Inhibition of the microglial response is essential for the neuroprotective effects of Rho-kinase inhibitors on MPTP-induced dopaminergic cell death
Abstract
Several recent studies have shown that activation of the RhoA/Rho-associated kinase (ROCK) pathway is involved in the MPTP-induced dopaminergic cell degeneration and possibly in Parkinson's disease. ROCK inhibitors have been suggested as candidate neuroprotective drugs for Parkinson's disease. However, the mechanism responsible for the increased survival of dopaminergic neurons after treatment with ROCK inhibitors is not clear. We exposed primary (neuron-glia) mesencephalic cultures, cultures of the MES 23.5 dopaminergic neuron cell line and primary mesencephalic cultures lacking microglial cells to the dopaminergic neurotoxin MPP+ and the ROCK inhibitor Y-27632 in order to study the effects of ROCK inhibition on dopaminergic cell loss and the length of neurites of surviving dopaminergic neurons. In primary (neuron-glia) cultures, simultaneous treatment with MPP+ and the ROCK inhibitor significantly reduced the loss of dopaminergic neurons. In the absence of microglia, treatment with the ROCK inhibitor did not induce a significant reduction in the dopaminergic cell loss. Treatment with the ROCK inhibitor induced a significant decrease in axonal retraction in primary cultures with and without microglia and in cultures of the MES 23.5 neuron cell line. In conclusion, inhibition of microglial ROCK is essential for the neuroprotective effects of ROCK inhibitors against cell death induced by the dopaminergic neurotoxin MPP+. In addition, ROCK inhibition induced a direct effect aga…
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The neuroprotective effect of ROCK inhibition in MPTP models is attributed to inhibition of the MPTP-induced microglial inflammatory response and to a direct protective effect on the dopaminergic neuritic network in vitro and the striatal axonal innervation in vivo.
“The neuroprotective effect was attributed to inhibition of the MPTP-induced microglial inflammatory response [171,173,174] and to a direct protective effect on the dopaminergic neuritic network in vitro and the striatal axonal innervation in vivo [172,174].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [174]
Cites
Microglial Activation and Chronic Neurodegeneration
Lull, M. E., & Block, M. L. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.014 · Cited by 1,047 · see citing works
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Vulnerability of mesostriatal dopaminergic neurons in Parkinson’s disease
González-Hernández, T. (2010) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2010.00140 · Cited by 65 · see citing works
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RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
- Authors
- Borrajo, A., Rodriguez-Perez, A. I., Villar-Cheda, B., Guerra, M. J., & Labandeira-Garcia, J. L.
- Affiliations
- Universidade de Santiago de Compostela (ES)
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 85
- Pages
- 1-8
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2141771317
- Cited by
- 75
- References
- 3
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 3 · 2019: 9 · 2018: 7 · 2017: 5 · 2016: 11 · 2015: 8 · 2014: 4
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministerio de Ciencia e Innovación (BFU2012-37087)
- European Regional Development Fund
- Consejería de Salud y Familias, Junta de Andalucía (RD12/0019/0020)
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Federación Española de Enfermedades Raras
- 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
- ROCK inhibitor, ROCK inhibition, microglia, dopaminergic neuron death, MPTP, MPP+, Parkinson's disease, neuroprotection, axonal retraction, RhoA signaling, Y-27632
- MeSH terms
- Amides, Animals, Axons, Cells, Cultured, Mesencephalon, Pyridines, Neurites, Cell Death, Microglia, Neuroprotective Agents, Cell Culture Techniques, MPTP Poisoning, Cell Line, Tumor, Rats, rho-Associated Kinases, Dopaminergic Neurons
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