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Microglia Reviews: 2003
(48 References)
Annunziata, P. (2003). "Blood-brain barrier changes during invasion of the central nervous system by HIV-1. Old and new insights into the mechanism." J Neurol 250(8): 901-6.
The mechanism underlying the early invasion of the central nervous system by HIV-1 is unclear. Here, we summarize old and new findings supporting blood-brain barrier changes during HIV and experimental simian immunodeficiency virus (SIV) infection. The effect of inflammatory and toxic molecules secreted by monocytes and microglia on the functional integrity of tight junctions of brain endothelium is highlighted. Furthermore, recent findings on a possible direct role of the envelope and regulatory HIV-1 proteins (gp120, Tat, Nef) in causing the blood-brain barrier changes are reviewed. The possibility that these proteins, as circulating molecules, may bind to microvessel endothelial cells and cause blood-brain changes with no direct participation of the virus is raised. Several issues deserve further investigation and answers to these questions may provide keys for new therapeutic strategies in HIV-1 infection of the central nervous system.
Asanuma, M., I. Miyazaki, et al. (2003). "[New aspects of neuroprotective effects of nonsteroidal anti-inflammatory drugs]." Nihon Shinkei Seishin Yakurigaku Zasshi 23(3): 111-9.
Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory, analgesic and antipyretic activities and are involved in the suppression of prostaglandin synthesis by inhibiting cyclooxygenase (COX), a prostaglandin synthesizing enzyme. It has been recently revealed that NSAIDs also possess inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors and nuclear receptors which are related to inflammatory reactions. Since it has been reported that inflammatory processes are associated with the pathophysiology of several neurodegenerative diseases and that NSAIDs inhibit amyloid beta-protein-induced neurotoxicity to reduce the risk for Alzheimer's disease, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs. It has been clarified that the drugs exert neuroprotective effects, which are not related to their COX-inhibiting property, on pathophysiology of various neurological disorders. In this article, new aspects of neuroprotective effects of NSAIDs have been reviewed, especially, in Alzheimer's disease and Parkinson's disease, discussing various pharmacological effects of NSAIDs other than their inhibitory action on COX.
Banati, R. B. (2003). "Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain." Br Med Bull 65: 121-31.
Glial cells form a structural and functional network with complex cell-cell communication pathways that enable fast and slow signalling amongst themselves as well as with neurons. They exert regulatory influence on normal synaptic transmission and alter it in disease. It is becoming increasingly clear that an understanding of brain function in disease conditions requires a better account of the highly plastic, disease-associated changes in glial physiology in vivo. Particularly, microglia, the brain's ubiquitous but normally inconspicuous immune effector cell, are prominently involved in many brain diseases. They respond rapidly and in a territorially highly confined way to subtle, acute and chronic pathological stimuli. Detection of microglial activation provides diagnostically useful formal parameters of disease, such as the accurate spatial localisation, disease progression and the secondary neurodegenerative or adaptive changes remote from the primary site of disease. The latter has potential relevance for the understanding of disease-induced brain plasticity. Systematic attempts are now undertaken, using positron emission tomography and a ligand with relative selectivity for activated microglia, to develop generic imaging tools for a cellular in vivo neuropathology.
Barron, K. D. (2003). "Microglia: history, cytology, and reactions." J Neurol Sci 207(1-2): 98.
Beal, M. F. (2003). "Mitochondria, oxidative damage, and inflammation in Parkinson's disease." Ann N Y Acad Sci 991: 120-31.
The pathogenesis of Parkinson's disease (PD) remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. The present paper reviews the experimental and clinical evidence implicating these processes in PD. There is substantial evidence that there is a deficiency of complex I activity of the mitochondrial electron transport chain in PD. There is also evidence for increased numbers of activated microglia in both PD postmortem tissue as well as in animal models of PD. Impaired mitochondrial function and activated microglia may both contribute to oxidative damage in PD. A number of therapies targeting inflammation and mitochondrial dysfunction are efficacious in the MPTP model of PD. Of these, coenzyme Q(10) appears to be particularly promising based on the results of a recent phase 2 clinical trial in which it significantly slowed the progression of PD.
Brown, G. C. and A. Bal-Price (2003). "Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria." Mol Neurobiol 27(3): 325-55.
In inflammatory, infectious, ischemic, and neurodegenerative pathologies of the central nervous system (CNS) glia become "activated" by inflammatory mediators, and express new proteins such as the inducible isoform of nitric oxide synthase (iNOS). Although these activated glia have benefi- cial roles, in vitro they potently kill cocultured neurons, and there is increasing evidence that they contribute to pathology in vivo. Nitric oxide (NO) from iNOS appears to be a key mediator of such glial-induced neuronal death. The high sensitivity of neurons to NO is partly due to NO causing inhibition of respiration, rapid glutamate release from both astrocytes and neurons, and subsequent excitotoxic death of the neurons. NO is a potent inhibitor of mitochondrial respiration, due to reversible binding of NO to cytochrome oxidase in competition with oxygen, resulting in inhibition of energy production and sensitization to hypoxia. Activated astrocytes or microglia cause a potent inhibition of respiration in cocultured neurons due to glial NO inhibiting cytochrome oxidase within the neurons, resulting in ATP depletion and glutamate release. In some conditions, glutamate- induced neuronal death can itself be mediated by N-methyl-D-aspartate (NMDA)-receptor activation of the neuronal isoform of NO synthase (nNOS) causing mitochondrial damage. In addition NO can be converted to a number of reactive derivatives such as peroxynitrite, NO2, N2O3, and S-nitrosothiols that can kill cells in part by inhibiting mitochondrial respiration or activation of mitochondrial permeability transition, triggering neuronal apoptosis or necrosis.
Chaney, M. O., J. Baudry, et al. (2003). "A beta, aging, and Alzheimer's disease: a tale, models, and hypotheses." Neurol Res 25(6): 581-9.
