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Cited by 176Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNerve injury and regeneration

Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease

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Tonges, L., Frank, T., Tatenhorst, L., Saal, K. A., Koch, J. C., Szego, E. M., Bahr, M., Weishaupt, J. H. +1 more·2012·Brain
DOI 10.1093/brain/aws254PMC PMC3501973
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Abstract

Axonal degeneration is one of the earliest features of Parkinson's disease pathology, which is followed by neuronal death in the substantia nigra and other parts of the brain. Inhibition of axonal degeneration combined with cellular neuroprotection therefore seem key to targeting an early stage in Parkinson's disease progression. Based on our previous studies in traumatic and neurodegenerative disease models, we have identified rho kinase as a molecular target that can be manipulated to disinhibit axonal regeneration and improve survival of lesioned central nervous system neurons. In this study, we examined the neuroprotective potential of pharmacological rho kinase inhibition mediated by fasudil in the in vitro 1-methyl-4-phenylpyridinium cell culture model and in the subchronic in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Application of fasudil resulted in a significant attenuation of dopaminergic cell loss in both paradigms. Furthermore, dopaminergic terminals were preserved as demonstrated by analysis of neurite network in vitro, striatal fibre density and by neurochemical analysis of the levels of dopamine and its metabolites in the striatum. Behavioural tests demonstrated a clear improvement in motor performance after fasudil treatment. The Akt survival pathway was identified as an important molecular mediator for neuroprotective effects of rho kinase inhibition in our paradigm. We conclude that inhibition of rho kinase using the clinically approved small molecule inhibitor fasudil may be a promising new therapeutic strategy for Parkinson's disease.

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  • ROCK inhibition protects against MPTP-induced dopaminergic cell death in both mice and primary cultures of dopaminergic neurons.

    “ROCK inhibition was found to protect against the MPTP-induced dopaminergic cell death in both mice and primary cultures of dopaminergic neurons [172,173].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [172]

    The Results section reports that fasudil, a ROCK inhibitor, protected dopaminergic neurons in MPTP-treated mice and improved survival in midbrain dopaminergic neuron cultures. The distinction is that the cultures were exposed to MPP+, not MPTP; the claim attributes MPTP-induced cell death to both settings. Page numbers were not available in our copy. (LLM, conf=0.88)

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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 [172]

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Cited by

Sorted by citations

Authors
Tonges, L., Frank, T., Tatenhorst, L., Saal, K. A., Koch, J. C., Szego, E. M., Bahr, M., Weishaupt, J. H., & Lingor, P.
Affiliations
  • Universitätsmedizin Göttingen (DE)
  • Universität Ulm (DE)
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2012-10-19
Volume
135
Issue
11
Pages
3355-3370
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/aws254
PMC
PMC3501973
OpenAlex
W2018644247
Cited by
176
References
6
Citations by year
2026: 6 · 2025: 6 · 2024: 10 · 2023: 4 · 2022: 10 · 2021: 17 · 2020: 17 · 2019: 9 · 2018: 15 · 2017: 16 · 2016: 16 · 2015: 21 · 2014: 19 · 2013: 10
FWCI
10.04
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by-nc)
  • GRO (submittedVersion, cc-by-nc)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords
Parkinson's disease, Rho kinase inhibition, fasudil, dopaminergic neurons, axonal degeneration, neuroprotection, axon regeneration, MPP+, MPTP mouse model, substantia nigra, striatal dopamine, motor performance
MeSH terms
Animals, Axons, Behavior, Animal, Cell Survival, Cells, Cultured, Corpus Striatum, Disease Models, Animal, Dopamine, Male, Mice, Inbred C57BL, Nerve Degeneration, Parkinson Disease, Secondary, Substantia Nigra, 1-Methyl-4-phenylpyridinium, Neurites, Rats, Wistar, Neuroprotective Agents, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, MPTP Poisoning, Proto-Oncogene Proteins c-akt, Mice, Rats, rho-Associated Kinases, Dopaminergic Neurons

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