The Experts below are selected from a list of 50166 Experts worldwide ranked by ideXlab platform
James J Pestka - One of the best experts on this subject based on the ideXlab platform.
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high sensitivity of aged mice to deoxynivalenol vomitoxin induced anorexia corresponds to elevated Proinflammatory Cytokine and satiety hormone responses
Toxins, 2015Co-Authors: Erica S Clark, Brenna M Flannery, Elizabeth M Gardner, James J PestkaAbstract:Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher Proinflammatory Cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.
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tissue distribution and Proinflammatory Cytokine induction by the trichothecene deoxynivalenol in the mouse comparison of nasal vs oral exposure
Toxicology, 2008Co-Authors: Chidozie J Amuzie, Jack R Harkema, James J PestkaAbstract:Abstract Oral exposure to the trichothecene deoxynivalenol (DON), a common cereal grain contaminant, adversely affects growth and immune function in experimental animals. Besides foodborne exposure, the potential exists for DON to become airborne during the harvest and handling of grains and therefore pose a risk to agricultural workers. The purpose of this study was to compare the effects of oral and intranasal exposure to DON (5 mg/kg bw) on tissue distribution and Proinflammatory Cytokine induction in the adult female mouse. Competitive direct ELISA revealed that, regardless of exposure route, DON concentrations in plasma, spleen, liver, lung and kidney were maximal within 15–30 min and declined by 75–90% after 120 min. However, plasma and tissue DON concentrations were 1.5–3 times higher following intranasal exposure as compared to oral exposure. The functional significance of elevated DON tissue concentrations was assessed by measuring IL-1β, IL-6, and TNF-α mRNA responses in spleen, liver and lung. Oral exposure to DON-induced robust Proinflammatory Cytokine gene expression after 60 and 120 min. In contrast, inductions of IL-1β, IL-6 and TNF-α mRNAs in nasally exposed mice were 2–10, 2–5 and 2–4 times greater, respectively, than those in the tissues of orally exposed mice. Taken together, these data suggest that DON was more toxic to the mouse when nasally exposed than when orally exposed, and that this might relate to greater tissue burden of the toxin.
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tissue distribution and Proinflammatory Cytokine induction by the trichothecene deoxynivalenol in the mouse comparison of nasal vs oral exposure
Toxicology, 2008Co-Authors: Chidozie J Amuzie, Jack R Harkema, James J PestkaAbstract:Abstract Oral exposure to the trichothecene deoxynivalenol (DON), a common cereal grain contaminant, adversely affects growth and immune function in experimental animals. Besides foodborne exposure, the potential exists for DON to become airborne during the harvest and handling of grains and therefore pose a risk to agricultural workers. The purpose of this study was to compare the effects of oral and intranasal exposure to DON (5 mg/kg bw) on tissue distribution and Proinflammatory Cytokine induction in the adult female mouse. Competitive direct ELISA revealed that, regardless of exposure route, DON concentrations in plasma, spleen, liver, lung and kidney were maximal within 15–30 min and declined by 75–90% after 120 min. However, plasma and tissue DON concentrations were 1.5–3 times higher following intranasal exposure as compared to oral exposure. The functional significance of elevated DON tissue concentrations was assessed by measuring IL-1β, IL-6, and TNF-α mRNA responses in spleen, liver and lung. Oral exposure to DON-induced robust Proinflammatory Cytokine gene expression after 60 and 120 min. In contrast, inductions of IL-1β, IL-6 and TNF-α mRNAs in nasally exposed mice were 2–10, 2–5 and 2–4 times greater, respectively, than those in the tissues of orally exposed mice. Taken together, these data suggest that DON was more toxic to the mouse when nasally exposed than when orally exposed, and that this might relate to greater tissue burden of the toxin.