In this paper we explore the potential functional role of the A beta peptides in the context of Alzheimer's disease (AD). We begin by defining the morphology of the amyloid deposits in relation to surrounding glial cells and, more importantly, in relation to the brain vasculature. Amyloid accumulation in the brain's microvasculature causes disturbances in the blood-brain barrier (BBB), and in larger arteries, impairment in control of regional cerebral blood flow due to myocyte degeneration. We postulate that the deposition of vascular amyloid may represent a hydrophobic protein plaster to seal leaks in the BBB, occasionally observed in aging and catastrophically common in AD. The vasoconstrictive activity of A beta may also be related to leaky vessels whereby decreasing the arterial diameter may also help to control breaches in the BBB. The admission of plasma neurotoxic proteins into the brain may be controlled by activation of microglia elicited by soluble A beta peptides creating a subtle, but permanent brain inflammatory reaction. We also delve into the influence that cholesterol metabolism may have in membrane topology and A beta production, and the close correlations that exist between cardiovascular disease and AD. Finally, we speculate about the possibility of a peripheral source of A beta that may, by crossing the BBB, contribute to the vascular and parenchymal deposits of A beta in the AD brain.
Danton, G. H. and W. D. Dietrich (2003). "Inflammatory mechanisms after ischemia and stroke." J Neuropathol Exp Neurol 62(2): 127-36.
Inflammation has been implicated as a secondary injury mechanism following ischemia and stroke. A variety of experimental models, including thromboembolic stroke, focal and global ischemia, have been used to evaluate the importance of inflammation. The vasculature endothelium promotes inflammation through the upregulation of adhesion molecules such as ICAM, E-selectin, and P-selectin that bind to circulating leukocytes and facilitate their migration into the CNS. Once in the CNS, the production of cytotoxic molecules may facilitate cell death. The macrophage and microglial response to injury may either be beneficial by scavenging necrotic debris or detrimental by facilitating cell death in neurons that would otherwise recover. While many studies have tested these hypotheses, the importance of inflammation in these models is inconclusive. This review summarizes data regarding the role of the vasculature, leukocytes, blood-brain barrier, macrophages, and microglia after experimental and clinical stroke.
De Keyser, J., E. Zeinstra, et al. (2003). "Are astrocytes central players in the pathophysiology of multiple sclerosis?" Arch Neurol 60(1): 132-6.
An interaction between antimyelin T cells and antigen-presenting glial cells is a crucial step in the cascade of immune events that lead to the inflammatory lesions in multiple sclerosis (MS). One of the most debated and controversial issues is whether microglial cells or astrocytes are the key players in initiating the (auto)immune reactions in the central nervous system in MS. Many investigators consider microglia to be the responsible intrinsic immunoeffector cells. In this review, we speculate that in MS astrocytes may serve as primary (facultative) antigen-presenting cells due to a failure of noradrenergic suppression of class II major histocompatibility complex molecules, which is caused by a loss of beta(2)-adrenergic receptors. If this hypothesis is correct, pharmacologic suppression of the antigen-presenting capacities of astrocytes may be a potential therapy for MS.
Dick, A. D., D. Carter, et al. (2003). "Control of myeloid activity during retinal inflammation." J Leukoc Biol 74(2): 161-6.
Combating myeloid cell-mediated destruction of the retina during inflammation or neurodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cytokine responses, modulate infiltrating macrophage activation, and facilitate healthy tissue repair. Success is dependent on response of the resident myeloid-cell populations [microglia (MG)] to activation signals, commonly cytokines, and the control of infiltrating macrophage activation during inflammation, both of which appear highly programmed in normal and inflamed retina. The evidence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 receptor (R) interaction supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display normal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in "classical" activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity.
Dodel, R. C., H. Hampel, et al. (2003). "Immunotherapy for Alzheimer's disease." Lancet Neurol 2(4): 215-20.
Recent studies in murine models of Alzheimer's disease (AD) have found that active immunisation with amyloid-beta peptide (Abeta) or passive immunisation with Abeta antibodies can lessen the severity of Abeta-induced neuritic plaque pathology through the activation of microglia. These antibodies can be detected in the serum and CSF. Whether they slow down or speed up the development and progression of AD has not been determined. Furthermore, the conditions that induce formation of such antibodies are unknown, or how specific they are to AD. However, the evidence suggests at least a potential beneficial role for some features of neuroinflammation in AD. A clinical phase II study of an active immunisation approach with AN1792 was started in 2001, but was recently suspended after some patients developed serious adverse events. These were most likely caused by the activation of the proinflammatory cascade. Immunotherapy approaches represent fascinating ways to test the amyloid hypothesis and may offer genuine opportunities to modify disease progression. This review focuses on immunisation strategies and details of the pathways involved in antibody clearance of Abeta.
Donato, R. (2003). "Intracellular and extracellular roles of S100 proteins." Microsc Res Tech 60(6): 540-51.
S100, a multigenic family of non-ubiquitous Ca(2+)-modulated proteins of the EF-hand type expressed in vertebrates exclusively, has been implicated in intracellular and extracellular regulatory activities. Members of this protein family have been shown to interact with several effector proteins within cells thereby regulating enzyme activities, the dynamics of cytoskeleton constituents, cell growth and differentiation, and Ca(2+) homeostasis. Structural information indicates that most of S100 proteins exist in the form of antiparallelly packed homodimers (in some cases heterodimers), capable of functionally crossbridging two homologous or heterologous target proteins in a Ca(2+)-dependent (and, in some instances, Ca(2+)-independent) manner. In addition, extracellular roles have been described for several S100 members, although secretion (via an unknown mechanism) has been documented for a few of them. Extracellular S100 proteins have been shown to exert regulatory effects on inflammatory cells, neurons, astrocytes, microglia, and endothelial and epithelial cells, and a cell surface receptor, RAGE, has been identified as a potential S100A12 and S100B receptor transducing the effects of these two proteins on inflammatory cells and neurons. Other cell surface molecules with ability to interact with S100 members have been identified, suggesting that RAGE might not be a universal S100 protein receptor and/or that a single S100 protein might interact with more than one receptor. Collectively, these data indicate that members of the S100 protein family are multifunctional proteins implicated in the regulation of a variety of cellular activities.
