AM 095 / BMS - LARVOL DELTA

SIGNALING MECHANISMS UNDERLYING NOCICEPTIVE EFFECTS OF BACTERIAL LYSOPHOSPHATIDYLCHOLINE (LPC) AND LYSOPHOSPHATIDIC ACID (LPA) (DDW 2025) - "Dorsal root ganglion (DRG) neurons from conventional mice C57BL/6 (n=22) were pretreated with TRPC5 inhibitor (AC1903; 30 μM), or a LPAR 1 antagonist (AM095; 10 μM), or a LPAR 1 and LPAR 3 antagonist (Ki16425; 10 μM) or their vehicle (0.1% DMSO), and then treated with LPC (10 μM) or LPA (10 μM), respectively... Bacterial LPC and LPA induce neuronal activation and visceral hypersensitivity through TRPC5 and LPAR 1 /LPAR 3 -dependent mechanisms, respectively. DRG neurons signal to the spinal second-order neurons through the production of SP and CGRP."

Gastrointestinal Disorder • Immunology • Neuralgia • Pain

Role of the Lysophosphatidic Acid 1 Receptor in Goblet Cell Hyperplasia in Chronic Bronchial Asthma (ATS 2025) - "The LPA1 antagonist AM095 (10 µg/mouse) was administered intraperitoneally 30 min before Dp challenge... These findings suggest that LPA contributes to goblet cell hyperplasia in chronic bronchial asthma by modulating neuropeptide production in pulmonary neuroendocrine cells via LPA1 receptors."

Asthma • Immunology • Inflammation • Respiratory Diseases • ARG1 • IL13

Integration of an LPAR1 Antagonist into Liposomes Enhances Their Internalization and Tumor Accumulation in an Animal Model of Human Metastatic Breast Cancer. (PubMed, Mol Pharm) - "Molecular dynamics simulations show that the integration of AM095 or Ki16425 modified the physical and mechanical properties of the lipid bilayer, making it more flexible in these liposomal formulations compared with liposomes without drug. The incorporation of an LPAR1 antagonist within a liposomal drug delivery system represents a viable therapeutic approach for targeting the LPA-LPAR1 axis, which may hinder the progression of MBC."

Journal • Metastases • Preclinical • Breast Cancer • Oncology • Solid Tumor

INHIBITION OF THE LYSOPHOSPHATIDIC ACID PATHWAY IMPROVES HEPATIC FIBROSIS AND PORTAL HYPERTENSION IN EXPERIMENTAL ADVANCED CHRONIC LIVER DISEASE (AASLD 2023) - " Cirrhotic rats with ascites (16 weeks CCl4) randomly received either an inhibitor of autotaxin (ATXi, GLPG1690; 60 mg/kg/BID), an LPA receptor-1 antagonist (LPAR1i, AM095; 30 mg/kg/BID) or vehicle for 14 days (n=12/group). This study demonstrates that inhibition of the LPA pathway exerts beneficial effects in a pre-clinical model of decompensated cirrhosis, which lead to marked amelioration in fibrosis and portal hypertension. Our results encourage its clinical evaluation for the treatment of advanced chronic liver disease."

Metastases • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Inflammation • Liver Failure • Portal Hypertension • CASP8 • IL10 • IL6 • VCAM1

Lysophosphatidic Acid Induces Podocyte Pyroptosis in Diabetic Nephropathy by an Increase of Egr1 Expression via Downregulation of EzH2. (PubMed, Int J Mol Sci) - "In podocytes from STZ-induced diabetic mice, AM095 suppressed Egr1 expression increase and EzH2/H3K27me3 expression reduction. Collectively, these results demonstrate that LPA induces NLRP3 inflammasome activation by downregulating EzH2/H3K27me3 and upregulating Egr1 expression, resulting in podocyte damage and pyroptosis, which may be a potential mechanism of DN progression."

Journal • Diabetic Nephropathy • Inflammation • Nephrology • Renal Disease • EGR1 • EZH2 • NLRP3

TXA2 mediates LPA1-stimulated uterine contraction in late pregnant mouse. (PubMed, Prostaglandins Other Lipid Mediat) - "LPA1/3 antagonist, Ki-16425, and a potent LPA1 antagonist (AM-095) significantly inhibited the LPA-induced contractions. Further, the nonselective COX inhibitor, indomethacin, and potent thromboxane A2 synthase inhibitor, furegrelate significantly impaired LPA-induced contractions. Moreover, selective thromboxane receptor (TP) antagonist, SQ-29548, and Rho kinase inhibitor, Y-27632 almost eliminated LPA-induced uterine contractions. LPA1 stimulation elicits contractions in the late pregnant mouse uterus using the contractile prostanoid, TXA2 and may be targeted to induce labor in uterine dysfunctions/ dystocia."