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tissue distribution and Proinflammatory Cytokine induction by the trichothecene deoxynivalenol in the mouse comparison of nasal vs oral exposure
Toxicology, 2008Co-Authors: Chidozie J Amuzie, Jack R Harkema, James J PestkaAbstract:Oral exposure to the trichothecene deoxynivalenol (DON), a common cereal grain contaminant, adversely affects growth and immune function in experimental animals. Besides foodborne exposure, the potential exists for DON to become airborne during the harvest and handling of grains and therefore pose a risk to agricultural workers. The purpose of this study was to compare the effects of oral and intranasal exposure to DON (5mg/kg bw) on tissue distribution and Proinflammatory Cytokine induction in the adult female mouse. Competitive direct ELISA revealed that, regardless of exposure route, DON concentrations in plasma, spleen, liver, lung and kidney were maximal within 15-30 min and declined by 75-90% after 120 min. However, plasma and tissue DON concentrations were 1.5-3 times higher following intranasal exposure as compared to oral exposure. The functional significance of elevated DON tissue concentrations was assessed by measuring IL-1beta, IL-6, and TNF-alpha mRNA responses in spleen, liver and lung. Oral exposure to DON-induced robust Proinflammatory Cytokine gene expression after 60 and 120 min. In contrast, inductions of IL-1beta, IL-6 and TNF-alpha mRNAs in nasally exposed mice were 2-10, 2-5 and 2-4 times greater, respectively, than those in the tissues of orally exposed mice. Taken together, these data suggest that DON was more toxic to the mouse when nasally exposed than when orally exposed, and that this might relate to greater tissue burden of the toxin.
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lps priming potentiates and prolongs Proinflammatory Cytokine response to the trichothecene deoxynivalenol in the mouse
Toxicology and Applied Pharmacology, 2006Co-Authors: Zahidul Islam, James J PestkaAbstract:Simultaneous exposure to lipopolysaccharide (LPS) markedly amplifies induction of Proinflammatory Cytokine expression as well as IL-1-driven lymphocyte apoptosis by trichothecene deoxynivalenol (DON) in the mouse. The purpose of this research was to test the hypothesis that LPS priming will sensitize a host to DON-induced Proinflammatory Cytokine induction and apoptosis. In mice primed with LPS (1 mg/kg bw) ip. and treated 8 h later with DON po., the minimum DON doses for inducing IL-1alpha, IL-1beta, IL-6 and TNF-alpha serum proteins and splenic mRNAs were significantly lower than the DON doses required for vehicle-primed mice. LPS priming also decreased onset time and dramatically increased magnitude and duration of Cytokine responses. LPS-primed mice maintained heightened sensitivity to DON for up to 24 h. LPS priming doses as low as 50 microg/kg bw evoked sensitization. DNA fragmentation analysis and flow cytometry also revealed that mice primed with LPS (1 mg/kg) for 8 h and exposed to DON (12.5 mg/kg) exhibited massive thymocyte loss by apoptosis 12 h later compared to mice exposed to DON or LPS alone. LPS priming decreased DON-induced p38 and ERK 1/2 phosphorylation suggesting that enhanced mitogen-activated protein kinase activation was not involved in increased Cytokine responses. Taken together, exposure to LPS rendered mice highly susceptible to DON induction of Cytokine expression and this correlated with increased apoptosis in the thymus.
Jerry L Nadler - One of the best experts on this subject based on the ideXlab platform.
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lisofylline a novel antiinflammatory agent protects pancreatic β cells from Proinflammatory Cytokine damage by promoting mitochondrial metabolism
Endocrinology, 2002Co-Authors: Meng Chen, Zandong Yang, Runpei Wu, Jerry L NadlerAbstract:Proinflammatory Cytokine-mediated pancreatic β-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1β-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known. Increasing evidence suggests that the mitochondria play an important role in regulating the β-cell insulin release capacity and the control of cellular viability. To examine the direct effects of LSF on β-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1β, TNFα, and IFNγ with or without LSF for 18 h. Basal and glucose-stimulated static insulin release were measured using RIA. INS-1 cell viability was determined using in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and LIVE/DEAD dual fluorescence labeling. To evaluate INS-1 mitochondrial function, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism, c...