Fukaura, H. and S. Kikuchi (2003). "[IL-18 in multiple sclerosis]." Nippon Rinsho 61(8): 1416-21.
IL-18, previously named interferon-gamma inducing factor, is produced by monocytes/macropharges, dendritic cells, B cells and other APC cells as well as by astrocytes, microglia. IL-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Caspase-1 regulates the cellular export of IL-18. Anti IL-18 antibodies prevent EAE. IL-18 directs autoreactive T cells and promotes autodestruction in CNS via induction of IFN-gamma by NK cells in EAE. IL-18 is expressed in MS plaque. Common IL-18 promoter polymorphisms influence the expression on IL-18. IL-18 is linked to raised IFN-gamma in MS and is induced by activated CD4(+) T cells via CD40-CD40 ligand interaction. IL-18 in MS is suppressed by treatments such as GA and IFN-beta.
Gao, H. M., B. Liu, et al. (2003). "Novel anti-inflammatory therapy for Parkinson's disease." Trends Pharmacol Sci 24(8): 395-401.
Parkinson's disease (PD) is a movement disorder that is characterized by progressive degeneration of the nigrostriatal dopamine system. Although dopamine replacement can alleviate symptoms of the disorder, there is no proven therapy to halt the underlying progressive degeneration of dopamine-containing neurons. Recently, increasing evidence from human and animal studies has suggested that neuroinflammation is an important contributor to the neuronal loss in PD. Moreover, the pro-inflammatory agent lipopolysaccharide itself can directly initiate degeneration of dopamine-containing neurons or combine with other environmental factor(s), such as the pesticide rotenone, to exacerbate such neurodegeneration. These effects provide strong support for the involvement of inflammation in the pathogenesis of PD. Furthermore, growing experimental evidence demonstrates that inhibition of the inflammatory response can, in part, prevent degeneration of nigrostriatal dopamine-containing neurons in several animal models of PD, suggesting that inhibition of inflammation might become a promising therapeutic intervention for PD.
Gras, G., F. Chretien, et al. (2003). "Regulated expression of sodium-dependent glutamate transporters and synthetase: a neuroprotective role for activated microglia and macrophages in HIV infection?" Brain Pathol 13(2): 211-22.
It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate-mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glutamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT-1 and that expression varies according to the disease stage. This suggests that, besides their recognized neurotoxic properties in HIV infection, these cells also have a neuroprotective function, and may partly make up for the inhibited astrocytic function, at least temporarily. This hypothesis might explain the discrepancy between microglial activation which occurs early in the disease, and neuronal apoptosis and neuronal loss which is a late event. In this review article, we discuss the possible neuroprotective and neurotrophic roles of activated microglia and macrophages that may be generated by the expression of high affinity glutamate transporters and glutamine synthetase, 2 major effectors of glial glutamate metabolism, and the implications for HIV-induced neuronal dysfunction, the underlying cause of HIV dementia.
Hansson, E. and L. Ronnback (2003). "Glial neuronal signaling in the central nervous system." Faseb J 17(3): 341-8.
Glial cells are known to interact extensively with neuronal elements in the brain, influencing their activity. Astrocytes associated with synapses integrate neuronal inputs and release transmitters that modulate synaptic sensitivity. Glial cells participate in formation and rebuilding of synapses and play a prominent role in protection and repair of nervous tissue after damage. For glial cells to take an active part in plastic alterations under physiological conditions and pathological disturbances, extensive specific signaling, both within single cells and between cells, is required. In recent years, intensive research has led to our first insight into this signaling. We know there are active connections between astrocytes in the form of networks promoting Ca2+ and ATP signaling; we also know there is intense signaling between astrocytes, microglia, oligodendrocytes, and neurons, with an array of molecules acting as signaling substances. The cells must be functionally integrated to facilitate the enormous dynamics of and capacity for reconstruction within the nervous system. In this paper, we summarize some basic data on glial neuronal signaling to provide insight into synaptic modulation and reconstruction in physiology and protection and repair after damage.
Henningson, C. T., Jr., M. A. Stanislaus, et al. (2003). "28. Embryonic and adult stem cell therapy." J Allergy Clin Immunol 111(2 Suppl): S745-53.
Stem cells are characterized by the ability to remain undifferentiated and to self-renew. Embryonic stem cells derived from blastocysts are pluripotent (able to differentiate into many cell types). Adult stem cells, which were traditionally thought to be monopotent multipotent, or tissue restricted, have recently also been shown to have pluripotent properties. Adult bone marrow stem cells have been shown to be capable of differentiating into skeletal muscle, brain microglia and astroglia, and hepatocytes. Stem cell lines derived from both embryonic stem and embryonic germ cells (from the embryonic gonadal ridge) are pluripotent and capable of self-renewal for long periods. Therefore embryonic stem and germ cells have been widely investigated for their potential to cure diseases by repairing or replacing damaged cells and tissues. Studies in animal models have shown that transplantation of fetal, embryonic stem, or embryonic germ cells may be able to treat some chronic diseases. In this review, we highlight recent developments in the use of stem cells as therapeutic agents for three such diseases: Diabetes, Parkinson disease, and congestive heart failure. We also discuss the potential use of stem cells as gene therapy delivery cells and the scientific and ethical issues that arise with the use of human stem cells.
Hide, I. (2003). "[Mechanism of production and release of tumor necrosis factor implicated in inflammatory diseases]." Nippon Yakurigaku Zasshi 121(3): 163-73.
