Dataset Information

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA₂), UCM-14216, Ameliorates Spinal Cord Injury in Mice.

ABSTRACT: Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA₂) has recently emerged as a new potential pharmacological approach to decrease SCI-associated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA₂ antagonists, among which compound 54 (UCM-14216) stands out as a potent and selective LPA₂ receptor antagonist (E_max = 90%, IC₅₀ = 1.9 μM, K_D = 1.3 nM; inactive at LPA_1,3-6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA₂-dependent manner, confirming the potential of LPA₂ inhibition for providing a new alternative for treating SCI.

SUBMITTER: Khiar-Fernandez N

PROVIDER: S-EPMC9421655 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA<sub>2</sub>), UCM-14216, Ameliorates Spinal Cord Injury in Mice.

Khiar-Fernández Nora N Zian Debora D Vázquez-Villa Henar H Martínez R Fernando RF Escobar-Peña Andrea A Foronda-Sainz Román R Ray Manisha M Puigdomenech-Poch Maria M Cincilla Giovanni G Sánchez-Martínez Melchor M Kihara Yasuyuki Y Chun Jerold J López-Vales Rubèn R López-Rodríguez María L ML Ortega-Gutiérrez Silvia S

Journal of medicinal chemistry 20220810 16

Spinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA<sub>2</sub>) has recently emerged as a new potential pharmacological approach to decrease SCI-associa ...[more]

PMID: 35948083

Similar Datasets

Project description:Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA1 and LPA3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA1 and LPA3 in the heart is unknown. Methods and Results: By using LPA3 and LPA1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA1/LPA3 inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA3 knockout mice and the Ki16425-treated rats but not in the LPA1 knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA3 KO mice and increased in the AAV9-mediated cardiac-specific LPA3 overexpression mice. By using lineage tracing and AAV9-LPA3, we further found that LPA3 overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA3 signaling in vivo. Conclusion: Our study reports that LPA3-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.

Project description:The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein-coupled receptor LPA6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA6 and LPA6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS.

Dataset Information

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA₂), UCM-14216, Ameliorates Spinal Cord Injury in Mice.

Publications

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA<sub>2</sub>), UCM-14216, Ameliorates Spinal Cord Injury in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice.

Publications

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA<sub>2</sub>), UCM-14216, Ameliorates Spinal Cord Injury in Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Novel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA₂), UCM-14216, Ameliorates Spinal Cord Injury in Mice.