Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Specialized glia, termed reactive astrocytes, accompany numerous pathologic conditions affecting the central nervous system, including stroke, multiple sclerosis, and neoplasia. To better define this important cell type, we employed high-density microarray gene expression profiling using two in vitro models of reactive gliosis (stimulation with dbcAMP or IL-1beta/IFNgamma). We identified 44 differentially expressed transcripts common to both in vitro models and demonstrated that a subset of these genes are also differentially expressed in response to experimental autoimmune encephalomyelitis and focal cerebral ischemia in vivo. Moreover, this pattern of differential gene expression is not observed in hyperproliferating or neoplastic glia.
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PMID:Expression profiling identifies a molecular signature of reactive astrocytes stimulated by cyclic AMP or proinflammatory cytokines. 1805 18

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS not to disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses are mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly regulating immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier control immune cell entry into the CNS, which is rare under physiological conditions. During a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis (MS), immunocompetent cells readily traverse the BBB and subsequently enter the CNS parenchyma. Most of our current knowledge on the molecular mechanisms involved in immune cell entry into the CNS has been derived from studies performed in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Thus, a large part of our current knowledge on immune cell entry across the BBBs is based on the results obtained in this animal model. Similarly, knowledge on the benefits and potential risks associated with therapeutic targeting of immune cell recruitment across the BBB in human diseases are mostly derived from such treatment regimen in MS. Other mechanisms of immune cell entry into the CNS might therefore apply under different pathological conditions such as bacterial meningitis or stroke and need to be considered.
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PMID:Therapeutic targeting of leukocyte trafficking across the blood-brain barrier. 1822 Sep 56

Different pathologic patterns in multiple sclerosis (MS) are reflected by alterations of metabolites in (1)H MR spectroscopy of the brain. Elevated choline (Cho), lactate (Lac), lipids and macromolecules are reliable markers for acute demyelination regardless of the clinical entity (also in acute disseminated encephalomyelitis). N-acetyl-aspartate (NAA) is a suitable marker for neuronal integrity. It is reduced in acute MS lesions and in normal appearing white matter, even distant to acute and chronic-lesions. Recovery from reduced NAA levels to subnormal values during remyelination, and varying time courses of NAA in normal appearing white matter during relapsing remitting disease indicate the value of this spectroscopic marker for monitoring activity and recovery. Inositol (Ins) is increased in chronic MS lesions being a marker for astrocytic gliosis. In viral disease, Cho and Ins are always increased, whereas a reduction of NAA mostly reflects an advanced or a detoriated clinical state. In bacterial brain abscesses, numerous amino acids, lipids and Lac can be elevated. In ischemia, especially the Lac/NAA in comparison with perfusion and diffusion weighted imaging seems to be a new measure for areas of metabolic need, and may help to better characterise the penumbra of the stroke and the final infarct size.
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PMID:(1)H MR spectroscopy of inflammation, infection and ischemia of the brain. 1840 47

Inflammation plays a central role in the pathophysiology of numerous disorders of the nervous system, but is also pivotal for repair processes like peripheral nerve regeneration. In this review we summarize recent advances in cellular magnetic resonance imaging (MRI) while nuclear imaging methods to visualize neuroinflammation are covered by Wunder et al. [Wunder A, Klohs J, Dirnagl U (2009) Non-invasive imaging of central nervous system inflammation with nuclear and optical imaging. Neuroscience, in press]. Use of iron oxide-contrast agents allows assessment of inflammatory processes in living organisms. Upon systemic application, circulating small (SPIO) and ultrasmall particles of iron oxide (USPIO) are preferentially phagocytosed by monocytes before clearance within the reticuloendothelial system of the liver, spleen and lymph nodes. Upon acute migration into the diseased nervous system these iron oxide-laden macrophages become visible on MRI by the superparamagnetic effects of iron oxide resulting in a signal loss on T2-w and/or bright contrast on T1-w MRI. There is an ongoing controversy, however, to what extent SPIO/USPIO also diffuses passively into the brain after disruption of the blood-brain barrier pretending macrophage invasion. Other confounding factors include circulating SPIO/USPIO particles within the blood pool, local hemorrhages, and intrinsic iron oxide-loading of phagocytes. These uncertainties can be overcome by in vitro preloading of cells with iron oxide contrast agents and consecutive systemic application into animals. Iron oxide-contrast-enhanced MRI allowed in vivo visualization of cellular inflammation during wallerian degeneration, experimental autoimmune neuritis and encephalomyelitis, and stroke in rodents, but also in patients with multiple sclerosis and stroke. Importantly, cellular MRI provides additional information to gadolinium-DTPA-enhanced MRI since cellular infiltration and breakdown of the blood-brain barrier are not closely linked. Coupling of antibodies to iron oxide particles opens new avenues for molecular MRI and has been successfully used to visualize cell adhesion molecules guiding inflammation.
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PMID:Imaging of inflammation in the peripheral and central nervous system by magnetic resonance imaging. 1865 96

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.
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PMID:Altered lipid metabolism in brain injury and disorders. 1875 14

