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Glial Activation (glial + activation)

Distribution by Scientific Domains

Life Sciences	55%
Medical Sciences	45%

Selected Abstracts

Hippocampal Pathology in the Human Neuronal Ceroid-Lipofuscinoses: Distinct Patterns of Storage Deposition, Neurodegeneration and Glial Activation

BRAIN PATHOLOGY, Issue 4 2004
Jaana Tyynelä
The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies. [source]

Aldose Reductase Inhibition Counteracts Diabetes-Induced Retinal Oxidative Injury, Glial Activation, and Apoptosis

ACTA OPHTHALMOLOGICA, Issue 2007
IG OBROSOVA
Purpose: To access the role for increased aldose reductase (AR) activity in oxidative injury, glial activation, and apoptosis in retinae of diabetic rats and high glucose-exposed cultured retinal pericytes and endothelial cells. Methods: Control (C) and STZ-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg/kg/g, for 10 wks after 2 wks without treatment). The rate of apoptosis was assessed in flat-mounted retinas by TUNEL assay with immunoperoxidase staining, and nitrotyrosine (NT), poly(ADP-ribose) [PAR, a marker of poly(ADP-ribose) polymerase activation] and glial fibrillary acidic protein (GFAP) expression in retinal sections by immunohistochemistry. Primary bovine retinal pericytes and endothelial cells were cultured in 5 mM or 30 mM glucose with/without F (10 microM) for 3-14 d. Apoptosis was assessed by TUNEL assay, NT and PAR by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Results: The number of TUNEL-positive nuclei (Mean ± SEM) was increased ~4-fold in D (207 ± 33 vs 49 ± 4 in C, p < 0.01), and this increase was partially corrected in D+F (106 ± 34, p < 0.05 vs D). The apoptotic cell number increased with prolongation of exposure of both pericytes and endothelial cells to high glucose. F counteracted high glucose-induced apoptosis, and NT and PAR accumulation in both cell types. Antiapoptotic effect of F in high glucose-exposed retinal pericytes was not associated with inhibition of Bax or increase in Bcl-2 expression (endothelial cell studies are in progress). Conclusions: AR inhibition with fidarestat conteracts diabetes-associated retinal oxidative injury, glial activation, and apoptosis. [source]

The induction of HIF-1 reduces astrocyte activation by amyloid beta peptide

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2009
David Schubert
Abstract Reduced glucose metabolism and astrocyte activation in selective areas of the brain are pathological features of Alzheimer's disease (AD). The underlying mechanisms of low energy metabolism and a molecular basis for preventing astrocyte activation are not, however, known. Here we show that amyloid beta peptide (A,)-dependent astrocyte activation leads to a long-term decrease in hypoxia-inducible factor (HIF)-1, expression and a reduction in the rate of glycolysis. Glial activation and the glycolytic changes are reversed by the maintenance of HIF-1, levels with conditions that prevent the proteolysis of HIF-1,. A, increases the long-term production of reactive oxygen species (ROS) through the activation of nicotinamide adenine dinucleotide phosphate oxidase and reduces the amount of HIF-1, via the activation of the proteasome. ROS are not required for glial activation, but are required for the reduction in glycolysis. These data suggest a significant role for HIF-1,-mediated transcription in maintaining the metabolic integrity of the AD brain and identify the probable cause of the observed lower energy metabolism in afflicted areas. They may also explain the therapeutic success of metal chelators in animal models of AD. [source]

Could chronic pain and spread of pain sensation be induced and maintained by glial activation?

ACTA PHYSIOLOGICA, Issue 1-2 2006
E. Hansson
Abstract An injury often starts with acute physiological pain, which becomes inflammatory or neuropathic, and may sometimes become chronic. It has been proposed recently that activated glial cells, astrocytes and microglia within the central nervous system could maintain the pain sensation even after the original injury or inflammation has healed, and convert it into chronic by altering neuronal excitability. Glial cell activation has also been proposed to be involved in the phenomenon of spread of pain sensation ipsilaterally or to the contralateral side (i.e. mirror image pain). Substance P and calcitonin gene-related peptide, released due to an inflammatory process, interact with the endothelial cells of the blood,spinal cord and blood,brain barriers. The barriers open partially and substances may influence adjacent glial cells. Such substances are also released from neurones carrying the ,pain message' all the way from the injury to the cerebral cortex. Pro-inflammatory cytokines may be released from the microglial cells, and astroglial Ca2+ -transients or oscillations may spread within the astroglial networks. One theory is that Ca2+ -oscillations could facilitate the formation of new synapses. These new synapses could establish neuronal contacts for maintaining and spreading the pain sensation. If this theory holds true, it is possible that Ca2+ waves, production of cytokines and growth factors could be modified by selective anti-inflammatory drugs to achieve a balance in the activities of the different intercellular and intracellular processes. This paper reviews current knowledge about glial mechanisms underlying the phenomena of chronic pain and spread of the pain sensation. [source]

