Evaluation of different systemic lipopolysaccharide treatment paradigms to induce parkinsonism in mice
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1
Vrije Universiteit Brussel, Department of Pharmaceutical Biotechnology and Molecular Biology, Belgium
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2
Vrije Universiteit Brussel, Department of Pharmaceutical Chemistry and Drug Analysis, Belgium
Inflammation and microglial activation are common features in the pathogenesis of multiple neurodegenerative diseases, including Parkinson's disease (PD). Lipopolysaccharide (LPS), an endotoxin from gram-negative bacteria, has been shown to be a potent inducer of inflammation and causes, in certain circumstances, the progressive and cumulative loss of dopamine (DA)-ergic neurons over time both in vivo and in vitro, but only in the presence of microglia (1). Even more, it has been suggested that LPS is able to ‘prime’ microglial cells, thereby causing an exaggerated response to a subsequent (inflammatory) trigger (2). DA-ergic neurons of the substantia nigra pars compacta (SNpc) are more susceptible to inflammatory damage compared with other neuronal subtypes, possibly due to stronger microglial reaction in the midbrain (3). In this study we compared the effects of two systemic LPS treatment paradigms in mice: a single high-dose and repeated low-dose intraperitoneal (i.p.) injections. We first tested whether a single peripheral high-dose LPS exposure of 5mg/kg in adult male mice would result in delayed (i.e. 10 months after injection) (i) loss of DA-ergic neurons in the SNpc, (ii) DA depletion in the striatum and (iii) parkinsonian symptoms. Analysis of the nigrostriatal DA-ergic pathway revealed no significant differences in striatal DA content nor in loss of DA-ergic neurons in the SNpc between LPS- and vehicle-treated mice, suggesting an intact nigrostriatal pathway. However, a significant decrease in motor function was detected during the rotarod test in LPS-treated mice, whereas no effect on sensorimotor function was present in the adhesive removal test. Also, no differences were observed between LPS- and vehicle-treated mice in any of the tests examining cognitive, anxiety- and depressive-like behaviour. Next, we evaluated the effect of a repeated systemic challenge with low-dose LPS (250µg/kg) over four consecutive days on the nigrostriatal pathway. Here as well, low-dose LPS treatment did not seem to affect the nigrostriatal pathway as no striatal DA depletion nor DA-ergic neuronal loss was seen on day 5 or day 12 after the first LPS injection. Finally, we examined whether this low-dose of LPS was able to prime microglial cells to respond more strongly to a subsequent neurotoxic stimulus. To do so, we added lactacystin (LAC), a proteasome inhibitor, as a second stimulus to acutely induce DA-ergic neurodegeneration. During four consecutive days, mice were i.p. injected with a low-dose of LPS and on the fifth day, LAC or saline was stereotactically injected in the left SNpc. Seven days after administration of LAC, motor performance on the rotarod was affected in this dual-hit model, yet to a same degree in the LPS- and vehicle-treated group. Accordingly, immunohistochemical analysis of the SNpc revealed a significant decrease in DA-ergic neurons in the ipsilateral part of the SNpc after LAC lesion, without any additional treatment effect. In contrast, a significant increase in striatal DA loss was observed in LPS-treated LAC-lesioned mice compared to vehicle-treated LAC-lesioned mice. At this point, we can conclude that a single occurrence of high-dose LPS or repeated occurrence of low-dose LPS, does not negatively affect the nigrostriatal pathway. Yet, repeated low-dose peripheral LPS administration increases the susceptibility to striatal DA depletion induced by intranigral proteasome inhibition. Additional experiments are warranted to achieve insight in the potential of the latter model to be used as a dual-hit mouse model for PD.
References
(1) Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam. Clin. Pharmacol. 2008;22:453-464.
(2) Bodea L-G, Wang Y, Linnartz-Gerlach B, et al. Neurodegeneration by Activation of the Microglial Complement-Phagosome Pathway. J. Neurosci. 2014;34(25):8546-8556.
(3) Liu M, Bing G. Lipopolysaccharide Animal Models for Parkinson’s Disease. Parkinsons. Dis. 2011;2011:1-7.
Keywords:
lipopolysaccharide (LPS),
Neuroinflammation,
Parkinson’s disease,
neurodegeneration,
Lactacystin
Conference:
12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017.
Presentation Type:
Poster Presentation
Topic:
Disorders of the Nervous System
Citation:
Deneyer
L,
Albertini
G,
Verbruggen
L,
Smolders
IJ,
Bentea
E and
Massie
A
(2019). Evaluation of different systemic lipopolysaccharide treatment paradigms to induce parkinsonism in mice.
Front. Neurosci.
Conference Abstract:
12th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2017.94.00037
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Received:
27 Apr 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Miss. Lauren Deneyer, Vrije Universiteit Brussel, Department of Pharmaceutical Biotechnology and Molecular Biology, Jette, 1090, Belgium, lauren.deneyer@vub.ac.be