Tumor necrosis factor (TNF) is a potent inflammatory cytokine involved in many pathophysiological conditions including rheumatoid arthritis and Crohn's disease. Despite recent evidence regarding signal transduction via TNF receptor and its biological actions, the mechanism of TNF release remains poorly understood. To clarify how production and release of TNF are regulated, we focused on mast cells and microglia which are involved in allergic inflammation and brain damage or recovery, respectively. In RBL-2H3 mast cells, anti-allergic drugs including azelastine inhibited the release of TNF more potently than degranulation in response to antigen or ionomycin. It was also demonstrated that TNF releasing steps are regulated via the PKC alpha-dependent pathway. Furthermore, Rho GTPases, possibly Rac, were shown to be involved in antigen-induced TNF transcription through activating PKC beta I. In cultured rat brain microglia, we found that extracellular ATP triggers the release of TNF via the P2X7 receptor. ERK and JNK are also involved in ATP-induced TNF transcription, while p38 regulates the transport of TNF mRNA from the nucleus to the cytosol. Additionally, JNK and p38, but not ERK, are activated via the P2X7 receptor. A better understanding of the specific pathways that regulate TNF release for each effector cell may offer further possible therapeutic targets for inflammatory diseases.
Hisahara, S., H. Okano, et al. (2003). "Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination." Neurosci Res 46(4): 387-97.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. MS is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory and cytokines that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, nitric oxide, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. Transgenic mice that express the anti-apoptotic protein specifically in OLGs and caspase-11-deficient mice are significantly resistant to EAE induction. Histopathological analyses show that the number of caspase-activated OLGs and dead OLGs are reduced in the CNS of these mice. The numbers of infiltrating immune cells and the amounts of cytokines are also markedly reduced in EAE lesions. Therefore, caspase-mediated OLG death leads to the exacerbation of demyelination and the deterioration of neurological manifestations by inducing local inflammatory events.
Irie-Sasaki, J., T. Sasaki, et al. (2003). "CD45 regulated signaling pathways." Curr Top Med Chem 3(7): 783-96.
CD45 is expressed on all nucleated haematopoietic cells and was originally identified as the first and prototypic transmembrane protein tyrosine phosphatase (PTPase). CD45 has been extensively studied for over two decades as a PTPase that functions in antigen receptor signaling by dephosphorylation of Src-kinases. CD45 can operate as a positive as well negative regulator of Src-family kinases. In CD45 mutant cell lines, CD45-deficient mice, and CD45-deficient human SCID patients, CD45 is required for signal transduction through antigen receptors. Our group has recently shown that CD45 can also function as a Janus kinase (JAK) tyrosine phosphatase that negatively regulates cytokine receptor signaling involved in the differentiation, proliferation, and antiviral immunity of haematopoietic cells. Moreover, a point mutation in CD45, implicated in affecting CD45 dimerization, and a genetic polymorphism that affects alternative CD45 splicing have been implicated in autoimmunity in mice and humans. CD45 is expressed in multiple isoforms and modulation of specific CD45 splice variants with antibodies can prevent transplant rejections. Moreover, loss of CD45 can affect microglia activation in a mouse model for Alzheimer's disease. Modulation of CD45 splice variants and CD45 activity might provide a unique opportunity to design drugs that turn off or turn-on antigen and cytokine receptor signaling in cancer, allergy, transplantation, or autoimmunity.
John, G. R., S. C. Lee, et al. (2003). "Cytokines: powerful regulators of glial cell activation." Neuroscientist 9(1): 10-22.
It is now clear that cytokines function as powerful regulators of glial cell function in the central nervous system (CNS), either inhibiting or promoting their contribution to CNS pathology. Although these interactions are complex, the availability of animals with targeted deletions of these genes and/or their receptors, as well as transgenic mice in which cytokine expression has been targeted to specific cell types, and the availability of purified populations of glia that can be studied in vitro, has provided a wealth of interesting and frequently surprising data relevant to this activity. A particular feature of many of these studies is that it is the nature of the receptor that is expressed, rather than the cytokine itself, that regulates the functional properties of these cytokines. Because cytokine receptors are themselves modulated by cytokines, it becomes evident that the effects of these cytokines may change dramatically depending upon the cytokine milieu present in the immediate environment. An additional exciting aspect of these studies is the previously underappreciated role of these factors in repair to the CNS. In this review, we focus on current information that has helped to define the role of cytokines in regulating glial cell function as it relates to the properties of microglia and astrocytes.
Kato, H. and A. Suzumura (2003). "[Cytokines in MS lesion]." Nippon Rinsho 61(8): 1428-34.
A variety of cytokines are involved in the pathogenesis of multiple sclerosis(MS), either in induction phase and effector phase. In order to interact with immune cells, the cells in the brain have to express MHC antigens which they do not usually express. Cytokines such as IFN gamma, IL-3 and TNF alpha induce MHC antigen expression on neural cells. IFN gamma also induces costimulatory molecule for antigen presentation and also induce IL-12, a critical cytokine in T helper cell differentiation, in microglia. Although TNF alpha is a critical cytokines in effector phase, other cytokines and chemokines have also been shown to play roles on the development of inflammatory demyelination and gliosis. In this chapter, we will review the cytokine profile of MS lesions.
Kielian, T. and P. D. Drew (2003). "Effects of peroxisome proliferator-activated receptor-gamma agonists on central nervous system inflammation." J Neurosci Res 71(3): 315-25.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays a critical role in glucose and lipid metabolism. More recently, PPAR-gamma ligands have been reported to inhibit the expression of proinflammatory molecules by monocytes/macrophages. Of relevance to CNS disease is that PPAR-gamma agonists have been demonstrated to have similar effects on microglia. PPAR-gamma agonists also ameliorate experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This Mini-Review summarizes the effects of PPAR-gamma agonists in mediating immune responses and the potential of these agonists in the treatment of inflammatory disorders of the CNS.
Kitamura, Y. and Y. Nomura (2003). "Stress proteins and glial functions: possible therapeutic targets for neurodegenerative disorders." Pharmacol Ther 97(1): 35-53.
