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The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery
Open accessAbstract
Research in the last two decades has unveiled an important role for neuroinflammation in the degeneration of the nigrostriatal dopaminergic (DA) pathway that constitutes the pathological basis of the prevailing movement disorder, Parkinson’s disease (PD). Neuroinflammation is characterized by the activation of brain glial cells, primarily microglia and astrocytes that release various soluble factors that include free radicals (reactive oxygen and nitrogen species), cytokines, and lipid metabolites. The majority of these glia‐derived factors are proinflammatory and neurotoxic and are particularly deleterious to oxidative damage‐vulnerable nigral DA neurons. As a proof of concept, various immunologic stimuli have been employed to directly induce glial activation to model DA neurodegeneration in PD. The bacterial endotoxin, lipopolysaccharide (LPS), has been the most extensively utilized glial activator for the induction of inflammatory DA neurodegeneration. In this review, we will summarize the various in vitro and in vivo LPS PD models. Furthermore, we will highlight the contribution of the LPS PD models to the mechanistic studies of PD pathogenesis and the search for neuroprotective agents for the treatment of PD.
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“Neuroinflammation is characterised by the activation of microglia and astrocytes [29].”
From Neuroprotective Effect of Ceftriaxone on MPTP‐Induced Parkinson’s Disease Mouse Model by Regulating Inflammation and Intestinal Microbiota (2021) · cites this paper as [29]
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“Lipopolysaccharide (LPS), a bacterial endotoxin, activates microglia and can cause neurodegeneration (reviewed in Dutta et al., 2008; Perry and Andersson, 1992; Zielasek and Hartung, 1996).”
Cebrián, C., Loike, J. D., & Sulzer, D. (2014) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2014_356 · Cited by 65
“2002) or neutralizing antibodies against TNF-α or IL-1 that block microglial activation (Dutta et al. 2008; McCoy and Tansey 2008).”
BackgroundSong, X.-M., Yu, Q., Dong, X., Yang, H. O., Zeng, K.-W., Li, J., & Tu, P.-F. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.06.005 · Cited by 60
“In neurodegenerative diseases, the inflammatory response is mediated by activated microglia which release pro-inflammatory mediators such as TNF-α, IL-1β to exacerbate these diseases [17,18].”
BackgroundAnimal models of neurodegenerative diseases
Ribeiro, F. M., Camargos, E. R. D. S., de Souza, L. C., & Teixeira, A. L. (2013) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2013-1157 · Cited by 62
Cognitive dysfunction and depression in Parkinson’s disease: what can be learned from rodent models?
Lindgren, H. S., & Dunnett, S. B. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08162.x · Cited by 56
“This results in an inflammatory DA neurodegeneration to a variable extent depending on the dosing regimen (Dutta et al., 2008), but the accompanying motor impairment has not been reproducible between studies (Liu et al., 2008; Choi et al., 2009; Ariza et al., 2010).”
BackgroundGentile, F., Doneddu, P. E., Riva, N., Nobile‐Orazio, E., & Quattrini, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207471 · Cited by 58
“Intrastriatal injection of LPS has been shown to replicate PD‐like phenotype and progressive neurodegeneration in mice [258].”
BackgroundRNA-Seq transcriptomic profiling of primary murine microglia treated with LPS or LPS + IFNγ
Pulido-Salgado, M., Vidal-Taboada, J. M., Barriga, G. G.-D., Solà, C., & Saura, J. (2018) · Scientific Reports · doi:10.1038/s41598-018-34412-9 · Cited by 53
Zhu, Y., Chen, X., Liu, Z., Peng, Y.-P., & Qiu, Y. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms17010025 · Cited by 55
“LPS has been the most extensively utilized glial activator for the induction of inflammatory dopaminergic neurodegeneration [2].”
BackgroundInfluentialSocías, S. B., González‐Lizárraga, F., Ávila, C. L., Vera, C., Acuña, L., Sepulveda-Diaz, J. E., Bel, E. A. D., Raisman‐Vozari, R., & Chehín, R. N. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.12.002 · Cited by 55
“On the other hand, since it was demonstrated that the oxidation of Ab by free radicals induces peptide fibrillization (Dyrks et al., 1992), antioxidant agents may exert anti-aggregating effects on the Ab peptide.”
BackgroundHuman neuromelanin an endogenous microglial activator for dopaminergic neuron death
Zhang, W. (2012) · Frontiers in Bioscience-Elite · doi:10.2741/e591 · Cited by 54
“9 Strong evidence indicates that in the disease states, over-activated microglia produce and secret a myriad of factors, including reactive oxygen species (ROS), nitrogen species, cytokines, prostaglandins and chemokines (18-19), which may cause neuronal damage.”
