Cited by 1,047Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsInflammasome and immune disorders

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Microglial Activation and Chronic Neurodegeneration

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Lull, Melinda E., Block, Michelle L.·2010·Neurotherapeutics

DOI 10.1016/j.nurt.2010.05.014PMC PMC2951017

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Abstract

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurodegenerative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson's disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype.

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Background
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Background
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Background
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Background
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Background
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Background
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“A close functional relationship between neurons and microglial cells, the long-lived and self-propelling microglia response to neuronal cells damage, leads to “reactive microgliosis” [122,123].”
Background
Mechanism of miR-132-3p Promoting Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson’s Disease
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“Discussion Neuroinflammation is a characteristic of neurodegenerative diseases, including PD, in which microglia confer pathogenic and exacerbating effects (Lull and Block, 2010; Zhao et al., 2020).”
Background
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Background
2-Pentadecyl-2-Oxazoline Reduces Neuroinflammatory Environment in the MPTP Model of Parkinson Disease
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“In their activated, amoeboid form, microglia have the capacity to upregulate and release a myriad of secretory products that can contribute to defense but may also damage or kill neurons [29-31,34,35].”
Background
Interweaving epilepsy and neurodegeneration: Vitamin E as a treatment approach
Upaganlawar, A. B., Wankhede, N. L., Kale, M. B., Umare, M. D., Sehgal, A., Singh, S., Bhatia, S., Al-Harrasi, A., Najda, A., Nurzyńska-Wierdak, R., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112146 · Cited by 53
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Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease
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The protective effect of lactoferrin on ventral mesencephalon neurons against MPP+ is not connected with its iron binding ability
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The Effect of A 2A Receptor Antagonist on Microglial Activation in Experimental Glaucoma
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Extracellular cardiolipin regulates select immune functions of microglia and microglia-like cells
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“Thus, HIV does not harm neurons directly by productive infection, but rather, it harms by promoting the production of inflammatory factors like tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS) from infected macrophages and microglia [40, 59].”
Background
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“P2X7R gene expression was silenced for about 48 h continued with METH treatment for up to 48 h. Evaluation of proinflammatory cytokines in ESdM cells following METH treatment for 48 h showed increased production of TNF-a and IL-10 (data not shown).”
BackgroundInfluential
Cardiolipin in Central Nervous System Physiology and Pathology
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“The main types of glia, including astrocytes, oligodendrocytes, and microglia, provide structural, chemical, and nutritional support to neurons and are critical for maintaining brain homeostasis (Jessen 2004; Lull and Block 2010).”
Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1β Production in Microglia
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Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)
Come, J. H., Collier, P. N., Henderson, J. A., Pierce, A. C., Davies, R. J., LeTiran, A., O’Dowd, H., Bandarage, U. K., Cao, J., Deininger, D. D., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00085 · Cited by 51
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Triptolide up-regulates metabotropic glutamate receptor 5 to inhibit microglia activation in the lipopolysaccharide-induced model of Parkinson’s disease
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“In general, migration of microglia towards the site of injury is a part of an innate immune response that usually helps to resolve potential pathogenic conditions (Lull and Block 2010).”