The importance of lipids in cell signaling and tissue physiology is demonstrated by the many CNS pathologies involving deregulated lipid metabolism. One such critical metabolic event is the activation of phospholipase A(2) (PLA(2)), which results in the hydrolysis of membrane phospholipids and the release of free fatty acids, including arachidonic acid, a precursor for essential cell-signaling eicosanoids. Reactive oxygen species (ROS, a product of arachidonic acid metabolism) react with cellular lipids to generate lipid peroxides, which are degraded to reactive aldehydes (oxidized phospholipid, 4-hydroxynonenal, and acrolein) that bind covalently to proteins, thereby altering their function and inducing cellular damage. Dissecting the contribution of PLA(2) to lipid peroxidation in CNS injury and disorders is a challenging proposition due to the multiple forms of PLA(2), the diverse sources of ROS, and the lack of specific PLA(2) inhibitors. In this review, we summarize the role of PLA(2) in CNS pathologies, including stroke, spinal cord injury, Alzheimer's, Parkinson's, Multiple sclerosis-Experimental autoimmune encephalomyelitis and Wallerian degeneration.
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PMID:Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. 1875 70

We describe some of our studies on use of neuro-restorative agents for treatment of neural injury. We focus on cell-based therapies and select from a variety of statins. In addition, we show that cell-based and pharmacological-based therapies enhance brain plasticity and promote recovery of function after stroke and intracerebral hemorrhage (ICH). Injured brain recapitulates ontogeny. Cerebral tissue around the infarction expresses developmental genes, many of which are present only during embryonic or neonatal stages of development. Brain response to injury undergoes remodeling with induction of angiogenesis, neurogenesis, and synaptogenesis. The attempt at remodeling, although expressed as a partial improvement in patients with stroke and ICH, is clearly insufficient to promote substantial recovery in many patients. The goal of restorative therapies should be to activate and amplify this endogenous restorative brain plasticity process to potentiate functional recovery. The logic of restorative therapy is to treat intact or marginally compromised tissue and not injured or dying tissue. Thus, these treatments can be made available for all neurological injury. Once demonstrated to be effective for treatment of a large middle cerebral artery occlusion (MCAo), these restorative treatments can be applied to many types of injury, including ICH, traumatic brain injury, and neurodegenerative disease such as experimental autoimmune encephalomyelitis and multiple sclerosis.
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PMID:Treatment of stroke and intracerebral hemorrhage with cellular and pharmacological restorative therapies. 1906 87

In a wide variety of acute and chronic central nervous system (CNS) disorders, inflammatory processes contribute to the damage of brain cells and progression of the disease. Along with other regulatory cytokines, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is involved in the pathology of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE), bacterial meningitis (BM), HIV encephalitis (HIVE), stroke and Alzheimer's disease (AD). In these conditions, TRAIL is released within the brain mainly by activated microglia and leukocytes infiltrating from the blood stream. TRAIL promotes apoptosis of parenchymal cells in MS/EAE, HIVE, AD and stroke through interaction with TRAIL death receptors expressed on these cells. Frequently, cells in the diseased brain display increased susceptibility to apoptosis induction by TRAIL due to upregulation of death receptors and downregulation of decoy receptors. On the other hand, TRAIL inhibits the proliferation of encephalitogenic T cells in EAE, and it is involved in the clearance of infected brain macrophages in HIVE and of activated neutrophils in BM by interaction with their death receptors. Especially in BM, the ability of TRAIL to limit an acute granulocyte-driven inflammation carries significant neuroprotective potential. Given the diversity of beneficial and harmful effects in the immune and nervous system, TRAIL is a double-edged sword in diseases involving CNS inflammation.
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PMID:Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in central nervous system inflammation. 1944 43

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.
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PMID:Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. 1970 21

Dysregulation of the blood-brain barrier (BBB) is a hallmark feature of numerous neurologic disorders as diverse as multiple sclerosis, stroke, epilepsy, viral hemorrhagic fevers, cerebral malaria, and acute hemorrhagic leukoencephalitis. CD8 T cells are one immune cell type that have been implicated in promoting vascular permeability in these conditions. Our laboratory has created a murine model of CD8 T cell-mediated CNS vascular permeability using a variation of the Theiler's murine encephalomyelitis virus system traditionally used to study multiple sclerosis. Previously, we demonstrated that CD8 T cells have the capacity to initiate astrocyte activation, cerebral endothelial cell tight junction protein alterations and CNS vascular permeability through a perforin-dependent process. To address the downstream mechanism by which CD8 T cells promote BBB dysregulation, in this study, we assess the role of vascular endothelial growth factor (VEGF) expression in this model. We demonstrate that neuronal expression of VEGF is significantly upregulated prior to, and coinciding with, CNS vascular permeability. Phosphorylation of fetal liver kinase-1 is significantly increased early in this process indicating activation of this receptor. Specific inhibition of neuropilin-1 significantly reduced CNS vascular permeability and fetal liver kinase-1 activation, and preserved levels of the cerebral endothelial cell tight junction protein occludin. Our data demonstrate that CD8 T cells initiate neuronal expression of VEGF in the CNS under neuroinflammatory conditions, and that VEGF may be a viable therapeutic target in neurologic disease characterized by inflammation-induced BBB disruption.
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PMID:CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions. 2000 93


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