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lisofylline a novel antiinflammatory agent protects pancreatic β cells from Proinflammatory Cytokine damage by promoting mitochondrial metabolism
Endocrinology, 2002Co-Authors: Meng Chen, Zandong Yang, Jerry L NadlerAbstract:Proinflammatory Cytokine-mediated pancreatic beta-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1 beta-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known. Increasing evidence suggests that the mitochondria play an important role in regulating the beta-cell insulin release capacity and the control of cellular viability. To examine the direct effects of LSF on beta-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1 beta, TNF alpha, and IFN gamma with or without LSF for 18 h. Basal and glucose-stimulated static insulin release were measured using RIA. INS-1 cell viability was determined using in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and LIVE/DEAD dual fluorescence labeling. To evaluate INS-1 mitochondrial function, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism, change in mitochondrial membrane potential, and intracellular ATP levels were assessed. Cytokine addition reduced basal (7.8 +/- 0.30 vs. 10.0 +/- 0.46 ng/ml.h; P < 0.005), glucose-stimulated insulin secretion (11.6 +/- 0.86 vs. 17.4 +/- 1.86 ng/ml.h; P < 0.005), and MTT metabolism in INS-1 cells. Over 40% of the Cytokine-treated beta-cells exhibited nuclear DNA breakage, whereas the control cell death rate remained at 1-2%. Simultaneous application of LSF and Cytokines to INS-1 cells restored insulin secretion, MTT metabolism, mitochondrial membrane potential, and cell viability to control levels. LSF increased beta-cell MTT metabolism as well as insulin release and glucose responsiveness. In summary, Proinflammatory Cytokines lead to a reduction of glucose-induced insulin secretion, mitochondrial activity, and viability in INS-1 cells. LSF at concentrations achievable in vivo protected beta-cells from the Cytokine effects. The mechanism of LSF-induced protection may be by promoting mitochondrial metabolism.
Gregory E Rice - One of the best experts on this subject based on the ideXlab platform.
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n acetyl cysteine inhibits phospholipid metabolism Proinflammatory Cytokine release protease activity and nuclear factor κb deoxyribonucleic acid binding activity in human fetal membranes in vitro
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Martha Lappas, Michael Permezel, Gregory E RiceAbstract:The production of reactive oxygen species (ROS), prostaglandins (PGs), Proinflammatory Cytokines, and proteases has been implicated in the pathogenesis of term and preterm labor. The nuclear factor-κB (NF-κB) transcription pathway is activated by ROS and is a key regulator of PGs, Proinflammatory Cytokine release, and protease activity. N-Acetyl-cysteine (NAC) is an antioxidant that through its ability to scavenger ROS suppresses NF-κB DNA-binding activity and resultant gene expression. The aim of this study was to elucidate the effect of NAC on NF-κB DNA-binding activity, phospholipid metabolism, Cytokine release, and protease activity from human fetal membranes. Human amnion and choriodecidua (n = 9 separate placentas) were treated with 0 (control), 5, 10, or 15 mm NAC in the presence of 10 μg/ml lipopolysaccharide. After 6-h incubation, the tissues were collected, NF-κB DNA binding activity was assessed by gel shift binding assays, and matrix metalloproteinase-9 and urokinase-type plasminogen activator...
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n acetyl cysteine inhibits phospholipid metabolism Proinflammatory Cytokine release protease activity and nuclear factor kappa b deoxyribonucleic acid binding activity in human fetal membranes in vitro
The Journal of Clinical Endocrinology and Metabolism, 2003Co-Authors: Martha Lappas, Michael Permezel, Gregory E RiceAbstract:The production of reactive oxygen species (ROS), prostaglandins (PGs), Proinflammatory Cytokines, and proteases has been implicated in the pathogenesis of term and preterm labor. The nuclear factor-κB (NF-κB) transcription pathway is activated by ROS and is a key regulator of PGs, Proinflammatory Cytokine release, and protease activity. N-Acetyl-cysteine (NAC) is an antioxidant that through its ability to scavenger ROS suppresses NF-κB DNA-binding activity and resultant gene expression. The aim of this study was to elucidate the effect of NAC on NF-κB DNA-binding activity, phospholipid metabolism, Cytokine release, and protease activity from human fetal membranes. Human amnion and choriodecidua (n = 9 separate placentas) were treated with 0 (control), 5, 10, or 15 mm NAC in the presence of 10 μg/ml lipopolysaccharide. After 6-h incubation, the tissues were collected, NF-κB DNA binding activity was assessed by gel shift binding assays, and matrix metalloproteinase-9 and urokinase-type plasminogen activator...
Xuetao Cao - One of the best experts on this subject based on the ideXlab platform.
