Identification of potent lysophosphatidic acid receptor 5 (LPA5) antagonists as potential analgesic agents

Kawamoto, Y.; Seo, Ryushi; Murai, Norihiko; Hiyama, Hideki; Oka, Hiromasa

doi:10.1016/j.bmc.2017.11.038

Cited by 12 publications

(12 citation statements)

References 22 publications

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“…Moreover, depletion of LPAR5 in murine B16-F10 melanoma resulted in fewer lung metastasis [ 77 ], suggesting pharmaceutic inhibition of LPAR5 may also manage melanoma-mediated metastasis. On the other hand, since LPAR5 contributes to NP by affecting microglia biology and induces a distinct pro-inflammatory phenotype [ 111 ], various antagonists such as compound 7e [ 121 ] and AS2717638 [ 122 ] were considered to control chemotherapy-induced NP [ 76 , 111 ].…”

Section: Application Of Lpar Agonist/antagonist In Cancermentioning

confidence: 99%

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

Lin

Chen

2021

Cells

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Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.

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Section: Application Of Lpar Agonist/antagonist In Cancermentioning

confidence: 99%

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

Lin

Chen

2021

Cells

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“…Since the binding domain of LPAR5 represents an extracellular target, it is ideally suited for pharmacological intervention. Accordingly, LPAR5 specific antagonists were developed to modulate the LPA/LPAR5 axis and study its role in development and progression of (neuro-) inflammatory diseases (Kozian et al, 2012, 2016; Murai et al, 2017; Kawamoto et al, 2018). In the present study, we analyzed the potential of two structurally diverse non-lipid LPAR5 antagonists (compound 3 and AS2717638; Kozian et al, 2016; Murai et al, 2017) to interfere with LPA-induced inflammatory signaling cascades in BV-2 microglia cells.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Lysophosphatidic Acid Receptor 5 (LPAR5) Antagonists: Versatile Pharmacological Tools to Regulate Inflammatory Signaling in BV-2 Microglia Cells

Plastira

Joshi

Bernhart

et al. 2019

Front. Cell. Neurosci.

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Lysophosphatidic acid (LPA) species in the extracellular environment induce downstream signaling via six different G protein-coupled receptors (LPAR1–6). These signaling cascades are essential for normal brain development and function of the nervous system. However, in response to acute or chronic central nervous system (CNS) damage, LPA levels increase and aberrant signaling events can counteract brain function. Under neuro-inflammatory conditions signaling along the LPA/LPAR5 axis induces a potentially neurotoxic microglia phenotype indicating the need for new pharmacological intervention strategies. Therefore, we compared the effects of two novel small-molecule LPAR5 antagonists on LPA-induced polarization parameters of the BV-2 microglia cell line. AS2717638 is a selective piperidine-based LPAR5 antagonist (IC50 0.038 μM) while compound 3 is a diphenylpyrazole derivative with an IC50 concentration of 0.7 μM in BV-2 cells. Both antagonists compromised cell viability, however, at concentrations above their IC50 concentrations. Both inhibitors blunted LPA-induced phosphorylation of STAT1 and STAT3, p65, and c-Jun and consequently reduced the secretion of pro-inflammatory cyto-/chemokines (IL-6, TNFα, IL-1β, CXCL10, CXCL2, and CCL5) at non-toxic concentrations. Both compounds modulated the expression of intracellular (COX-2 and Arg1) and plasma membrane-located (CD40, CD86, and CD206) polarization markers yet only AS2717638 attenuated the neurotoxic potential of LPA-activated BV-2 cell-conditioned medium towards CATH.a neurons. Our findings from the present in vitro study suggest that the two LPAR5 antagonists represent valuable pharmacological tools to interfere with LPA-induced pro-inflammatory signaling cascades in microglia.

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“…In PF8380-injected animals, the brain LPA levels dropped to concentrations below the baseline at 120 min post application (Figure 7B). Transport of the AS2717638 compound across the BBB was demonstrated by Kawamoto and colleagues [33]. Finally, we investigated whether ATX and LPA5 antagonism would affect LPS-induced neuroinflammation in vivo.…”

Section: Resultsmentioning

confidence: 81%

“…In PF8380-injected animals, the brain LPA levels dropped to concentrations below the baseline at 120 min post application (Figure 7B). Transport of the AS2717638 compound across the BBB was demonstrated by Kawamoto and colleagues [33]. Next, we studied cyto-/chemokine secretion from LPS-stimulated BV-2 cells and the impact of the two inhibitors on extracellular accumulation of these analytes.…”

Section: Resultsmentioning

confidence: 90%

Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model

Joshi

Plastira

Bernhart

et al. 2021

IJMS

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Increasing evidence suggests that systemic inflammation triggers a neuroinflammatory response that involves sustained microglia activation. This response has deleterious consequences on memory and learning capability in experimental animal models and in patients. However, the mechanisms connecting systemic inflammation and microglia activation remain poorly understood. Here, we identify the autotaxin (ATX)/lysophosphatidic acid (LPA)/LPA-receptor axis as a potential pharmacological target to modulate the LPS-mediated neuroinflammatory response in vitro (the murine BV-2 microglia cell line) and in vivo (C57BL/6J mice receiving a single i.p. LPS injection). In LPS-stimulated (20 ng/mL) BV-2 cells, we observed increased phosphorylation of transcription factors (STAT1, p65, and c-Jun) that are known to induce a proinflammatory microglia phenotype. LPS upregulated ATX, TLR4, and COX2 expression, amplified NO production, increased neurotoxicity of microglia conditioned medium, and augmented cyto-/chemokine concentrations in the cellular supernatants. PF8380 (a type I ATX inhibitor, used at 10 and 1 µM) and AS2717638 (an LPA5 antagonist, used at 1 and 0.1 µM) attenuated these proinflammatory responses, at non-toxic concentrations, in BV-2 cells. In vivo, we demonstrate accumulation of PF8380 in the mouse brain and an accompanying decrease in LPA concentrations. In vivo, co-injection of LPS (5 mg/kg body weight) and PF8380 (30 mg/kg body weight), or LPS/AS2717638 (10 mg/kg body weight), significantly attenuated LPS-induced iNOS, TNFα, IL-1β, IL-6, and CXCL2 mRNA expression in the mouse brain. On the protein level, PF8380 and AS2717638 significantly reduced TLR4, Iba1, GFAP and COX2 expression, as compared to LPS-only injected animals. In terms of the communication between systemic inflammation and neuroinflammation, both inhibitors significantly attenuated LPS-mediated systemic TNFα and IL-6 synthesis, while IL-1β was only reduced by PF8380. Inhibition of ATX and LPA5 may thus provide an opportunity to protect the brain from the toxic effects that are provoked by systemic endotoxemia.

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Identification of potent lysophosphatidic acid receptor 5 (LPA5) antagonists as potential analgesic agents

Cited by 12 publications

References 22 publications

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

Small-Molecule Lysophosphatidic Acid Receptor 5 (LPAR5) Antagonists: Versatile Pharmacological Tools to Regulate Inflammatory Signaling in BV-2 Microglia Cells

Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model

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