BackgroundPeptidoglycan recognition protein genes and risk of Parkinson's disease
Goldman, S. M., Kamel, F., Ross, G. W., Jewell, S. A., Marras, C., Hoppin, J. A., Umbach, D. M., Bhudhikanok, G. S., Meng, C., Korell, M., et al. (2014) · Movement Disorders · doi:10.1002/mds.25895 · Cited by 53
“Systemic administration of gram-negative bacterial endotoxin (lipopolysaccharide [LPS]) activates microglia in the substantia nigra and induces progressive dopaminergic degeneration in a rodent model of parkinsonism.(18) However, little is known about possible effects of other bacterial components.”
BackgroundMaturana, C. J., Aguirre, A., & Sáez, J. C. (2016) · Developmental Neurobiology · doi:10.1002/dneu.22409 · Cited by 51
“The role of reactive astrocytes in this cell-cell conversation was specifically demonstrated by the effect of minocycline, which is an astrocyte activation inhibitor (Dutta et al., 2008), which also blocked oligodendrocyte hemichannel activity in brain slices of offspring from DEX-treated mice.”
BackgroundMethodFlores-Martinez, Y. M., Fernandez-Parrilla, M. A., Ayala-Dávila, J., Reyes-Corona, D., Blanco-Álvarez, V. M., Soto-Rojas, L. O., Luna-Herrera, C., González-Barrios, J. A., León‐Chávez, B. A., Gutiérrez-Castillo, M. E., et al. (2018) · Journal of Immunology Research · doi:10.1155/2018/1838921 · Cited by 53
“Lipopolysaccharide (LPS) appears to be a neuroinflammatory stimulus more suitable to mimic the acute response of microglia that might also occur in the early stage of Parkinson’s disease [20].”
BackgroundCheng, L. T., Chen, L., Wei, X., Wang, Y., Ren, Z.-P., Zeng, S., Zhang, X., Wen, H., Gao, C., & Liu, H. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1289-z · Cited by 53
RIFAMPICIN: An antibiotic with brain protective function
Yuluğ, B., Hanoğlu, L., Kılıç, E., & Schabitz, W. R. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2014.05.007 · Cited by 51
Considerations on the role of environmental toxins in idiopathic Parkinson’s disease pathophysiology
Pan-Montojo, F. J., & Reichmann, H. (2014) · Translational Neurodegeneration · doi:10.1186/2047-9158-3-10 · Cited by 54
“In animal experiments, exposure to the bacterial endotoxin lipopolysaccharide induced dopaminergic neurodegeneration [136,138,139].”
BackgroundNie, P.-Y., Tong, L., Li, M.-D., Fu, C.-H., Peng, J., & Ji, L.-L. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02064-0 · Cited by 49
“Most of these glia-derived factors are proinflammatory and neurotoxic and are particularly deleterious to neurons [9, 10].”
BackgroundHe, Q., Li, Y., Guo, S., Wang, Y., Lin, W., Zhang, Q., Wang, J., Ma, C., & Xiao, B. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13132 · Cited by 48
“, 1993), and has been used for the induction of dopamine neurodegeneration through intracranial and intraperitoneal injection (Dutta et al., 2008).”
BackgroundRetractedMouton, P. R., Kelley-Bell, B., Tweedie, D., Spangler, E. L., Perez, E., Carlson, O. D., Short, R. G., de Cabo, R., Chang, J. P., Ingram, D. K., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.09.025 · Cited by 48
“Studies carried out in vitro indicate that LPSactivated macrophages and microglial cells stimulate multiple signaling pathways of the innate immune system, including the up-regulation and release of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, anti-inflammatory cytokine IL-10, and reactive oxygen speci…”
BackgroundDutta, G., Barber, D. S., Zhang, P., Doperalski, N. J., & Liu, B. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07826.x · Cited by 45
“up-regulation was observed with LPS, a potent stimulator of immune cells (Liu 2006; Dutta et al. 2008).”
MethodSelf-citationFan, L., Tien, L., Lin, R. C. S., Simpson, K. L., Rhodes, P. G., & Cai, Z. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.011 · Cited by 46
Ketamine inhibits LPS‐mediated BV2 microglial inflammation via NMDA receptor blockage
Lu, Y., Ding, X., Wu, X., & Huang, S. (2019) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12508 · Cited by 46
Rifampicin and Parkinson’s disease
Bi, W., Zhu, L., Jing, X., Liang, Y., & Tao, E. (2012) · Neurological Sciences · doi:10.1007/s10072-012-1156-0 · Cited by 46
“Further investigations using LPS-stimulated BV2 microglial cells [49] demonstrate that rifampicin signifi-”
MethodLipoic acid protects dopaminergic neurons in LPS-induced Parkinson’s disease model
Li, Y., He, Q. W., Yu, J., Liu, C., Feng, L., Chai, Z., Wang, Q., Zhang, H., Zhang, G., Xiao, B., et al. (2015) · Metabolic Brain Disease · doi:10.1007/s11011-015-9698-5 · Cited by 45
“Microglia have both neurotoxic and neurotrophic effects and serve as key components of brain inflammatory response , exerting a deleterious role on dopaminergic neurons in PD. (Trudler et al. 2014) Type 1 macrophages/microglia (M1) produce inflammatory cytokines and oxidative metabolites to exacerbate tissue injury, t…”
BackgroundInfluentialBrandi, E., Torres-Garcia, L., Svanbergsson, A., Haikal, C., Liu, D., Li, W., & Li, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.910988 · Cited by 48
“This neuronal population is more sensitive to reactive oxygen species (ROS), which exacerbate the detrimental effect of pathological agents such as α-synuclein or toxins (Drechsel and Patel, 2008; Dutta et al., 2008; Gao et al., 2008; Ramsey and Tansey, 2013; Rai and Singh, 2020; Rai et al., 2020).”
