Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiological functions in the central nervous system. However, the role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet. Methods Here, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Results Pre-inhibition with LPAR1-3 antagonist Ki16425 deteriorated motor disability of EAE low . Specifically, LPAR1-3 antagonist (intraperitoneal) deteriorated symptoms of EAE low 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 EAE low 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 EAE high and

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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