Abstract
BackgroundLysophosphatidic 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.MethodsHere, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS.ResultsPre-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.ConclusionsOur findings strongly suggest that some agents that can stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.
Highlights
Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiologi‐ cal functions in the central nervous system
Since cellular adhesion molecules such as Intercellular adhesion molecule-1 (ICAM-1) and Vascular cell adhesion molecule-1 (VCAM-1) are involved in the adhesion of peripheral inflammatory cells such as lymphocytes and macrophages to endothelial cells in lesion area during multiple sclerosis (MS) and EAElow, we investigated the effect of Ki16425 treatment on their expression by real-time polymerase chain reaction (PCR) analysis (Fig. 5J, K)
Ki16425 upregulated protein expression levels of Glial fibrillary acidic protein (GFAP) and PECAM as well as mRNA expression levels of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in spinal cords of E AElow mice (Fig. 5), in agreement with impaired motor disability of EAElow (Fig. 2). These results suggest that LPAR1–3 antagonist, Ki16425, might deteriorate EAE symptom associated with impaired blood–brain barrier (BBB) disruption caused by excessive astrocytic activation and increased expression levels of ICAM-1 and VCAM-1 in the spinal cord (Fig. 5)
Summary
Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiologi‐ cal functions in the central nervous system. The role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet. Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune, and demyelinating disease of the central nervous system (CNS). MS patients usually take intravenous steroids, anti-inflammatory medications (corticosteroids), diseasemodifying drugs, and so on, to improve their function after an attack and prevent new attacks [2, 3, 6]. It is essential to research and develop innovative medications for delaying the onset of MS or forestalling its progression
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