BackgroundAhn, S. K., Hong, S., Park, Y. M., Choi, J. Y., Lee, W. T., Park, K. A., & Lee, J. E. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.10.010 · Cited by 44
“And LPS, a bacterial endotoxin, has been widely utilized as a potent inflammation inducer in various experimental systems (Dutta et al., 2008).”
Cai, Z., Fan, L., Kaizaki, A., Tien, L., Ma, T., Pang, Y., Lin, S., Lin, R. C. S., & Simpson, K. L. (2013) · Developmental Neuroscience · doi:10.1159/000346156 · Cited by 43
Geloso, M. C., Zupo, L., & Corvino, V. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105872 · Cited by 43
Quantitative Proteomic Characterization of Ethanol-Responsive Pathways in Rat Microglial Cells
Bell‐Temin, H., Zhang, P., Chaput, D., King, M. A., You, M., Liu, B., & Stevens, S. M. (2013) · Journal of Proteome Research · doi:10.1021/pr301038f · Cited by 43
Self-citationMorales-Garcia, J. A., Morante, D. A., Hernández-Encinas, E., Alonso‐Gil, S., Gil, C., Martı́nez, A., Santos, Á., & Pérez‐Castillo, A. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.10.008 · Cited by 41
Jurado-Coronel, J. C., Ávila-Rodriguez, M., Capani, F., González, J., Echeverrı́a, V., & Barreto, G. E. (2016) · Current Pharmaceutical Design · doi:10.2174/138161282210160304112133 · Cited by 39
Lipopolysaccharide administration for a mouse model of cerebellar ataxia with neuroinflammation
Hong, J., Yoon, D., Nam, Y., Seo, D., Kim, J., Kim, M. S., Lee, T. Y., Kim, K. S., Ko, P., Lee, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-70390-7 · Cited by 37
Wei, B.-R., Zhao, Y., Cheng, Y., Huang, C., & Zhang, F. (2024) · Immunity & Ageing · doi:10.1186/s12979-023-00404-1 · Cited by 38
“Mean-while, LPS up-regulates the expression of inducible nitric oxide synthase (iNOS) to promote NO release from microglia and astrocytes [64].”
BackgroundInfluentialL’Episcopo, F., Tirolo, C., Testa, N., Caniglia, S., Morale, M. C., Impagnatiello, F., & Marchetti, B. (2011) · Rejuvenation Research · doi:10.1089/rej.2010.1134 · Cited by 39
“In addition, LPS-induced microglial ROS production herein observed, further combined with iNOS-derived NO, forms the more damaging peroxynitrite.(25,31,51,61) In addition, a rise in intracellular ROS can further enhance the gene expression of TNF-a and IL-1b.”
InfluentialPlant-Derived Natural Products for Parkinson’s Disease Therapy
Sengupta, T. K., Vinayagam, J., Singh, R. P., Jaisankar, P., & Mohanakumar, K. P. (2016) · Advances in neurobiology · doi:10.1007/978-3-319-28383-8_23 · Cited by 39
Metadata
- Authors
- Dutta, G., Zhang, P., & Liu, B.
- Affiliations
- University of Florida (US)
- Corresponding author
- Liu, Bin
- ORCID
- Liu, Bin
- Venue
- Fundamental & Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2008-09-21
- Volume
- 22
- Issue
- 5
- Pages
- 453-464
- ISSN
- 0767-3981 (ISSN-L)
- 1472-8206
- PMC
- PMC2632601
- OpenAlex
- W2057913943
- Cited by
- 235
- References
- 106
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 14 · 2023: 10 · 2022: 15 · 2021: 19 · 2020: 15 · 2019: 10 · 2018: 13 · 2017: 14 · 2016: 14 · 2015: 13 · 2014: 14 · 2013: 16 · 2012: 22
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Fundamental and Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Environmental Health Sciences (ES013265, R01ES013265)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, lipopolysaccharide, neuroinflammation, nigrostriatal pathway, dopaminergic neuron loss, microglial activation, astrocytes, glial activation, neuroprotection, drug discovery, oxidative stress, cytokines, Parkinson's disease model
- MeSH terms
- Animals, Antiparkinson Agents, Disease Models, Animal, Humans, Lipopolysaccharides, Parkinson Disease, Drug Discovery
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