Background
The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Nav 1.6
Hossain, M. M., Weig, B., Reuhl, K. R., Gearing, M., Wu, L., & Richardson, J. R. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.07.005 · Cited by 48
“In experimental animal models of PD, sustained release of TNF-α and production of ROS by activated microglia leads to DA neuron degeneration, suggesting the regulation of microglial function could be a potential therapeutic target (Kempuraj et al., 2013; Lull and Block, 2010; Richardson and Hossain, 2013; Wang et al.,…”
Background
Blockade of sustained tumor necrosis factor in a transgenic model of progressive autoimmune encephalomyelitis limits oligodendrocyte apoptosis and promotes oligodendrocyte maturation
Valentin-Torres, A., Savarin, C., Barnett, J., & Bergmann, C. C. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1164-y · Cited by 48
“astrocytic extensions and mesh formation [21, 24], as well as retraction and thickening of microglia/macrophage protrusions [61].”
Antioxidant and Antineuroinflammatory Mechanisms of Kaempferol-3- O -β- d -Glucuronate on Lipopolysaccharide-Stimulated BV2 Microglial Cells through the Nrf2/HO-1 Signaling Cascade and MAPK/NF-κB Pathway
Lim, H. J., Prajapati, R., Seong, S. H., Jung, H. A., & Choi, J. S. (2023) · ACS Omega · doi:10.1021/acsomega.2c06916 · Cited by 57
The Tumor Suppressor p53 Fine-Tunes Reactive Oxygen Species Levels and Neurogenesis via PI3 Kinase Signaling
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“ROS have long been implicated in the pathogenesis of neurodegenerative disorders of inflammatory and primarily neurodegenerative origin (Lull and Block, 2010; Patten et al., 2010), and p53 has been associated both with neuroregeneration and neurodegeneration (Floriddia et al., 2012; Lanni et al.,…”
Background
Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts
Sairazi, N. S. M., Sirajudeen, K. N. S., Asari, M. A., Mustapha, M., Mummedy, S., & Sulaiman, S. A. (2015) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2015/972623 · Cited by 47
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“Activation of microglia as a consequence of neuronal injury augments their neurotoxicity (Polazzi and Contestabile 2002), and this microglial response to neuronal damage can be long-lived and self-propelling (Lull and Block 2010).”
In Vivo Imaging of Microglia With Multiphoton Microscopy
Hierro‐Bujalance, C., Bacskai, B. J., & García-Alloza, M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00218 · Cited by 50
“While the concept of resting and activated microglia might be ambiguous, since different phenotypic and morphological stages of microglia are represented in vivo (Madore et al., 2013), previous studies have analyzed the acute effect of different lesions on microglial responses.”
Result
Polyphenols Derived from Lychee Seed Suppress Aβ (1-42)-Induced Neuroinflammation
Tang, Y., Xiong, R., Wu, A., Yu, C., Zhao, Y., Qiu, W., Wang, X., Teng, J., Liu, J., Chen, H., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072109 · Cited by 49
Microglial Cells Depletion Increases Inflammation and Modifies Microglial Phenotypes in an Animal Model of Severe Sepsis
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Authors: Lull, M. E., & Block, M. L.
Affiliations: Virginia Commonwealth University (US)
Corresponding author: Block, Michelle L.
ORCID: Lull, Melinda E.
Block, Michelle L.
Venue: Neurotherapeutics
Publisher: Elsevier BV
Published: 2010-10
Volume: 7
Issue: 4
Pages: 354-365
ISSN: 1878-7479 (ISSN-L)
DOI: 10.1016/j.nurt.2010.05.014
PMC: PMC2951017
OpenAlex: W2050320551
Cited by: 1,047
References: 182
Citations by year: 2026: 50 · 2025: 112 · 2024: 94 · 2023: 60 · 2022: 84 · 2021: 95 · 2020: 84 · 2019: 78 · 2018: 83 · 2017: 76 · 2016: 73 · 2015: 43 · 2014: 38 · 2013: 28 · 2012: 30
FWCI: 14.71
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4696 d)
Locations: Neurotherapeutics (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Fisher Digital Publications (St. John Fisher College) (submittedVersion)
Funders: National Institutes of Health
National Institute of Environmental Health Sciences (R01ES016951, R00ES01549)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: microglial activation, neurodegeneration, reactive microgliosis, reactive oxygen species, neuroinflammation, neurotoxicity, Parkinson's disease, neuronal cell death, lipopolysaccharide, TNF-α, nitric oxide, IL-1β
MeSH terms: Animals, Chronic Disease, Dopamine, Humans, Models, Biological, Neurons, Oxidation-Reduction, Signal Transduction, Reactive Oxygen Species, Microglia, NADPH Oxidases, Neurodegenerative Diseases

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