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shp 2 phosphatase negatively regulates the trif adaptor protein dependent type i interferon and Proinflammatory Cytokine production
Immunity, 2006Co-Authors: Wei Zhao, Jin Hou, Yan Zhang, Yun Xie, Yuejuan Zheng, Cheng Qian, Jun Zhou, Shuxun Liu, Gensheng Feng, Xuetao CaoAbstract:The Toll-like receptor 3 (TLR3) and TLR4-signaling pathway that involves the adaptor protein TRIF activates type I interferon (IFN) and Proinflammatory Cytokine expression. Little is known about how TRIF pathway-dependent gene expression is regulated. SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a widely expressed cytoplasmic tyrosine phosphatase. Here we demonstrate that SHP-2 negatively regulated TLR4- and TLR3-activated IFN-beta production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated Proinflammatory Cytokine IL-6 and TNF-alpha production. SHP-2 inhibited poly(I:C)-induced Cytokine production by a phosphatase activity-independent mechanism. C-terminal domain of SHP-2 directly bound TANK binding kinase (TBK1) by interacting with the kinase domain of TBK1. SHP-2 deficiency increased TBK1-activated IFN-beta and TNF-alpha expression. TBK1 knockdown inhibited poly(I:C)-induced IL-6 production in SHP-2-deficient cells. SHP-2 also inhibited poly(I:C)-induced activation of MAP kinase pathways. These results demonstrate that SHP-2 specifically negatively regulate TRIF-mediated gene expression in TLR signaling, partially through inhibiting TBK1-activated signal transduction.
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shp 2 phosphatase negatively regulates the trif adaptor protein dependent type i interferon and Proinflammatory Cytokine production
Immunity, 2006Co-Authors: Wei Zhao, Jin Hou, Yan Zhang, Yun Xie, Yuejuan Zheng, Cheng Qian, Jun Zhou, Shuxun Liu, Gensheng Feng, Xuetao CaoAbstract:Summary The Toll-like receptor 3 (TLR3) and TLR4-signaling pathway that involves the adaptor protein TRIF activates type I interferon (IFN) and Proinflammatory Cytokine expression. Little is known about how TRIF pathway-dependent gene expression is regulated. SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a widely expressed cytoplasmic tyrosine phosphatase. Here we demonstrate that SHP-2 negatively regulated TLR4- and TLR3-activated IFN-β production. SHP-2 inhibited TLR3-activated but not TLR2-, TLR7-, and TLR9-activated Proinflammatory Cytokine IL-6 and TNF-α production. SHP-2 inhibited poly(I:C)-induced Cytokine production by a phosphatase activity-independent mechanism. C-terminal domain of SHP-2 directly bound TANK binding kinase (TBK1) by interacting with the kinase domain of TBK1. SHP-2 deficiency increased TBK1-activated IFN-β and TNF-α expression. TBK1 knockdown inhibited poly(I:C)-induced IL-6 production in SHP-2-deficient cells. SHP-2 also inhibited poly(I:C)-induced activation of MAP kinase pathways. These results demonstrate that SHP-2 specifically negatively regulate TRIF-mediated gene expression in TLR signaling, partially through inhibiting TBK1-activated signal transduction.
Martin D Watterson - One of the best experts on this subject based on the ideXlab platform.
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early stage drug treatment that normalizes Proinflammatory Cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age dependent progression of alzheimer s disease related pathology
The Journal of Neuroscience, 2012Co-Authors: Adam D Bachstetter, Martin D Watterson, Christopher M Norris, Pradoldej Sompol, Donna M Wilcock, Danielle S Goulding, Janna H Neltner, Daret K St Clair, Linda J. Van EldikAbstract:Overproduction of Proinflammatory Cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial Proinflammatory Cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial Proinflammatory Cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates Proinflammatory Cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in Proinflammatory Cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and Proinflammatory Cytokine production in the cortex and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that the therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD.