Protective effects of naloxone in two-hit seizure model

EPILEPSIA, Issue 3 2010
Lu Yang
Summary Purpose:, Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA),induced two-hit seizure model. Methods:, After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1, [IL-1,], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. Results:, Naloxone reduced IL-1, synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions:, Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood. [source]

The induction of HIF-1 reduces astrocyte activation by amyloid beta peptide

Dopamine transporter knock-out mice are hypersensitive to 3-nitropropionic acid-induced striatal damage

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002
Pierre-O.
Abstract Evidence suggests that dopamine is involved in the modulation of striatal excitotoxic processes. To further investigate this issue, we studied the effects of systemic ,low-dose' (total dose, 340 mg/kg in 7 days) 3-nitropropionic acid (3-NP) intoxication in dopamine transporter knock-out mice (DAT,/,) compared to wildtype (DAT+/+) mice. Systemic ,low-dose' 3-NP induced a significant impairment in a rotarod task only in DAT,/, mice. Histopathology also demonstrated a significant reduction of the striatal volume (,7%, P < 0.05), neuronal density (,12.5%, P < 0.001) and absolute number estimates of striatal neurons (,11.5%, P < 0.001) in DAT,/, compared to DAT+/+ mice, with increased glial activation, independent of the degree of succinate dehydrogenase inhibition. These findings strengthen the hypothesis for dopamine modulation of excitotoxicity within the nigrostriatal system. [source]

Astrocytic factors protect neuronal integrity and reduce microglial activation in an in vitro model of N -methyl- d -aspartate-induced excitotoxic injury in organotypic hippocampal slice cultures

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2001
Nils P. Hailer
Abstract Acute CNS lesions lead to neuronal injury and a parallel glial activation that is accompanied by the release of neurotoxic substances. The extent of the original neuronal damage can therefore be potentiated in a process called secondary damage. As astrocytes are known to secrete immunomodulatory and neuroprotective substances, we investigated whether astrocytic factors can attenuate the amount of neuronal injury as well as the degree of microglial activation in a model of excitotoxic neurodegeneration. Treatment of organotypic hippocampal slice cultures with N-methyl- d -aspartate (NMDA) resulted in a reproducible loss of viable granule cells, partial destruction of the regular hippocampal cytoarchitecture and a concomitant accumulation of amoeboid microglial cells at sites of neuronal damage. Astrocyte-conditioned media reduced the amount of NMDA-induced neuronal injury by 45.3%, diminished the degree of microglial activation and resulted in an improved preservation of the hippocampal cytoarchitecture. Transforming growth factor (TGF)-, failed to act as a neuroprotectant and even enhanced the amount of neuronal injury by 52.5%. Direct effects of astrocytic factors on isolated microglial cells consisted of increased microglial ramification and down-regulated expression of intercellular adhesion molecule-1, whereas incubation with TGF-, had no such effects. In summary, our findings show that hitherto unidentified astrocyte-derived factors that are probably not identical with TGF-, can substantially enhance neuronal survival, either by eliciting direct neuroprotective effects or by modulating the microglial response to neuronal injury. [source]

In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the ,6,4 integrin and dystroglycan

GLIA, Issue 10 2010
Longxuan Li
Abstract Cerebral hypoxia induces a profound angiogenic response in the central nervous system (CNS). Using a mouse model of chronic cerebral hypoxia, we previously demonstrated that angiogenic vessels in the hypoxic CNS show marked upregulation of the extracellular matrix (ECM) protein fibronectin, along with increased expression of its major receptor, ,5,1 integrin on brain endothelial cells (BEC). As cerebral hypoxia also leads to glial activation, the aim of the current study was to define the temporal relationship between BEC responses and glial cell activation in this model of cerebral hypoxia. This revealed that BEC fibronectin/,5,1 integrin expression and proliferation both reached maximal level after 4-day hypoxia. Interestingly, up to 4-day hypoxia, all dividing cells were BEC, but at later time-points proliferating astrocytes were also observed. GFAP staining revealed that hypoxia induced marked astrocyte activation that reached maximal level between 7- and 14-day hypoxia. As newly formed cerebral capillaries require ensheathment by astrocyte end-feet to acquire mature brain endothelium characteristics, we next examined how expression of astrocyte end-feet adhesion molecules is regulated by hypoxia. This showed that the astrocyte adhesion receptors ,6,4 integrin and dystroglycan were both markedly upregulated, with a time-course that closely resembled astrocyte activation. Taken together, this evidence shows that cerebral hypoxia promotes first an endothelial response, in which fibronectin promotes BEC proliferation. This is then followed by an astrocyte response, involving astrocyte activation, proliferation, and reorganization of astrocyte end-feet, which correlates with increased expression of astrocyte end-feet adhesion molecules. © 2010 Wiley-Liss, Inc. [source]

