Abstract | BACKGROUND: METHODS: RESULTS: Pre-inhibition with LPAR1-3 antagonist Ki16425 deteriorated motor disability of EAElow. Specifically, LPAR1-3 antagonist (intraperitoneal) deteriorated symptoms of EAElow associated with increased demyelination, chemokine expression, cellular infiltration, and immune cell activation (microglia and macrophage) in spinal cords of mice compared to the sham group. This LPAR1-3 antagonist also increased the infiltration of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells into spinal cords of EAElow mice along with upregulated mRNA expression of IFN-γ and IL-17 and impaired blood-brain barrier (BBB) in the spinal cord. The underlying mechanism for negative effects of LPAR1-3 antagonist was associated with the overproduction of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate ( NADPH) oxidases (NOX) 2 and NOX3. Interestingly, LPAR1/2 agonist 1-oleoyl-LPA (LPA 18:1) (intraperitoneal) ameliorated symptoms of EAEhigh and improved representative pathological features of spinal cords of EAEhigh mice. CONCLUSIONS: Our findings strongly suggest that some agents that can stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.
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Authors | Jong Hee Choi, Jinhee Oh, Min Jung Lee, Hyunsu Bae, Seong-Gyu Ko, Seung-Yeol Nah, Ik-Hyun Cho |
Journal | Journal of neuroinflammation
(J Neuroinflammation)
Vol. 18
Issue 1
Pg. 240
(Oct 19 2021)
ISSN: 1742-2094 [Electronic] England |
PMID | 34666785
(Publication Type: Journal Article)
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Copyright | © 2021. The Author(s). |
Chemical References |
- 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
- Isoxazoles
- LPAR2 protein, human
- Lpar3 protein, mouse
- Myelin-Oligodendrocyte Glycoprotein
- Peptide Fragments
- Propionates
- Receptors, Lysophosphatidic Acid
- lysophosphatidic acid receptor 1, mouse
- myelin oligodendrocyte glycoprotein (35-55)
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Topics |
- Animals
- Dose-Response Relationship, Drug
- Encephalomyelitis, Autoimmune, Experimental
(chemically induced, metabolism)
- Female
- Isoxazoles
(pharmacology, toxicity)
- Mice
- Mice, Inbred C57BL
- Myelin-Oligodendrocyte Glycoprotein
(toxicity)
- Oxidative Stress
(drug effects, physiology)
- Peptide Fragments
(toxicity)
- Propionates
(pharmacology, toxicity)
- Receptors, Lysophosphatidic Acid
(antagonists & inhibitors, metabolism)
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