Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis
Open accessAbstract
Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons (MN) and their axons, but is also influenced by neighboring cells such as astrocytes and microglial cells. The role of microglia in ALS is complex as it switches from an anti‐inflammatory and neuroprotective phenotype in early disease to a proinflammatory and neurotoxic phenotype in later stages. Our previous studies in models of neurodegeneration identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression. Here, we examined the neuroprotective potential of the ROCK inhibitor Fasudil to target the central pathogenic features of ALS. Application of Fasudil to kainic acid‐lesioned primary MN in vitro resulted in a strong prosurvival effect. In vivo , SOD1 G93A mice benefited from oral treatment with Fasudil showing prolonged survival and improved motor function. These findings were correlated to an improved survival of motor neurons and a pronounced alteration of astroglial and microglial cell infiltration of the spinal cord under Fasudil treatment. Modeling a proinflammatory microglial phenotype by stimulation with LPS in vitro , Fasudil decreased the release of proinflammatory cytokines and chemokines TNFα, Il6, CCL2, CCL3, and CCL5 while CXCL1 release was only transiently suppressed. In sciatic nerve motor axons, neuromuscular junction remodeling processes were increased. In conclusion, we provide preclinical and neurobiological evidence that inhibition of ROCK by the clinically approved small molecule inhibitor Fasudil may be a novel therapeutic approach in ALS combining both neuroprotection and immunomodulation for the cure of this devastating disease. GLIA 2014;62:217–232
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ROCK inhibition reduces reactive gliosis and increases astrocytic expression of prosurvival genes.
“In astrocytes, RhoA/ROCK signaling plays a major role in determining astrocyte morphology and reactive state [118,160,161], and ROCK inhibition reduces reactive gliosis and increases astrocytic expression of prosurvival genes [162,163].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [163]
ROCK inhibition reduces microgliosis in SOD1G93A mice.
“ROCK inhibition has been shown to preserve neuromuscular junctions and extend the survival of SOD1G93A mice via reduced microgliosis and decreased release of proinflammatory cytokines and chemokines such as TNFα and IL6 [163].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [163]
ROCK inhibition decreases release of proinflammatory cytokines and chemokines such as TNFα and IL6 in SOD1G93A mice.
“ROCK inhibition has been shown to preserve neuromuscular junctions and extend the survival of SOD1G93A mice via reduced microgliosis and decreased release of proinflammatory cytokines and chemokines such as TNFα and IL6 [163].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [163]
Activation of the RhoA/ROCK pathway has been implicated in the pathogenesis of ALS, although studied to a lesser degree and focusing on the disease-modifying effects of ROCK inhibition.
“Activation of the RhoA/ROCK pathway has also been implicated in the pathogenesis of ALS, although studied to a lesser degree and focusing on the disease-modifying effects of ROCK inhibition.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [163]
ROCK inhibition extends survival of SOD1G93A mice.
“ROCK inhibition has been shown to preserve neuromuscular junctions and extend the survival of SOD1G93A mice via reduced microgliosis and decreased release of proinflammatory cytokines and chemokines such as TNFα and IL6 [163].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [163]
ROCK inhibition preserves neuromuscular junctions in SOD1G93A mice.
“ROCK inhibition has been shown to preserve neuromuscular junctions and extend the survival of SOD1G93A mice via reduced microgliosis and decreased release of proinflammatory cytokines and chemokines such as TNFα and IL6 [163].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [163]
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- Authors
- Tönges, L., Günther, R., Suhr, M., Jansen, J., Balck, A., Saal, K., Barski, E., Nientied, T., Götz, A. A., Koch, J., Mueller, B. K., Weishaupt, J. H., Sereda, M. W., Hanisch, U., Bähr, M., & Lingor, P.
- Affiliations
- Universitätsmedizin Göttingen (DE)
- Department of Neurology University Medicine Göttingen Robert‐Koch‐Str. 40 Göttingen Germany
- Max Planck Institute of Experimental Medicine (DE)
- AbbVie (Germany) (DE)
- Universität Ulm (DE)
- Corresponding author
- Tönges, Lars
- Lingor, Paul
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2013-12-06
- Volume
- 62
- Issue
- 2
- Pages
- 217-232
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- OpenAlex
- W1593989848
- Cited by
- 121
- References
- 6
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 11 · 2023: 9 · 2022: 5 · 2021: 10 · 2020: 12 · 2019: 9 · 2018: 9 · 2017: 8 · 2016: 9 · 2015: 18 · 2014: 8
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, Rho kinase inhibition, fasudil, microglial activation, neuroprotection, motor neuron survival, SOD1 G93A mice, kainic acid lesion, inflammatory cytokines, chemokines, TNF-α, interleukin-6, immunomodulation, therapeutic target
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Axons, Cell Survival, Cells, Cultured, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Spinal Cord, Microglia, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Protein Kinase Inhibitors, Mice, rho-Associated Kinases
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