Blockade of IL-15 activity inhibits microglial activation through the NF,B, p38, and ERK1/2 pathways, reducing cytokine and chemokine release

GLIA, Issue 3 2010
Diego Gomez-Nicola
Abstract Reactive glia formation is one of the hallmarks of damage to the CNS, but little information exists on the signals that direct its activation. Microglial cells are the main regulators of both innate and adaptative immune responses in the CNS. The proinflammatory cytokine IL-15 is involved in regulating the response of T and B cells, playing a key role in regulating nervous system inflammatory events. We have used a microglial culture model of inflammation induced by LPS and IFN, to evaluate the role of IL-15 in the proinflammatory response. Our results indicate that IL-15 is necessary for the reactive response, its deficiency (IL-15-/-) leading to the development of a defective proinflammatory response. Blockade of IL-15, both with blocking antibodies or with the ganglioside Neurostatin, inhibited the activation of the NF,B pathway, decreasing iNOS expression and NO production. Inhibiting IL-15 signaling also blocked the activation of the mitogen-activated protein kinase (MAPK) pathways ERK1/2 and p38. The major consequence of these inhibitory effects, analyzed using cytokine antibody arrays, was a severe decrease in the production of chemokines, cytokines and growth factors, like CCL17, CCL19, IL-12, or TIMP-1, that are essential for the development of the phenotypic changes of glial activation. In conclusion, activation of the IL-15 system seems a necessarystep for the development of glial reactivity and the regulation of the physiology of glial cells. Modulating IL-15 activity opens the possibility of developing new strategies to control gliotic events upon inflammatory stimulation. © 2009 Wiley-Liss, Inc. [source]

Interleukin 15 expression in the CNS: Blockade of its activity prevents glial activation after an inflammatory injury

GLIA, Issue 5 2008
Diego Gómez-Nicola
Abstract Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma. © 2008 Wiley-Liss, Inc. [source]

The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases

JOURNAL OF NEUROCHEMISTRY, Issue 1 2007
Grace Y. Sun
Abstract Reactive oxygen species (ROS) are produced in mammalian cells through enzymic and non-enzymic mechanisms. Although some ROS production pathways are needed for specific physiological functions, excessive production is detrimental and is regarded as the basis of numerous neurodegenerative diseases. Among enzymes producing superoxide anions, NADPH oxidase is widespread in mammalian cells and is an important source of ROS in mediating physiological and pathological processes in the cardiovascular and the CNS. ROS production is linked to the alteration of intracellular calcium homeostasis, activation of Ca2+ -dependent enzymes, alteration of cytoskeletal proteins, and degradation of membrane glycerophospholipids. There is evolving evidence that ROS produced by NADPH oxidase regulate neuronal functions and degrade membrane phospholipids through activation of phospholipases A2 (PLA2). This review is intended to cover recent studies describing ROS generation from NADPH oxidase in the CNS and its downstream activation of PLA2, namely, the group IV cytosolic cPLA2 and the group II secretory sPLA2. A major focus is to elaborate the dual role of NADPH oxidase and PLA2 in mediating the oxidative and inflammatory responses in neurodegenerative diseases, including cerebral ischemia and Alzheimer's disease. Elucidation of the signaling pathways linking NADPH oxidase with the multiple forms of PLA2 will be important in understanding the oxidative and degradative mechanisms that underline neuronal damage and glial activation and will facilitate development of therapeutic intervention for prevention and treatment of these and other neurodegenerative diseases. [source]

Involvement of nerve injury and activation of peripheral glial cells in tetanic sciatic stimulation-induced persistent pain in rats

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2010
Lingli Liang
Abstract Tetanic stimulation of the sciatic nerve (TSS) produces long-lasting pain hypersensitivity in rats. Long-term potentiation (LTP) of C- and A-fiber-evoked field potentials in the spinal cord has been explored as contributing to central sensitization in pain pathways. However, the peripheral mechanism underlying TSS-induced pain hypersensitivity remains largely unknown. We investigated the effect of TSS on peripheral nerve and the expression of activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) as a marker of neuronal injury. TSS induced a mechanical allodynia for at least 35 days and induced ATF3 expression in the ipsilateral DRG. ATF3 is colocalized with NF200-labeled myelinated DRG neurons or CGRP- and IB4-labeled unmyelinated ones. Furthermore, we found that TSS induced Wallerian degeneration of sciatic nerve at the level of myelinisation by S100 protein (to label Schwann cells) immunohistochemistry, luxol fast blue staining, and electron microscopy. TSS also elicited the activation of satellite glial cells (SGCs) and enhanced the colocalization of GFAP and P2X7 receptors. Repeated local treatment with tetrodotoxin decreased GFAP expression in SGCs and behavioral allodynia induced by TSS. Furthermore, reactive microglia and astrocytes were found in the spinal dorsal horn after TSS. These results suggest that TSS-induced nerve injury and glial activation in the DRG and spinal dorsal horn may be involved in cellular mechanisms underlying the development of persistent pain after TSS and that TSS-induced nerve injury may be used as a novel neuropathic pain model. © 2010 Wiley-Liss, Inc. [source]

Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficits

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2005
Qun Wang
Abstract Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death. © 2005 Wiley-Liss, Inc. [source]

Antecedent Ethanol Attenuates Cerebral Ischemia/Reperfusion-Induced Leukocyte-Endothelial Adhesive Interactions and Delayed Neuronal Death: Role of Large Conductance, Ca2+ -activated K+ Channels

MICROCIRCULATION, Issue 6 2010
QUN WANG
Please cite this paper as: Wang, Kalogeris, Wang, Jones and Korthuis (2010). Antecedent Ethanol Attenuates Cerebral Ischemia/Reperfusion-Induced Leukocyte-Endothelial Adhesive Interactions and Delayed Neuronal Death: Role of Large Conductance, Ca2+ -activated K+ Channels. Microcirculation17(6), 427,438. Abstract EtOH-PC reduces postischemic neuronal injury in response to cerebral (I/R). We examined the mechanism underlying this protective effect by determining (i) whether it was associated with a decrease in I/R-induced leukocyte-endothelial adhesive interactions in postcapillary venules, and (ii) whether the protective effects were mediated by activation of large conductance, calcium-activated potassium (BKCa) channels. Mice were administered ethanol by gavage or treated with the BKCa channel opener, NS1619, 24 hours prior to I/R with or without prior treatment with the BKCa channel blocker, PX. Both CCA were occluded for 20 minutes followed by two and three hours of reperfusion, and rolling (LR) and adherent (LA) leukocytes were quantified in pial venules using intravital microscopy. The extent of DND, apoptosis and glial activation in hippocampus were assessed four days after I/R. Compared with sham, I/R elicited increases in LR and LA in pial venules and DND and apoptosis as well as glial activation in the hippocampus. These effects were attenuated by EtOH-PC or antecedent NS1619 administration, and this protection was reversed by prior treatment with PX. Our results support a role for BKCa channel activation in the neuroprotective effects of EtOH-PC in cerebral I/R. [source]

Role of spinal cord glia in the central processing of peripheral pain perception

NEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2010
S. Bradesi
Abstract Background, The discovery that glial activation plays a critical role in the modulation of neuronal functions and affects the spinal processing of nociceptive signalling has brought new understanding on the mechanisms underlying central sensitization involved in chronic pain facilitation. Spinal glial activation is now considered an important component in the development and maintenance of allodynia and hyperalgesia in various models of chronic pain, including neuropathic pain and pain associated with peripheral inflammation. In addition, spinal glial activation is also involved in some forms of visceral hyperalgesia. Purpose, We discuss the signalling pathways engaged in central glial activation, including stress pathways, and the neuron,glia bidirectional relationships involved in the modulation of synaptic activity and pain facilitation. In this expanding field of research, the characterization of the mechanisms by which glia affect spinal neuro-transmission will increase our understanding of central pain facilitation, and has the potential for the development of new therapeutic agents for common chronic pain conditions. [source]

Hippocampal Pathology in the Human Neuronal Ceroid-Lipofuscinoses: Distinct Patterns of Storage Deposition, Neurodegeneration and Glial Activation

Spinal glial TLR4-mediated nociception and production of prostaglandin E2 and TNF

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2010
O Saito
Background and purpose:, Toll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E2 (PGE2) and tumour necrosis factor (TNF), and the role these factors play in TLR4-induced tactile allodynia. Experimental approach:, Toll-like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO2 -Lipid A (KDO2) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE2 and TNF levels were measured by mass spectometry and elisa. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF-blocker) and ketorolac (COX-inhibitor) were given i.t. prior to injection of the TLR4-agonists, in order to determine if these agents alter TLR4-mediated nociception and the spinal release of PGE2 and TNF. Key results:, Spinal administration of LPS and KDO2 produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE2 and TNF. Intrathecal pentoxifylline blunted PGE2 and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE2 induced by LPS and KDO2 was attenuated by i.t. administration of ketorolac. Conclusions and implications:, Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia. [source]