Recent findings suggest that unfolded or misfolded proteins participate in the pathology of several neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Usually, several stress proteins and glial cells act as intracellular molecular chaperones and show chaperoning neuronal function, respectively. In the brains of patients with neurodegenerative disorders, however, stress proteins are expressed and frequently associated with protein aggregates, and glial cells are activated around degenerative regions. In addition, several stress proteins and glial cells may also regulate neuronal cell death and loss. Therefore, some types of stress proteins and glial cells are considered to be neuroprotective targets. We summarize the current findings regarding the neuroprotective effects of stress proteins and glial cells, and discuss the possibility of using this knowledge to develop new therapeutic strategies to treat neurodegeneration.
Kwidzinski, E., L. K. Mutlu, et al. (2003). "Self-tolerance in the immune privileged CNS: lessons from the entorhinal cortex lesion model." J Neural Transm Suppl(65): 29-49.
Upon peripheral immunization with myelin epitopes, susceptible rats and mice develop T cell-mediated demyelination similar to that observed in the human autoimmune disease multiple sclerosis (MS). In the same animals, brain injury does not induce autoimmune encephalomyelitis despite massive release of myelin antigens and early expansion of myelin specific T cells in local lymph nodes, indicating that the self-specific T cell clones are kept under control. Using entorhinal cortex lesion (ECL) to induce axonal degeneration in the hippocampus, we identified possible mechanisms of immune tolerance after brain trauma. Following ECL, astrocytes upregulate the death ligand CD95L, allowing apoptotic elimination of infiltrating activated T cells. Myelin-phagocytosing microglia express MHC-II and the costimulatory molecule CD86, but lack CD80, which is found only on activated antigen presenting cells (APCs). Restimulation of invading T cells by such immature APCs (e.g. CD80 negative microglia) may lead to T cell anergy and/or differentiation of regulatory/Th3-like cells due to insufficient costimulation and presence of high levels of TGF-beta and IL-10 in the CNS. Thus, T cell -apoptosis, -anergy, and -suppression apparently maintain immune tolerance after initial expansion of myelin-specific T lymphocytes following brain injury. This view is supported by a previous metastatistical analysis which rejected the hypothesis that brain trauma is causative of MS (Goddin et al., 1999). However, concomitant trauma-independent proinflammatory signals, e.g., those evoked by clinically quiescent infections, may trigger maturation of APCs, thus shifting a delicate balance from immune tolerance and protective immune responses to destructive autoimmunity.
Lambotte, O., K. Deiva, et al. (2003). "HIV-1 persistence, viral reservoir, and the central nervous system in the HAART era." Brain Pathol 13(1): 95-103.
HAART therapy has led to a significant reduction of general and neurological morbidity, and mortality among HIV-1 infected patients. It can also decrease HIV-1 RNA titres in plasma and CSF towards undetectable level. However, the initial hope of achieving total eradication of the virus from the body has vanished. Even in patients who do not develop viral resistance or treatment intolerance, two kinds of viral persistence have been demonstrated both in lymphoid and central nervous system. The first one is a smoldering infection that persists, despite prolonged and apparently efficient HAART, in monocytes, tissue macrophages and most probably microglia. The second one is an integration of proviral DNA in the genome of subpopulations of CD4 lymphocytes of patients receiving efficient HAART. A similar viral integration in astrocytes and less likely in resting microglia is suggested by several studies, although it has yet to be demonstrated conclusively.
Lassmann, H. (2003). "Hypoxia-like tissue injury as a component of multiple sclerosis lesions." J Neurol Sci 206(2): 187-91.
Recent data suggest that the mechanisms of demyelination and tissue damage in multiple sclerosis (MS) are heterogenous. In this review, evidence is discussed, which show that in a subset of multiple sclerosis patients the central nervous system (CNS) lesions show profound similarities to tissue alterations found in acute white matter stroke, thus suggesting that a hypoxia-like metabolic injury is a pathogenetic component in a subset of inflammatory brain lesions. Both, vascular pathology as well as metabolic disturbances induced by toxins of activated macrophages and microglia may be responsible for such lesions in multiple sclerosis.
Lazarini, F., T. N. Tham, et al. (2003). "Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system." Glia 42(2): 139-48.
alpha-chemokines, which control the activation and directed migration of leukocytes, participate in the inflammatory processes in host defense response. One of the alpha-chemokines, CXCL12 or stromal cell-derived factor 1 (SDF-1), not only regulates cell growth and migration of hematopoietic stem cells but may also play a central role in brain development as we discuss here. SDF-1 indeed activates the CXCR4 receptor expressed in a variety of neural cells, and this signaling results in diverse biological effects. It enhances migration and proliferation of cerebellar granule cells, chemoattracts microglia, and stimulates cytokine production and glutamate release by astrocytes. Moreover, it elicits postsynaptic currents in Purkinje cells, triggers migration of cortical neuron progenitors, and produces pain by directly exciting nociceptive neurons. By modulating cell signaling and survival during neuroinflammation, SDF-1 may also play a role in the pathogenesis of brain tumors, experimental allergic encephalitis, and the nervous system dysfunction associated with acquired immunodeficiency syndrome.
Liu, B., H. M. Gao, et al. (2003). "Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation." Environ Health Perspect 111(8): 1065-73.
Idiopathic Parkinson's disease (PD) is a devastating movement disorder characterized by selective degeneration of the nigrostriatal dopaminergic pathway. Neurodegeneration usually starts in the fifth decade of life and progresses over 5-10 years before reaching the fully symptomatic disease state. Despite decades of intense research, the etiology of sporadic PD and the mechanism underlying the selective neuronal loss remain unknown. However, the late onset and slow-progressing nature of the disease has prompted the consideration of environmental exposure to agrochemicals, including pesticides, as a risk factor. Moreover, increasing evidence suggests that early-life occurrence of inflammation in the brain, as a consequence of either brain injury or exposure to infectious agents, may play a role in the pathogenesis of PD. Most important, there may be a self-propelling cycle of inflammatory process involving brain immune cells (microglia and astrocytes) that drives the slow yet progressive neurodegenerative process. Deciphering the molecular and cellular mechanisms governing those intricate interactions would significantly advance our understanding of the etiology and pathogenesis of PD and aid the development of therapeutic strategies for the treatment of the disease.
