of these molecules on axon growth is unknown at present. The expression of the chondroitin sulphotransferases, which sulphate the disaccharide residues of CSPGs and thus are responsible for the structural diversity of the chondroitin sulphate sugar chains, is regulated differently in central nervous system during development and after injury, suggesting the implication of a specific sulphation pattern in the inhibitory activity of CSPGs.     

IL-1与NMDAR在中枢神经系统惊厥性损伤的相互作用

惊厥性疾病是最常见的神经系统疾病之一,惊厥造成的脑损伤均为兴奋毒性损伤,在惊厥脑损伤中兴奋性氨基酸释放增加,N-甲基-D-天门冬氨酸受体(NMDAR)激活起主要作用,细胞内钙稳态失衡,导致细胞功能受损起着关键的作用,白细胞介素1(IL-1)起重要的调质作用。IL-1在中枢神经系统病理状态下与NMDA受体活化有关,它们之间相互作用,共同在脑惊厥性损伤中发挥重要作用,深入研究它们之间的相互关系有可能为治疗婴幼儿惊厥性疾病提供新策略。     

Mechanisms of radiation injury to the central nervous system: implications for neuroprotection

The central nervous system (CNS) is a major dose-limiting organ in clinical radiotherapy (XRT). The underlying mechanisms of radiation-induced injury in this organ remain unclear. For many years, research has focused on identifying the major target cells of damage, and depletion of target cells due to reproductive or clonogenic cell death was believed to be the primary cause of tissue damage and organ failure. There is now an increasing body of data indicating that the response of the CNS after XRT is a continuous and interacting process. This review addresses some of the recent advances in our understanding of the mechanisms of CNS radiation damage. Specifically, the focus is on apoptotic cell death, and cell death and injury mediated by secondary damage. These potentially reversible components of the injury response provide important targets for neuroprotective interventions.     

Dietary influence on central nervous system myelin production,injury, and regeneration

Oligodendrocytes not only produce myelin to facilitate nerve impulse conduction, but are also essential metabolic partners of the axon. Oligodendrocyte loss and myelin destruction, as occurs in multiple sclerosis (MS), leaves axons vulnerable to degeneration and permanent neurological deficits ensue. Many studies now propose that lifestyle factors such as diet may impact demyelinating conditions, including MS. Most prior reviews have focused on the regulatory role of diet in the inflammatory events that drive MS pathogenesis, however the potential for dietary factors to modulate oligodendrocyte biology, myelin injury and myelin regeneration remain poorly understood. Here we review the current evidence from clinical and animal model studies regarding the impact of diet or dietary factors on myelin integrity and other pathogenic features of MS. Some limited evidence exists that certain foods may decrease risk or influence the progression of MS, such as increased intake of fish or polyunsaturated fatty acids, caloric restriction and fasting-mimicking diets. In addition, evidence suggests adolescent obesity or insufficient vitamin D levels increase the risk for developing MS. However, no clear or consistent evidence exists that dietary components exacerbate disease progression. Cumulatively, current evidence highlights the need for more extensive clinical trials to validate dietary effects on MS and to identify diets or supplements that may be beneficial as food-based strategies in the management of MS alone or in combination with conventional disease modifying therapies.