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Cited by 43Multiple Sclerosis Research StudiesProtein Kinase Regulation and GTPase SignalingPeroxisome Proliferator-Activated Receptors

Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-α-dependent mechanism

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Paintlia, Ajaib S., Paintlia, Manjeet K., Singh, Avtar K., Singh, Inderjit·2013·Glia
DOI 10.1002/glia.22537PMC PMC3919553
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Abstract

We earlier documented that lovastatin (LOV)‐mediated inhibition of small Rho GTPases activity protects vulnerable oligodendrocytes (OLs) in mixed glial cell cultures stimulated with Th1 cytokines and in a murine model of multiple sclerosis (MS). However, the precise mechanism of OL protection remains unclear. We here employed genetic and biochemical approaches to elucidate the underlying mechanism that protects LOV treated OLs from Th1 (tumor necrosis factor‐α) and Th17 (interleukin‐17) cytokines toxicity in in vitro. Cytokines enhanced the reactive oxygen species (ROS) generation and mitochondrial membrane depolarization with corresponding lowering of glutathione (reduced) level in OLs and that were reverted by LOV. In addition, the expression of ROS detoxifying enzymes (catalase and superoxide‐dismutase 2) and the transactivation of peroxisome proliferators‐activated receptor (PPAR)‐α/‐β/‐γ including PPAR‐γ coactivator‐1α were enhanced by LOV in similarly treated OLs. Interestingly, LOV‐mediated inhibition of small Rho GTPases, i.e., RhoA and cdc42, and Rho‐associated kinase (ROCK) activity enhanced the levels of PPAR ligands in OLs via extracellular signal regulated kinase (1/2)/p38 mitogen‐activated protein kinase/cytoplasmic phospholipase 2/cyclooxygenase‐2 signaling cascade activation. Small hairpin RNA transfection‐based studies established that LOV mainly enhances PPAR‐α and less so of PPAR‐β and PPAR‐γ transactivation that enhances ROS detoxifying defense in OLs. In support of this, the observed LOV‐mediated protection was lacking in PPAR‐α‐deficient OLs exposed to cytokines. Collectively, these data provide unprecedented evidence that LOV‐mediated inhibition of the Rho–ROCK signaling pathway boosts ROS detoxifying defense in OLs via PPAR‐α‐dependent mechanism that has implication in neurodegenerative disorders including MS.

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  • RhoA/ROCK signaling regulates ROS production in oligodendrocytes.

    “In oligodendrocytes, RhoA/ROCK signaling causes a failure in oligodendrocyte precursor cell differentiation and process extension required for myelination [164,165] and also regulates ROS production [166].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [166]

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Cited by

Sorted by citations

Authors
Paintlia, A. S., Paintlia, M. K., Singh, A. K., & Singh, I.
Affiliations
  • Medical University of South Carolina (US)
  • Ralph H. Johnson VA Medical Center (US)
Corresponding author
Singh, Inderjit
ORCID
Venue
Glia
Publisher
Wiley
Published
2013-07-10
Volume
61
Issue
9
Pages
1500-1517
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.22537
PMC
PMC3919553
OpenAlex
W2115652505
Cited by
43
References
6
Citations by year
2025: 3 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 6 · 2017: 1 · 2015: 4 · 2014: 4 · 2013: 1 · 2012: 1
FWCI
2.24
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Glia (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001072)
  • National Institutes of Health (1c06rr018823-01)
  • National Institute of Neurological Disorders and Stroke (NS-22576, NS 37766, R01NS037766, R01NS022576, R37NS022576)
  • National Center for Research Resources (C06 RR-018823)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
Rho/ROCK signaling, lovastatin, oligodendrocytes, PPARα, cytokine toxicity, Th1 cytokines, Th17 cytokines, reactive oxygen species, glutathione, mitochondrial depolarization, PPARγ coactivator-1α, RhoA, Cdc42, ERK1/2, p38 MAPK, cyclooxygenase-2, multiple sclerosis, neuroprotection
MeSH terms
Analysis of Variance, Animals, Animals, Newborn, Cell Survival, Cells, Cultured, Cerebral Cortex, Enzyme Inhibitors, Female, Galactosides, Glutathione, L-Lactate Dehydrogenase, Lovastatin, Neurons, Oligodendroglia, Pregnancy, Transfection, Signal Transduction, Cytokines, Rats, Sprague-Dawley, Reactive Oxygen Species, Mice, Knockout, Hydroxymethylglutaryl-CoA Reductase Inhibitors, rho GTP-Binding Proteins, PPAR alpha, Mice, Rats, Membrane Potential, Mitochondrial, rho-Associated Kinases

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