Liu, B. and J. S. Hong (2003). "Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention." J Pharmacol Exp Ther 304(1): 1-7.
Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.
McGeer, E. G. and P. L. McGeer (2003). "Inflammatory processes in Alzheimer's disease." Prog Neuropsychopharmacol Biol Psychiatry 27(5): 741-9.
Neuroinflammation is a characteristic of pathologically affected tissue in several neurodegenerative disorders. These changes are particularly observed in affected brain areas of Alzheimer's disease (AD) cases. They include an accumulation of large numbers of activated microglia and astrocytes as well as small numbers of T-cells, mostly adhering to postcapillary venules. Accompanying biochemical alterations include the appearance or up-regulation of numerous molecules characteristic of inflammation and free radical attack. Particularly important may be the complement proteins, acute phase reactants and inflammatory cytokines. These brain phenomena combined with epidemiological evidence of a protective effect of antiinflammatory agents suggest that such agents may have a role to play in treating the disease.
Monsonego, A. and H. L. Weiner (2003). "Immunotherapeutic approaches to Alzheimer's disease." Science 302(5646): 834-8.
Although neurodegenerative diseases such as Alzheimer's disease are not classically considered mediated by inflammation or the immune system, in some instances the immune system may play an important role in the degenerative process. Furthermore, it has become clear that the immune system itself may have beneficial effects in nervous system diseases considered neurodegenerative. Immunotherapeutic approaches designed to induce a humoral immune response have recently been developed for the treatment of Alzheimer's disease. These studies have led to human trials that resulted in both beneficial and adverse effects. In animal models, it has also been shown that immunotherapy designed to induce a cellular immune response may be of benefit in central nervous system injury, although T cells may have either a beneficial or detrimental effect depending on the type of T cell response induced. These areas provide a new avenue for exploring immune system-based therapy of neurodegenerative diseases and will be discussed here with a primary focus on Alzheimer's disease. We will also discuss how these approaches affect microglia activation, which plays a key role in therapy of such diseases.
Morgan, D. (2003). "Antibody therapy for Alzheimer's disease." Expert Rev Vaccines 2(1): 53-9.
The economic, social and emotional impact of Alzheimer's dementia is increasing dramatically as greater numbers live to advanced ages. The dearth of effective therapies has led to innovative approaches to treat the disease. This review summarizes the rationale, progress and setbacks regarding the use of antibody-based therapies to treat Alzheimer's disease and discusses future directions for this approach in Alzheimer's and other disorders.
Nakanishi, H. (2003). "Microglial functions and proteases." Mol Neurobiol 27(2): 163-76.
There is accumulating evidence that intracellular and extracellular proteases of microglia contribute to various events in the central nervous system (CNS) through both nonspecific and limited proteolysis. Cathepsin E and cathepsin S, endosomal/lysosomal proteases, have been shown to play important roles in the major histocompatibility complex (MHC) class II-mediated antigen presentation of microglia by processing of exogenous antigens and degradation of the invariant chain associated with MHC class II molecules, respectively. Some members of cathepsins are also involved in neuronal death after secreted from microglia and clearance of phagocytosed amyloid- beta peptides. Tissue-type plasminogen activator, a serine protease, secreted from microglia participates in neuronal death, enhancement of N-methyl-D-aspartate receptor-mediated neuronal responses, and activation of microglia via either proteolytic or nonproteolytic activity. Calpain, a calcium-dependent cysteine protease, has been shown to play a pivotal role in the pathogenesis of multiple sclerosis by degrading myelin proteins extracellulary. Furthermore, matrix metalloproteases secreted from microglia also receive great attention as mediators of inflammation and tissue degradation through processing of pro-inflammatory cytokines and damage to the blood-brain barrier. The growing knowledge about proteolytic events mediated by microglial proteases will not only contribute to better understanding of microglial functions in the CNS but also may aid in the development of protease inhibitors as novel neuroprotective agents.
Neumann, H. (2003). "Molecular mechanisms of axonal damage in inflammatory central nervous system diseases." Curr Opin Neurol 16(3): 267-73.
PURPOSE OF REVIEW: Axonal dysfunction and damage is an early pathological sign of autoimmune central nervous system disease, viral and bacterial infections, and brain trauma. Axonal injury has attracted considerable interest during the past few years because the degree of axonal damage appears to determine long-term clinical outcome. RECENT FINDINGS: Advanced magnetic resonance spectroscopic imaging techniques have suggested that axonal loss and dysfunction is responsible for the persistent neurological deficits that occur in patients with multiple sclerosis. Histopathological methods have shown that axonal damage is defined primarily by dysfunction of axonal transport, and finally by complete transection and degeneration of axons. Recent studies have demonstrated that the extent of axonal damage in the primary demyelinating lesion of multiple sclerosis patients is associated with the number of activated microglia/macrophages and cytotoxic CD8+ T lymphocytes. In addition, diffuse axonal dysfunction independent of demyelination develops in normal appearing white matter, possibly due to indirect effects of inflammation. SUMMARY: The fact that axonal damage in response to overt inflammatory reactions may occur gradually, leaving a window for therapeutical intervention, has important clinical implications. Determination of the exact molecular mechanism might help in finding new therapies for inflammatory axonal damage.
Perry, V. H., T. A. Newman, et al. (2003). "The impact of systemic infection on the progression of neurodegenerative disease." Nat Rev Neurosci 4(2): 103-12.
