Activation of microglial cells by β-amyloid protein and interferon-γ

Meda, Lucia; Cassatella, Marco A.; Szendrei, Gyorgyi I.; Ötvös, László; Baron, Pierluigi; Villalba, Martín; Ferrari, Davide; Rossi, Filippo

doi:10.1038/374647a0

Cited by 1,258 publications

(834 citation statements)

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“…4 These proliferated microglia possibly accelerate neuronal damage by releasing toxic substances. [6][7][8] We previously reported that microglial proliferation and activation were observed in the damaged spinal cord, and that the time course of the progress of hind-limb function loss was quite similar to that of the microglia proliferation in spinal cord after a compression injury. The proliferated microglia were positively stained by anti-TNF-a and anti-iNOS antibodies.…”

Section: Discussionmentioning

confidence: 99%

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Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury

et al. 2008

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Study Design: A basic study using a spinal cord injury (SCI) model in rats. Objectives: The effect of mild hypothermic treatment on histological changes and motor function after a rat spinal cord compression injury was assessed. Methods: Mild spinal cord compression was performed at the eleventh thoracic vertebral level by a 20 g weight for 20 min. Rats in the mild hypothermic model were kept at a body temperature of 33 1C and rats in the normothermic group were kept at 37 1C for 1 h from beginning of compression. Motor function was evaluated by measuring the frequency of standing. Microglia were stained by isolectin B4 and observed in the compressed portion of the spinal cord. The amount of tumor necrosis factor-a (TNF-a) in the compressed spinal cord was measured by the ELISA method. Results: In the normothermic rats, microglia proliferated up to 72 h after the compression. Proliferation was substantially inhibited at 48 and 72 h after compression in the hypothermic rats. The motor function of the hypothermic rats improved at 48 and 72 h after the compression, whereas no improvement was seen in the normothermic rats. The amount of TNF-a in the compressed portion of the spinal cord was lower in hypothermic rats compared with normothermic rats throughout the experiment. Conclusions: These results suggest that hypothermic treatment is effective for the amelioration of delayed motor dysfunction via inhibition of microglial inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

“…These pathologically activated microglia accelerate neuronal damage by releasing nitric oxide, superoxide and inflammatory cytokines such as TNF-a. [6][7][8] Previously, we developed a model for mild spinal cord compression injuries using rats. 9 In this model, microglia proliferated and were activated after spinal cord compression.…”

Section: Introductionmentioning

confidence: 99%

Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury

et al. 2008

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“…These pro-inflammatory cytokines stimulate inflammatory cells to release damaging reactive oxygen and nitrogen species, raise glutamate levels to excitotoxic levels, impair the ability of glia cells to buffer extracellular potassium, compromise the blood-brain barrier, and attract more inflammatory cells into the brain (Tanaka et al, 1994, Meda et al, 1995, Soares et al, 1995, Hu et al, 1997, Keeling et al, 2000. Once initiated, the inflammatory cascade becomes a toxic positivefeedback loop, further exacerbating brain pathology.…”

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confidence: 99%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

133

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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“…Alternative therapeutic strategies against amyloid toxicity could increase proteostatic capacity or target reactive oxygen species (ROS). It has been described that deposition of misfolded proteins increases the amount of ROS [37], by causing inflammation in neuroglia, which, in turn, catalyzes ROS formation [38,39]. Aβ, αS, and PrP also complex metal ions, such as FeII and CuI, that strongly catalyze ROS formation [40,41].…”

Section: Toxicity and Amyloid Formationmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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Activation of microglial cells by β-amyloid protein and interferon-γ

Cited by 1,258 publications

References 21 publications

Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury

Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury

Modulation of the cAMP signaling pathway after traumatic brain injury

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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