FTY720 requires vitamin B-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis.

Vitamin B (B) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P. Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B pathways.

Molecular and neuroimmune pharmacology of S1P receptor modulators and other disease-modifying therapies for multiple sclerosis.

Multiple sclerosis (MS) is a neurological, immune-mediated demyelinating disease that affects people in the prime of life. Environmental, infectious, and genetic factors have been implicated in its etiology, although a definitive cause has yet to be determined. Nevertheless, multiple disease-modifying therapies (DMTs: including interferons, glatiramer acetate, fumarates, cladribine, teriflunomide, fingolimod, siponimod, ozanimod, ponesimod, and monoclonal antibodies targeting ITGA4, CD20, and CD52) have been developed and approved for the treatment of MS.

CAQK, a peptide associating with extracellular matrix components targets sites of demyelinating injuries.

The destruction of the myelin sheath that encircles axons leads to impairments of nerve conduction and neuronal dysfunctions. A major demyelinating disorder is multiple sclerosis (MS), a progressively disabling disease in which immune cells attack the myelin. To date, there are no therapies to target selectively myelin lesions, repair the myelin or stop MS progression.

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

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) has recently emerged as a new potential pharmacological approach to decrease SCI-associated damage.

Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures.

Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate.

Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR-G-protein complexes remain unclear.

Ponesimod inhibits astrocyte-mediated neuroinflammation and protects against cingulum demyelination via S1P -selective modulation.

Ponesimod is a sphingosine 1-phosphate (S1P) receptor (S1PR) modulator that was recently approved for treating relapsing forms of multiple sclerosis (MS). Three other FDA-approved S1PR modulators for MS-fingolimod, siponimod, and ozanimod-share peripheral immunological effects via common S1P interactions, yet ponesimod may access distinct central nervous system (CNS) mechanisms through its selectivity for the S1P receptor. Here, ponesimod was examined for S1PR internalization and binding, human astrocyte signaling and single-cell RNA-seq (scRNA-seq) gene expression, and in vivo using murine cuprizone-mediated demyelination.

A Soluble Epoxide Hydrolase Inhibitor, 1-TrifluoromethoxyPhenyl-3-(1-Propionylpiperidin-4-yl) Urea, Ameliorates Experimental Autoimmune Encephalomyelitis.

Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/), resulting in the formation of toxic and pro-inflammatory vicinal diols (dihydroxy-FAs). Pharmacological inhibition of sEH is a promising strategy for the treatment of pain, inflammation, cardiovascular diseases, and other conditions.

S1P-Gα Signaling Controls Astrocytic Glutamate Uptake and Mitochondrial Oxygen Consumption.

Glutamate is the principal excitatory neurotransmitter in the human brain. Following neurotransmission, astrocytes remove excess extracellular glutamate to prevent neurotoxicity. Glutamate neurotoxicity has been reported in multiple neurologic diseases including multiple sclerosis (MS), representing a shared neurodegenerative mechanism.

Lysophosphatidic acid (LPA)-antibody (504B3) engagement detected by interferometry identifies off-target binding.

Background: Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that acts through its six cognate G protein-coupled receptors. As a family, lysophospholipids have already produced medicines (e.g.

Druggable Lipid GPCRs: Past, Present, and Prospects.

G protein-coupled receptors (GPCRs) have seven transmembrane spanning domains and comprise the largest superfamily with ~800 receptors in humans. GPCRs are attractive targets for drug discovery because they transduce intracellular signaling in response to endogenous ligands via heterotrimeric G proteins or arrestins, resulting in a wide variety of physiological and pathophysiological responses. The endogenous ligands for GPCRs are highly chemically diverse and include ions, biogenic amines, nucleotides, peptides, and lipids.

Introduction: Druggable Lipid Signaling Pathways.

Lipids are essential for life. They store energy, constitute cellular membranes, serve as signaling molecules, and modify proteins. In the long history of lipid research, many drugs targeting lipid receptors and enzymes that are responsible for lipid metabolism and function have been developed and applied to a variety of diseases.

Unlabeled lysophosphatidic acid receptor binding in free solution as determined by a compensated interferometric reader.

Native interactions between lysophospholipids (LPs) and their cognate LP receptors are difficult to measure because of lipophilicity and/or the adhesive properties of lipids, which contribute to high levels of nonspecific binding in cell membrane preparations. Here, we report development of a free-solution assay (FSA) where label-free LPs bind to their cognate G protein-coupled receptors (GPCRs), combined with a recently reported compensated interferometric reader (CIR) to quantify native binding interactions between receptors and ligands. As a test case, the binding parameters between lysophosphatidic acid (LPA) receptor 1 (LPA; one of six cognate LPA GPCRs) and LPA were determined.

A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA) receptor is a crucial factor in the initiation of NP.

LPA overactivation induces neonatal posthemorrhagic hydrocephalus through ependymal loss and ciliary dysfunction.

Posthemorrhagic hydrocephalus (PHH) in premature infants is a common neurological disorder treated with invasive neurosurgical interventions. Patients with PHH lack effective therapeutic interventions and suffer chronic comorbidities. Here, we report a murine lysophosphatidic acid (LPA)-induced postnatal PHH model that maps neurodevelopmentally to premature infants, a clinically accessible high-risk population, and demonstrates ventriculomegaly with increased intracranial pressure.

Systematic Understanding of Bioactive Lipids in Neuro-Immune Interactions: Lessons from an Animal Model of Multiple Sclerosis.

Bioactive lipids, or lipid mediators, are utilized for intercellular communications. They are rapidly produced in response to various stimuli and exported to extracellular spaces followed by binding to cell surface G protein-coupled receptors (GPCRs) or nuclear receptors. Many drugs targeting lipid signaling such as non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandins, and antagonists for lipid GPCRs are in use.

Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders.

Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration-approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS).

Lysophospholipid G protein-coupled receptor binding parameters as determined by backscattering interferometry.

Lysophosphatidic acid (LPA) activates cognate G protein-coupled receptors (GPCRs) to initiate biological signaling cascades. Lysophospholipid (LP) receptor binding properties remain incompletely assessed because of difficulties with ligand lipophilicity and lipid "stickiness." These inherent attributes produce high levels of nonspecific binding within cell-membrane preparations used to assess GPCRs, as has been shown in classical binding assays using radiolabeled ligands, making accurate measurements of lipid binding kinetics difficult to achieve.

A Functionally Defined Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes ().

Astrocytes have prominent roles in central nervous system (CNS) function and disease, with subpopulations defined primarily by morphologies and molecular markers often determined in cell culture. Here, we identify an astrocyte subpopulation termed immediate-early astrocytes () that is defined by functional c-Fos activation during CNS disease development. An unbiased screen for CNS cells showing c-Fos activation during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), was developed by using inducible, TetTag c-Fos reporter mice that label activated cells with a temporally stable, nuclear green fluorescent protein (GFP).

Septic arthritis of the cervical facets: Unusual cause of neck pain.

Sagittal T2-weighted fat saturation magnetic resonance imaging reveals erosion and a high-intensity area around the C3-C4 facet joint.

Lysophosphatidic acid receptor, LPA, regulates endothelial blood-brain barrier function: Implication for hepatic encephalopathy.

Cerebral edema is a life-threatening neurological condition characterized by brain swelling due to the accumulation of excess fluid both intracellularly and extracellularly. Fulminant hepatic failure (FHF) develops cerebral edema by disrupting blood-brain barrier (BBB). However, the mechanisms by which mediator induces brain edema in FHF remain to be elucidated.