Journal • Preclinical • Obstetrics

Positive association between plasmatic levels of orexin A and the endocannabinoid-derived 2-arachidonoyl lysophosphatidic acid in Alzheimer's disease. (PubMed, Front Aging Neurosci) - "By confocal microscopy and western blotting assay we found an OX-A- or 2-AGP-mediated phosphorylation of Tau at threonine 231 residue, in a manner prevented by LPA1R (2-AGP receptor) or OX1R (OX-A receptor) antagonism with AM095 or SB334867, respectively. Finally, by patch-clamp recording we documented that 2-AGP-mediated pT231-Tau phosphorylation impairs glutamatergic transmission in the mouse hippocampus. Although further additional research is still required to clarify the potential role of orexin signaling in neurodegeneration, this study provides evidence that counteraction of aberrant OX-A signaling, also via LPA-1R antagonism, may be beneficial in the mild-to-moderate age-related cognitive decline associated with sleep disturbances."

Journal • Alzheimer's Disease • CNS Disorders • Sleep Disorder

Hypoxia is a key driver of the formation of invadosomes, an abundant structure found in fibroblast derived from patients with IPF (ICLAF 2022) - "Addition of nintedanib (n=7) or pirfenidone (n=4) impaired invadosome formation (p<0.01). PDGF, LPA and hypoxia stimulation increased healthy fibroblasts invadosome formation by 1.9 times (p<0.01, n=5), 2.3 times (p<0.01, n=5) and 1.5 times (p<0.05, n=6) respectively. Interestingly, the addition of nintedanib (RTK inhibitor) or AM095 (LPA1 receptor antagonist) blocked hypoxia-induced invadosomes.We conclude that hypoxia may play a role in lung fibroblast invadosome formation in IPF, at least in part through pathways involving tyrosine kinase and LPA receptor signaling."

Clinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Lysophosphatidic Acid Promotes Epithelial-Mesenchymal Transition in Kidney Epithelial Cells via the LPAR1/MAPK-AKT/KLF5 Signaling Pathway in Diabetic Nephropathy. (PubMed, Int J Mol Sci) - "Similarly, we found that LPA decreased E-cadherin expression and increased vimentin expression in HK-2 cells, which was reversed by treatment with ki16425 or AM095 (LPAR1 inhibitor)...Inhibition of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and serine-threonine kinase (AKT) pathways decreased LPA-induced expression of KLF5 and EMT markers. In conclusion, these data suggest that LPA contributes to the pathogenesis of diabetic nephropathy by inducing EMT and renal tubular fibrosis via regulation of KLF5 through the LPAR1."

Journal • Diabetic Nephropathy • Fibrosis • Immunology • Nephrology • Renal Disease • CDH1 • FN1 • KLF5 • MAPK8 • VIM

Lysophosphatidic acid stimulates pericyte migration via LPA receptor 1. (PubMed, Biochem Biophys Res Commun) - "LPAR1 expression was also detected in human pericyte culture and LPA treatment of these cells also induced migration. Taken together these findings imply that LPA-LPAR1 signaling is one of the key mechanisms modulating pericyte migration, which may help to control vascular function during development and repair processes."

Journal

Effects of a lysophosphatidic acid receptor 1 antagonist on hypertensive renal injury in Dahl-Iwai salt-sensitive rats. (PubMed, J Pharmacol Sci) - "Furthermore, combined administration of AM095 with an angiotensin-converting enzyme (ACE) inhibitor reduced the levels of proximal tubular injury markers and kidney weight increase, and suppressed renal fibrosis more effectively than administration of either agent alone, independent of the antihypertensive effect of the ACE inhibitor. These results provide the first evidence of the potential efficacy of LPA antagonist in suppressing renal injury in hypertensive DS rats, suggesting the promise of LPA antagonists as a novel therapeutic option for hypertensive renal injury."

