Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents

Murai, Norihiko; Hiyama, Hideki; Kiso, Tetsuo; Sekizawa, Tsuyoshi; Watabiki, Tomonari; Oka, Hiromasa; Aoki, Toshiaki

doi:10.1016/j.neuropharm.2017.08.032

Cited by 30 publications

(31 citation statements)

References 34 publications

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“…LPAR antagonists entered clinical trials to test their pharmacological efficacy (e.g., the LPAR1 inhibitors BMS-986020 and SAR100842; NCT01766817 and NCT01651143, respectively). AS2717638, an LPAR5 inhibitor, displayed potent analgesic effects against neuropathic and inflammatory pain in preclinical rodent models [55], conditions mediated by activated microglia [56]. We have demonstrated that inhibition of LPAR5 by the inhibitor TCLPA5 reduces secretion of inflammatory cyto-/chemokines from primary microglia and reduces p38 and ERK1/2 activation [27].…”

Section: Discussionmentioning

confidence: 90%

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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Background: In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. Methods: In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACSsorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. Results: Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and-3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media.

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Section: Discussionmentioning

confidence: 90%

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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“…Cells/Recombinant Expression. Cells expressing LPA receptors were generated according to a previously reported method (Murai et al, 2017). Human and rat LPA 1 , human LPA 2 , and human LPA 5 were stably expressed in Chinese hamster ovary cells and cultured in minimum essential medium-a containing 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin/streptomycin, and 100 nM methotrexate.…”

Section: Methodsmentioning

confidence: 99%

“…Measurement of Intracellular cAMP. The effect of ASP6432 on LPA-induced cAMP production in cells expressing human LPA 5 was evaluated using a previously described method (Murai et al, 2017). In brief, Chinese hamster ovary cells expressing human LPA 5 were seeded at a density of 15,000 cells per well and cultured in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

Effect of ASP6432, a Novel Type 1 Lysophosphatidic Acid Receptor Antagonist, on Urethral Function and Prostate Cell Proliferation

Sakamoto¹,

Noguchi²,

Ueshima³

et al. 2018

J Pharmacol Exp Ther

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Current pharmacotherapies for lower urinary tract symptoms associated with benign prostate hyperplasia (LUTS/BPH) are in need of improvement. Lysophosphatidic acid (LPA) is a phospholipid with various biologic functions. However, its exact role in the lower urinary tract and its target receptor subtype have not been fully elucidated. We investigated the role of LPA and the type 1 LPA receptor (LPA) in urethral/prostatic contractile function and prostate cell proliferation by pharmacologically characterizing ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl--(3-phenylpropyl)benzamido]methyl}-1,3-thiazole-4-carbonyl)-3-ethyl-2,2-dioxo-2-diazathian-1-ide), a novel LPA antagonist. ASP6432 exhibited potent and selective antagonistic activity against LPA in cells expressing LPA receptor subtypes. In isolated rat tissue strips and anesthetized rats, ASP6432 concentration-/dose-dependently inhibited LPA-induced urethra and prostate contractions. In addition, in anesthetized rats, ASP6432 maximally decreased the urethral perfusion pressure (UPP) in the absence of exogenous LPA stimulation by 43% from baseline, whereas tamsulosin, an -adrenoceptor antagonist, reduced UPP by 22%. Further, in human prostate stromal cells, ASP6432 significantly and concentration-dependently suppressed LPA-induced bromodeoxyuridine incorporation. These results demonstrate a pivotal role for LPA and LPA in the regulation of urethral tonus and prostate cell proliferation. The potent urethral relaxation and inhibition of prostatic stromal cell growth indicate the potential of ASP6432 as a novel therapeutic agent for LUTS/BPH.

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“…Large amounts of LPAR5 are expressed in the spleen, small intestine, and colon, but are relatively low in most other tissues [7,40,41]. LPAR5 has multiple endogenous ligands including LPA, geranylgeranyl diphosphate (GGPP), farnesyl monophosphate, farnesyl pyrophosphate, N-arachidonoyl Glycine alkyl glycerophosphate and cyclic phosphatidic acid [41,42]. Stress fiber formation and neurite contraction are associated with the LPA-LPA5-Gα12/Gα13 pathway, whereas increased intracellular calcium levels and cAMP accumulation are associated with the LPA-LPA 5 -Gαq pathway [7,9,40].…”

Section: Lpar5mentioning

confidence: 99%

“…LPA binds to LPA 5 expressed on mouse and human CD8 + T cells, inhibited T cell antigen receptor (TCR)-induced intracellular calcium mobilization, extracellular regulated protein kinases (ERK) activation and Nur77 expression, thereby reduced granular exocytosis and cytotoxicity [43]. LPA 5 is also expressed in the spinal cord and dorsal root ganglia (DRG) and can promote the signaling of extensive pain in the spinal cord [42]. In intestinal epithelium, LPA 5 is the primary LPA receptor regulating Na + /H + Exchanger 3 (NHE3).…”

Section: Lpar5mentioning

confidence: 99%

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

Xiang¹,

Lü²,

Shao³

et al. 2020

J. Cancer

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Lysophosphatidic acid (LPA, 1-acyl-2-hemolytic-sn-glycerol-3-phosphate) extracted from membrane phospholipid is a kind of simple bioactive glycophospholipid, which has many biological functions such as stimulating cell multiplication, cytoskeleton recombination, cell survival, drug-fast, synthesis of DNA and ion transport. Current studies have shown that six G-coupled protein receptors (LPAR1-6) can be activated by LPA. They stimulate a variety of signal transduction pathways through heterotrimeric G-proteins (such as Gα12/13, Gαq/11, Gαi/o and GαS). LPA and its receptors play vital roles in cancers, nervous system diseases, cardiovascular diseases, liver diseases, metabolic diseases, etc. In this article, we discussed the structure of LPA receptors and elucidated their functions in various diseases, in order to better understand them and point out new therapeutic schemes for them.

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Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents

Cited by 30 publications

References 34 publications

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Effect of ASP6432, a Novel Type 1 Lysophosphatidic Acid Receptor Antagonist, on Urethral Function and Prostate Cell Proliferation

Lysophosphatidic Acid Receptors: Biochemical and Clinical Implications in Different Diseases

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