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1.
Hepatol Commun ; 7(12)2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37994050

ABSTRACT

BACKGROUND: NASH causes a tremendous health care burden in the United States. A glucagon-like peptide-1 agonist, semaglutide (Sema), treatment resulted in hepatic steatosis reduction in clinical trials of NASH. Lysophosphatidic acid receptor 1 antagonists are known to have antifibrotic effects in several organs. We tested Sema and a novel lysophosphatidic acid receptor 1 antagonist, EPGN2154, individually and in combination to evaluate their efficacy for NASH remission in preclinical models. METHODS: In the present study, we used (1) C57Bl6/J wild-type mice fed on a high-fat, high-carbohydrate (HFHC) diet for 16 weeks and (2) leptin-deficient mice (ob/ob) fed on an Amylin liver NASH diet for 16 weeks. After 16 weeks, the mice were randomly distributed in equal numbers in (1) no-drug, (2) EPGN2154, (3) Sema, and (4) EPGN2154+Sema treatment groups for 8 additional weeks at a dosage of 10 mg/kg body weight for EPGN2154 (oral gavage, 5 days a week) and 6.17 µg/kg body weight of Sema (subcutaneous injection every alternate day, 3 days a week). RESULTS: In the wild-type-high-fat, high-carbohydrate model, we observed the most body weight loss in the EPGN2154+Sema combination group compared to the other treatment groups. All groups led to a significant reduction in alanine transaminase levels when compared to high-fat, high-carbohydrate-fed wild type. However, no significant difference in alanine transaminase levels was observed among the treatment groups. In the ob/ob mice study, Sema did not cause body weight loss. Moreover, the EPGN2154 and the combination groups had a lower NAFLD Activity Score and incidence of advanced-stage hepatic fibrosis than the Sema group. CONCLUSIONS: EPGN2154 demonstrated a hepato-protective effect independent of body weight loss in preclinical NASH models.


Subject(s)
Non-alcoholic Fatty Liver Disease , Animals , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiology , Receptors, Lysophosphatidic Acid/therapeutic use , Alanine Transaminase , Body Weight , Diet, High-Fat/adverse effects , Carbohydrates/therapeutic use , Weight Loss
2.
Brain Behav Immun ; 56: 271-80, 2016 08.
Article in English | MEDLINE | ID: mdl-27044335

ABSTRACT

OBJECTIVE: Pain resulting from local tissue injury or inflammation typically resolves with time. Frequently, however, this pain may unexpectedly persist, becoming a pathological chronic state. Increasingly, the innate and adaptive immune systems are being implicated in the initiation and maintenance of these persistent conditions. In particular, Toll-like receptor 4 (TLR4) signaling has been shown to mediate the transition to a persistent pain state in a sex-dependent manner. In the present work, we explored this contribution using the TLR4 antagonist, TAK-242. METHODS: Male and female C57Bl/6 mice were given intravenous (IV), intrathecal (IT), or intraperitoneal (IP) TAK-242 prior to IT delivery of lipopolysaccharide (LPS), and tactile reactivity was assessed at regular intervals over 72-h. Additional groups of mice were treated with IP TAK-242 prior to intraplantar formalin, and flinching was monitored for 1-h. Tactile reactivity was assessed at 7-days after formalin delivery. RESULTS: LPS evoked TNF release from male and female macrophages and RAW267.4 cells, which was blocked in a concentration dependent fashion by TAK-242. In vivo, IT LPS evoked tactile allodynia to a greater degree in male than female mice. TAK-242, given by all routes, prevented development of IT LPS-induced tactile allodynia in male animals, but did not reverse their established allodynia. TLR4 deficiency and TAK-242 treatment attenuated IT LPS-induced allodynia in male, but not female mice. In the formalin model, pre-treatment with TAK-242 did not affect Phase 1 or Phase 2 flinching, but prevented the delayed tactile allodynia in both male and unexpectedly in female mice (Phase 3). CONCLUSIONS: Together, these results suggest that TAK-242 is a TLR4 antagonist that has efficacy after systemic and intrathecal delivery and confirms the role of endogenous TLR4 signaling in triggering the development of a delayed allodynia in both male and female mice.


Subject(s)
Chronic Pain/prevention & control , Hyperalgesia/prevention & control , Signal Transduction/physiology , Sulfonamides/pharmacology , Toll-Like Receptor 4/antagonists & inhibitors , Tumor Necrosis Factor-alpha/drug effects , Animals , Behavior, Animal , Chronic Pain/chemically induced , Disease Models, Animal , Disinfectants/administration & dosage , Disinfectants/pharmacology , Female , Formaldehyde/administration & dosage , Formaldehyde/pharmacology , Hyperalgesia/chemically induced , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , RAW 264.7 Cells , Sex Factors , Signal Transduction/drug effects , Sulfonamides/administration & dosage , Toll-Like Receptor 4/deficiency
3.
J Med Chem ; 56(20): 8032-48, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-24044867

ABSTRACT

Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson's disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels. We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC50 = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels. The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC50 = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.


Subject(s)
Drug Discovery/methods , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Administration, Oral , Animals , Area Under Curve , Biological Availability , Blood-Brain Barrier/metabolism , Brain/metabolism , Carbazoles/chemical synthesis , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cells, Cultured , Cognition Disorders/complications , Cognition Disorders/prevention & control , HIV Infections/complications , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Kinase Kinases/metabolism , Male , Mice , Mice, Inbred C57BL , Models, Chemical , Molecular Structure , Monocytes/drug effects , Monocytes/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Tumor Necrosis Factor-alpha/metabolism , tat Gene Products, Human Immunodeficiency Virus/pharmacology , Mitogen-Activated Protein Kinase Kinase Kinase 11
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