Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy
Open accessAbstract
Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD. Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells. Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.
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Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, has a neuroprotective effect in models of Parkinson's disease.
“Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, has a neuroprotective effect in models of Parkinson's disease.[214][215][216]”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [215]
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Self-citationAltered expression of Sialyl Lewis X in experimental models of Parkinson’s disease
Nunes, M. J., Carvalho, A. N., Rosa, A. I., Videira, P. A., Gama, M. J., Rodrigues, E., & Castro‐Caldas, M. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02415-3 · Cited by 6 · see citing works
“…parameters triggered by this dose of administration of MPTP that resemble most of the neuro-pathological features of human PD, including increased oxidative stress and mitochondrial dysfunction, astrogliosis and microgliosis, death of dopaminergic neurons and severe motor symptoms [4, 5, 31, 32].”
BackgroundMethodResultInfluentialSelf-citationSustained PGC-1α2 or PGC-1α3 expression induces astrocyte dysfunction and degeneration
Nunes, M. J., Carvalho, A. N., Sá-Lemos, C., Colaço, M. L., Červenka, I., Ciraci, V., Santos, S. G., Ribeiro, M. M., Castanheira, M., Jannig, P. R., et al. (2023) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2023.151377 · Cited by 5 · see citing works
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“…the suppression The ANXA1 protein regulates several cellular func ‐ tions across diverse cell types, including the suppression of inflammatory responses and the facilitation of nerve repair and protection [26]. inflammatory responses and the facilitation of nerve repair and protection [26].”
BackgroundMetabolomic Biomarkers in Parkinson’s Disease
Shao, Y., Xu, X., Wang, N., Xu, G., & Le, W. (2021) · Neuromethods · doi:10.1007/978-1-0716-1712-0_8 · Cited by 2 · see citing works
Neuroprotective effects of ursodeoxycholic acid in Parkinson's disease and Alzheimer's disease
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Exploring the complex role of protein glycosylation in the pathogenesis of Parkinson’s disease
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“MPTP triggered microglial and astrocytic activation, along with activation of the NLRP3 inflammasome in the nigrostriatal pathway [61].”
- Authors
- Mendes, M. O., Rosa, A. I., Carvalho, A. N., Nunes, M. J., Dionísio, P., Rodrigues, E., Costa, D., Duarte-Silva, S., Maciel, P., Rodrigues, C. M. P., Gama, M. J., & Castro-Caldas, M.
- Affiliations
- University of Lisbon (PT)
- ORCID
- Venue
- Molecular and Cellular Neuroscience
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 96
- Pages
- 1-9
- ISSN
- 1044-7431 (ISSN-L)
- OpenAlex
- W2911607215
- Cited by
- 31
- References
- 64
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 3
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-07-01)
- Open access
- green
- www.scopus.com
- Licence
- Locations
- Molecular and Cellular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Funders
- Foundation for Science and Technology (PTDC/NEU-NMC/0248/2012, UID/DTP/04138/2013, POCI-01-0145-FEDER-007038, SFRH/BPD72891/2010, SFRH/BPD/95855/2013, SFRH/BPD/98023/2013, SFRH/BD/102771/2014, UMINHO/BI/248/2016)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- MPTP, Parkinson's disease, cerebral cortex, neuroinflammation, neuroprotection, tauroursodeoxycholic acid, bile acids, annexin A1, microglia, Parkin, Nrf2, AMPK, oxidative stress, dopaminergic neuron loss, Lewy bodies
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Adenosine Triphosphate, Animals, Anti-Inflammatory Agents, Cell Line, Cerebral Cortex, Male, Mice, Inbred C57BL, Protein Kinases, Taurochenodeoxycholic Acid, Annexin A1, Microglia, Neuroprotective Agents, MPTP Poisoning, Ubiquitin-Protein Ligases, NF-E2-Related Factor 2, Mice
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