Journal • Preclinical • Cardiovascular • Fibrosis • Hypertension • Immunology • Renal Disease

Glucagon-like Peptide-1 Secretion Is Inhibited by Lysophosphatidic Acid. (PubMed, Int J Mol Sci) - "In agreement, inhibition of GLP-1 secretion was reversed by the LPAR1/3 antagonist Ki16425, the LPAR1 antagonists AM095 and AM966, or the LPAR2 antagonist LPA2-antagonist 1...GLUTag L-cell and mouse serum DPP4 activity was unchanged by LPA or LPAR antagonists. LPA therefore impairs GLP-1 secretion in vitro and in vivo through Gα-coupled LPAR1/3 signaling, providing a new mechanism linking inflammation with impaired GSIS."

Journal • Immunology • Inflammation

The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion. (PubMed, Int J Mol Sci) - "LPA receptor inhibitors Ki16425 and AM095 attenuated the LPA-induced changes in the endothelial permeability and junctional proteins...The upregulation of ATX with hypoxic reperfusion leads to LPA production in brain endothelial cells favoring permeability. Inhibition of the ATX-LPA-LPAR axis could be therapeutically targeted in stroke to achieve better outcomes."

Journal • Cardiovascular • Ischemic stroke • Reperfusion Injury

LPA signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis. (PubMed, J Neuroinflammation) - "Thus, LPA signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation."

Journal • CNS Disorders • Immunology • Inflammation • Pain • SOX10 • SOX2

[VIRTUAL] Protective effect of AM095, a lysophosphatidic acid receptor 1 antagonist, on renal aging (KSN 2021) - No abstract available

Interfering with lysophosphatidic acid receptor edg2/lpa signalling slows down disease progression in SOD1-G93A transgenic mice. (PubMed, Neuropathol Appl Neurobiol) - "These results suggest that stressed lpa-lpa signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa slows down disease progression. This highlights LPA signalling as a potential target and/or biomarker in ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

[VIRTUAL] LPA1 signal transduction drives Schwann cell dedifferentiation in experimental autoimmune neuritis (DGN 2020) - "The myelin thickness was not affected by AM095 treatment. These results suggest that disruption of LPA1 signal transduction may represent a new therapeutic target for the treatment of inflammatory neuropathies that may modulate the regenerative responses in the peripheral nerve Schwann cell differentiation."

Fibrosis • Immunology • Inflammation • Pain • Peripheral Neuropathic Pain • Scleroderma • Systemic Sclerosis • SOX10 • SOX2

Inhibition of LPA Signaling Impedes Conversion of Human Tenon's Fibroblasts into Myofibroblasts Via Suppressing TGF-β/Smad2/3 Signaling. (PubMed, J Ocul Pharmacol Ther) - "By using an LPA-specific inhibitor, AM095, we confirmed that LPA signaling but not LPA or LPA is involved in TGF-β1 induced HTFs activation. Our results show that inhibition of LPA signaling presents potent antifibrotic effect in HTFs, which may serve as a promising intervention strategy for preventing subconjunctival fibrosis caused by glaucoma filtration surgery."

Journal • Fibrosis • Glaucoma • Immunology • Ophthalmology

Lysophosphatidic acid receptor 1 (LPA) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia. (PubMed, J Neuroinflammation) - "This study demonstrates that LPA is a new etiological factor for cerebral ischemia, strongly indicating that its modulation can be a potential strategy to reduce ischemic brain damage."

Journal

Lysophosphatidic acid receptor 1 inhibitor, AM095, attenuates diabetic nephropathy in mice by downregulation of TLR4/NF-κB signaling and NADPH oxidase. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Pharmacological or siRNA inhibition of TLR4 and NADPH oxidase mimicked the effects of AM095 in vitro. In conclusion, AM095 is effective in preventing the pathogenesis of DN by inhibiting TLR4/NF-κB and the NADPH oxidase system, consequently inhibiting the inflammatory signaling cascade in renal tissue of diabetic mice, suggesting that LPAR1 antagonism might provide a potential therapeutic target for DN."

IO Biomarker • Journal • Preclinical

Potential therapeutic target for diabetic nephropathy (KSN 2019) - "In addition, AM095 treatment suppressed LPA-induced pro-inflammatory cytokines and fibrotic factors expression through downregulation of phosphorylated NFκBp65 and c-Jun N-terminal kinases (JNK) in vitro and in the kidney of STZ-induced diabetic mice. In conclusion, AM095 is effective in preventing the pathogenesis of DN by inhibiting TLR4/NF-κB and the NADPH oxidase system, consequently inhibiting the inflammatory signaling cascade in renal tissue of diabetic mice, suggesting that LPAR1 antagonism might provide a potential therapeutic target for DN."

IO Biomarker