Rauschka, H., K. Jellinger, et al. (2003). "Guillain-Barre syndrome with marked pleocytosis or a significant proportion of polymorphonuclear granulocytes in the cerebrospinal fluid: neuropathological investigation of five cases and review of differential diagnoses." Eur J Neurol 10(5): 479-86.
In cases with otherwise clinically typical Guillain-Barre syndrome (GBS), pronounced cerebrospinal fluid (CSF) pleocytosis or the mere presence of CSF-polymorphonuclear granulocytes should alert the physician to consider alternative diagnoses. Therefore, we retrospectively studied the neuropathology of central and peripheral nervous system in two cases with a CSF cell count of more than 50/microl and in three cases with a significant proportion of polymorphonuclear granulocytes in the CSF sediment. All cases fulfilled the required criteria for the diagnosis of GBS, the duration from onset to death ranged from 4 to 100 days. Neuropathological investigations included routine staining procedures and immunohistochemistry for antigens of glial and haematopoetic cells as well as for products of relevant neurotropic viruses. Demyelinating polyradiculitis was present in four cases, in one patient with a survival time of 4 days the type of damage to myelinated fibres was unclassifiable. In the central nervous system a consistent finding was diffuse activation of microglia, only one case showed mild meningeal and lower brainstem inflammation. Viral products were generally absent. In summary, the neuropathological findings confirm that marked CSF pleocytosis or the presence of polymorphonuclear granulocytes does not rule out the diagnosis of GBS.
Riess, O., D. Berg, et al. (2003). "Therapeutic strategies for Parkinson's disease based on data derived from genetic research." J Neurol 250 Suppl 1: I3-10.
Following the identification of mutations in alpha-synuclein as the cause of some rare forms of familial Parkinson's disease (PD), genetic research has uncovered numerous gene loci of PD. Meanwhile, several neurodegenerative diseases have been shown to accumulate a-synuclein in neuronal and glial cells summarizing this group of diseases as synucleinopathies. All currently known gene defects causing PD alter the ubiquitin-proteasomal pathway of protein degradation. Identification of these disease mutations allows studying the functional consequences which lead to cellular dysfunction and cell death in cell culture and transgenic animal models, to identify therapeutic targets and to test potential protective strategies in these models.
Rivest, S. (2003). "Molecular insights on the cerebral innate immune system." Brain Behav Immun 17(1): 13-9.
All species need an immediate reply to the microbial pathogens that is part of an effective immune response and is essential for the survival of most organisms. This reply is known as the innate immune response and is characterized by the de novo production of mediators that either kill the microbes directly or activate phagocytic cells to ingest and kill them. The innate immune response can be driven through specific recognition systems, the best example being an interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14 and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be a privileged organ from an immunological point of view, owing to its inability to mount an immune response and process antigens. Although this is partly true, the CNS shows a well-organized innate immune reaction in response to systemic bacterial infection and cerebral injury. The CD14 and TLR4 receptors are constitutively expressed in the circumventricular organs (CVOs), choroid plexus and leptomeninges. Circulating LPS is able to cause a rapid transcriptional activation of genes encoding CD14 and TLR2, as well as a wide variety of pro-inflammatory molecules in CVOs. A delayed response to LPS takes place in cells located at boundaries of the CVOs and in microglia across the CNS. Therefore, without having direct access to the brain parenchyma, pathogens have the ability to trigger an innate immune reaction throughout cerebral tissue. This review presents evidence supporting the existence of such a system in the brain, which is finely regulated at the transcription level. Transient activation of this system is not harmful toward neuronal elements.
Saha, R. N. and K. Pahan (2003). "Tumor necrosis factor-alpha at the crossroads of neuronal life and death during HIV-associated dementia." J Neurochem 86(5): 1057-71.
Human immunodeficiency type-1 (HIV-1) infection is known to cause disorders of the CNS, including HIV-associated dementia (HAD). It is suspected that tumor necrosis factor-alpha (TNF-alpha) released by infected microglia and macrophages play a role in neuronal injury seen in HAD patients. Accordingly, studies suggest that the level of TNF-alpha mRNA increases with increasing severity of dementia in patients, and that inhibitors of TNF-alpha release reduces neuronal injury in murine model of HAD. However, the exact role of TNF-alpha in relation to neuronal dysfunction is a matter of ongoing debate. One school of thought hails TNF-alpha as the inducer and mediator of neurodegeneration and their evidence suggest that TNF-alpha kill neurons directly by recruiting caspases or may kill indirectly by various means. In sharp contrast to this, another concept theory envisages a role for TNF-alpha in negotiating neuroprotection during HAD. The current compilation examines these contradictory concepts, and evaluates their efficacy in the light of TNF-alpha signaling. It also attempts to elaborate the current consensus outlook of TNF-alpha's role during HAD.
Sawynok, J. and X. J. Liu (2003). "Adenosine in the spinal cord and periphery: release and regulation of pain." Prog Neurobiol 69(5): 313-40.
In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.
Schwartz, M., I. Shaked, et al. (2003). "Protective autoimmunity against the enemy within: fighting glutamate toxicity." Trends Neurosci 26(6): 297-302.
Glutamate, a key neurotransmitter, is pivotal to CNS function. Alterations in its concentration can be dangerous, as seen for example in acute injuries of the CNS, chronic neurodegenerative disorders and mental disorders. Its homeostasis is attributed to the efficient removal of glutamate from the extracellular milieu by reuptake via local transport mechanisms. Our recent studies suggest that glutamate, either directly or indirectly, elicits a purposeful systemic T-cell-mediated immune response directed against immunodominant self-antigens that reside at the site of glutamate-induced damage. We suggest that the harnessed autoimmunity (which we have termed 'protective autoimmunity') helps the resident microglia in their dual function as antigen-presenting cells (serving the immune system) and as cells that clear the damaged site of potentially harmful material (serving the nervous system). The interplay between glutamate and an adaptive immune response illustrates the bidirectional dialog between the immune and nervous systems, under both physiological and pathological conditions. These results point to the possible development of a therapeutic vaccination with self-antigens, or with antigens cross-reactive with self-antigens, as a way to augment autoimmunity without inducing an autoimmune disease, thus providing a safe method of limiting degeneration. This approach, which boosts a physiological mechanism for the regulation of glutamate, and possibly also that of other self-compounds, might prove to be a feasible strategy for therapeutic protection against glutamate-associated neurodegenerative or mental disorders.