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enhanced microglial activation and Proinflammatory Cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a two hit seizure model
Brain Research, 2009Co-Authors: Kathleen C Someramolina, Linda J. Van Eldik, Martin D Watterson, Mark S Wainwright, Sangeetha NairAbstract:Early-life seizures result in increased susceptibility to seizures and greater neurologic injury with a second insult in adulthood. The mechanisms which link seizures in early-life to increased susceptibility to neurologic injury following a 'second hit' are not known. We examined the contribution of microglial activation and increased Proinflammatory Cytokine production to the subsequent increase in susceptibility to neurologic injury using a kainic acid (KA)-induced, established 'two-hit' seizure model in rats. Postnatal day (P)15 rats were administered intraperitoneal KA (early-life seizures) or saline, followed on P45 with either a 'second hit' of KA, a first exposure to KA (adult seizures), or saline. We measured the levels of Proinflammatory Cytokines (IL-1 beta, TNF-alpha, and S100B), the chemokine CCL2, microglial activation, seizure susceptibility and neuronal outcomes in adult rats 12 h and 10 days after the second hit on P45. The 'two-hit' group exposed to KA on both P15 and P45 had higher levels of Cytokines, greater microglial activation, and increased susceptibility to seizures and neurologic injury compared to the adult seizures group. Treatment after early-life seizures with Minozac, a small molecule experimental therapeutic that targets upregulated Proinflammatory Cytokine production, attenuated the enhanced microglial and Cytokine responses, the increased susceptibility to seizures, and the greater neuronal injury in the 'two-hit' group. These results implicate microglial activation as one mechanism by which early-life seizures contribute to increased vulnerability to neurologic insults in adulthood, and indicate the potential longer term benefits of early-life intervention with therapies that target up-regulation of Proinflammatory Cytokines.
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a novel p38α mapk inhibitor suppresses brain Proinflammatory Cytokine up regulation and attenuates synaptic dysfunction and behavioral deficits in an alzheimer s disease mouse model
Journal of Neuroinflammation, 2007Co-Authors: Linda J. Van Eldik, Hantamalala Ralay Ranaivo, Lenka Munoz, Jeffrey M Craft, Saktimayee M Roy, Laurie K Mcnamara, Laura Wing Chico, Martin D WattersonAbstract:Background An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in Proinflammatory Cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38α MAPK, a well-established drug discovery molecular target for altering Proinflammatory Cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of Proinflammatory Cytokines by glia activated with human amyloid-beta (Aβ) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38α MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive Cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes.
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glia Proinflammatory Cytokine upregulation as a therapeutic target for neurodegenerative diseases function based and target based discovery approaches
International Review of Neurobiology, 2007Co-Authors: Linda J Van Eldik, Wendy L Thompson, Hantamalala Ralay Ranaivo, Heather A Behanna, Martin D WattersonAbstract:Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory Cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation‐provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of Proinflammatory Cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting Proinflammatory Cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function‐driven and target‐based, that show promise for development of neuroinflammation‐targeted, disease‐modifying therapeutics for multiple neurodegenerative disorders.
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glia as a therapeutic target selective suppression of human amyloid beta induced upregulation of brain Proinflammatory Cytokine production attenuates neurodegeneration
The Journal of Neuroscience, 2006Co-Authors: Hantamalala Ralay Ranaivo, Linda J. Van Eldik, Laura K. Wing, Jeffrey M Craft, Ling Guo, Martin D WattersonAbstract:A corollary of the neuroinflammation hypothesis is that selective suppression of neurotoxic products produced by excessive glial activation will result in neuroprotection. We report here that daily oral administration to mice of the brain-penetrant compound 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine (MW01-5-188WH), a selective inhibitor of Proinflammatory Cytokine production by activated glia, suppressed the human amyloid-beta (Abeta) 1-42-induced upregulation of interleukin-1beta, tumor necrosis factor-alpha, and S100B in the hippocampus. Suppression of neuroinflammation was accompanied by restoration of hippocampal synaptic dysfunction markers synaptophysin and postsynaptic density-95 back toward control levels. Consistent with the neuropathophysiological improvements, MW01-5-188WH therapy attenuated deficits in Y maze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human Abeta decreased the numbers of activated astrocytes and microglia and the Cytokine levels in the hippocampus without modifying amyloid plaque burden or altering peripheral tissue Cytokine upregulation in response to an in vivo inflammatory challenge. The results provide a novel integrative chemical biology proof in support of the neuroinflammation hypothesis of disease progression, demonstrate that neurodegeneration can be attenuated independently of plaque modulation by targeting innate brain Proinflammatory Cytokine responses, and indicate the feasibility of developing efficacious, safe, and selective therapies for neurodegenerative disorders by targeting key glial activation pathways.
