LPA pathway modulators (AM-966) / BMS - LARVOL DELTA

[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

Lysophosphatidic acid induces thrombospondin-1 production in primary cultured rat cortical astrocytes. (PubMed, J Neurochem) - "LPA-induced TSP-1 production were inhibited by AM966 a LPA receptor antagonist, and Ki16425, LPA receptors antagonist, but not by H2L5146303, LPA receptor antagonist. Pertussis toxin, Gi/o inhibitor, but not YM-254890, Gq inhibitor, and NF499, Gs inhibitor, inhibited LPA-induced TSP-1 production, indicating LPA increases TSP-1 production through Gi/o-coupled LPA and LPA receptors...LPA-induced TSP-1 mRNA expression was inhibited by U0126, MAPK/ERK kinase (MEK) inhibitor, but not SB202190, p38 MAPK inhibitor, or SP600125, JNK inhibitor...Treatment with antidepressants, which bind to astrocytic LPA receptors, increased TSP-1 mRNA and protein production. The current findings show that LPA/LPA receptors signaling increases TSP-1 production in astrocytes, which could be important in the pathogenesis of affective disorders and could potentially be a target for the treatment of affective disorders."

Journal • Infectious Disease • MAPK8 • THBS1

Inhibition of Lysophosphatidic Acid Receptor 1 Attenuates Neuroinflammation via PGE2/EP2/NOX2 Signalling and Improves the Outcome of Intracerebral Haemorrhage in Mice. (PubMed, Brain Behav Immun) - "To elucidate potential inflammatory mechanisms of LPA1, the selective EP2 activator butaprost was administered by intracerebroventricular injection with either AM966 or LPA1 CRISPR knockout (KO)...This study demonstrated that inhibition of LPA1 attenuated neuroinflammation caused by ICH via PGE2/EP2/NOX2 signalling pathway in mice, which consequently improved neurobehavioral functions and alleviated brain oedema. LPA1 may be a promising therapeutic target to attenuate ICH-induced secondary brain injury."

Journal • Preclinical • Cerebral Hemorrhage • CNS Disorders • Immunology • Inflammation • Vascular Neurology • IL6 • TNFA

Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice. (PubMed, Cells) - "Repeated daily intrathecal (i.t.) treatments with LPA antagonist AM966 reversed these abnormal pain behaviors...Furthermore, streptozotocin-induced similar abnormal pain behaviors, but not elevated glucose levels or body weight loss were abolished in LPA and LPA mice. These results suggest that LPA and LPA play key roles in the development of both type I and type II diabetic neuropathic pain."

Journal • Preclinical • Diabetes • Diabetic Neuropathy • Immunology • Metabolic Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • Type 2 Diabetes Mellitus

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

Antidepressants induce profibrotic responses via the lysophosphatidic acid receptor LPA. (PubMed, Eur J Pharmacol) - "In both cell types amitriptyline, clomipramine and mianserin mimicked the ability of LPA to induce the phosphorylation/activation of extracellular signal -regulated kinases 1 and 2 (ERK1/2), which was blocked by the selective LPA receptor antagonist AM966 and the LPA antagonist Ki16425...Like LPA, antidepressants stimulated fibroblasts proliferation and this effect was blocked by either AM966 or the MEK1/2 inhibitor PD98059...Pharmacological blockade of TGF-β receptor type 1 prevented antidepressant- and LPA-induced α-SMA expression. These data indicate that in human dermal and lung fibroblasts different antidepressants can induce proliferative and differentiating responses by activating the LPA receptor coupled to ERK1/2 signalling and suggest that this property may contribute to the promotion of tissue fibrosis by these drugs."

Journal

Mirtazapine increases glial cell line-derived neurotrophic factor production through lysophosphatidic acid 1 receptor-mediated extracellular signal-regulated kinase signaling in astrocytes. (PubMed, Eur J Pharmacol) - "To mimic mirtazapine's putative mechanism of action, cells were treated with either a α-adrenoceptor antagonist (yohimbine), 5-HT receptor antagonist (ketanserin), 5-HT receptor antagonist (ondansetron), or a mixture of these--no effect on GDNF mRNA expression was observed. Mirtazapine treatment increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and the mirtazapine-induced GDNF and BDNF expression were blocked by MAPK/ERK kinase (MEK) inhibitor (U0126). Furthermore, the effect of mirtazapine on ERK phosphorylation and expressions of GDNF and BDNF was antagonized by Gi/o inhibitor (pertussis toxin), lysophosphatidic acid-1 (LPA) receptor antagonist (AM966), and LPA/LPA receptors antagonist (Ki16425). The current findings demonstrate that the NaSSA mirtazapine, similar to other classes of antidepressants, increases GDNF expression through a Gi/o coupled LPA receptor-mediated ERK pathway. The current findings suggest a general mechanism..."

Journal • Preclinical

Radiation Inducing Pulmonary Cellular Senescence through the LPA-LPA1-Akt Pathway (ASTRO 2019) - "All above were ameliorated by AM966 or MK2206 pretreatment, while SC79 could counteract the effect of AM966.Conclusion LPA in high concentrations participates in the radiation-induced pulmonary cellular senescence through the LPA-LPA1-Akt signaling. Selectively blocking LPA1 by AM966 in the early stage could significantly ameliorate pulmonary cellular senescence and injuries."

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