Schwartz, M. (2003). "Macrophages and microglia in central nervous system injury: are they helpful or harmful?" J Cereb Blood Flow Metab 23(4): 385-94.
Inflammation has been widely perceived as participating in the etiology of acute and chronic neurodegenerative conditions. Accordingly, in the context of traumatic injuries or chronic neurodegenerative diseases in the central nervous system (CNS), activated microglia have been viewed as detrimental and attempts have been made to treat both conditions by antiinflammatory therapy. Recent studies have suggested that microglia act as stand- by cells in the service of both the immune and the nervous systems. In the healthy CNS these cells are quiescent, but in the event of injury to axons or cell bodies they exercise their neural function by buffering harmful self-compounds and clearing debris from the damaged site, and their immune function by providing immune-related requirements for recovery. Proper regulation of the inflammatory (autoimmune) response to injury will arrest degeneration and promote regrowth, whereas inappropriate regulation will lead to ongoing degeneration. Regulation is achieved by the operation of a T cell-mediated response directed to abundant self-antigens residing in the damaged site. Since this immune-dependent mechanism was found to protect against glutamate toxicity (a major factor in neurodegenerative disorders), boosting of this response might constitute the basis for development of a therapeutic vaccination against neurodegenerative diseases, all of which exhibit similar pathways and patterns of progression.
Segal, B. M. (2003). "Experimental autoimmune encephalomyelitis: cytokines, effector T cells, and antigen-presenting cells in a prototypical Th1-mediated autoimmune disease." Curr Allergy Asthma Rep 3(1): 86-93.
Experimental autoimmune encephalomyelitis (EAE) is widely depicted as the prototypical CD4+ Th1-mediated autoimmune disease. Microglia and perivascular macrophages are believed to act as antigen-presenting cells during the effector phase of EAE. In this article, recent data that challenge these conceptions are reviewed. Several recent studies have shown that myelin-reactive CD8+ T cells can mediate inflammatory demyelination. Furthermore, dendritic-like cells have been detected in EAE lesions and implicated in encephalitogenic T-cell activation. Although Th1 polarizing monokines, such as interleukin-12 (IL-12) and possibly IL-23, are critical for the manifestation of EAE, individual Th1 effector cytokines were found to be dispensible.
Teismann, P., K. Tieu, et al. (2003). "Pathogenic role of glial cells in Parkinson's disease." Mov Disord 18(2): 121-9.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, and pro-inflammatory prostaglandin and cytokines. We discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how those factors may contribute to the pathogenesis of this disease.
Versijpt, J., K. Van Laere, et al. (2003). "Scintigraphic visualization of inflammation in neurodegenerative disorders." Nucl Med Commun 24(2): 209-21.
In the past few decades, our understanding of the central nervous system has evolved from one of an immune-privileged site, to one where inflammation is pathognomonic for some of the most prevalent and tragic neurodegenerative diseases. Current research indicates that diseases as diverse as multiple sclerosis, stroke and Alzheimer's disease exhibit inflammatory processes that contribute to cellular dysfunction or loss. Inflammation, whether in the brain or periphery, is almost always a secondary response to a primary pathogen. In head trauma, for example, the blow to the head is the primary event. What typically concerns the neurologist and neurosurgeon more, however, is the secondary inflammatory response that will ensue and likely cause more neuron loss than the initial injury. This paper reviews the basic neuroinflammatory mechanisms, the potential neurotoxic mediators during activation of microglia, the brain resident macrophages, and their role in neurodegeneration. Alzheimer's disease is taken as a prototype for exploring these mechanisms, as it expresses more than 40 inflammatory mediators, it is the most extensively studied disorder in terms of immune-related pathogenesis, and because of its importance as the most prevalent type of dementia. Tools for the visualization of these neuroinflammatory processes, both structural and mainly functional, are critically reviewed and discussed.
Watkins, L. R., E. D. Milligan, et al. (2003). "Glial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain." Adv Exp Med Biol 521: 1-21.
When you hurt yourself, you become consciously aware of the pain because a chain of neurons carries the pain message from the injury to the spinal cord, and then from the spinal cord up to consciousness in the brain. However, it has been known for more than two decades that neural circuits within the spinal cord can cause your conscious experience of pain to be amplified-that is, the pain you perceive is out of proportion to the injury that caused it. Until now, all research aimed at understanding how pain amplification occurs in the spinal cord and all drug therapies aimed at curing exaggerated pain have focused exclusively on neurons. This is because neurons were the only type of cell believed to be important in pain. The present review argues that neurons in fact are not the only cell type involved. Rather, that spinal cord cells called "glia" are also critically important. Indeed, when glia become activated, they begin releasing a variety of chemical substances that causes the pain message to become amplified, thus causing pain to hurt more. This review discusses evidence that glia cause pain to become amplified and describes how the glia cause this to happen. The take-home message is that drugs that target glia and the chemical substances that these glia release are predicted to be powerful remedies for pain problems in people.
Wullner, U. and T. Klockgether (2003). "Inflammation in Parkinson's disease." J Neurol 250 Suppl 1: I35-8.
Several studies of Parkinson's disease (PD) patients and experimental models of PD indicate the presence of an inflammatory process in PD. Although the primary cellular mechanisms remain to be clarified, activation of resident microglia appears to aggravate or even maintain the disease process in PD. Modulation of inflammatory mechanisms could provide a new neuroprotective therapy in PD.