Rationale: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. G protein-coupled receptor 40 (GPR40) is expressed in brain in addition to periphery and is associated with cognitive function such as space orientation, memory, and learning. However, the effects and mechanisms of GPR40 agonist in improving the AD progression remain largely unknown.
Objectives: The present study aimed to investigate the therapeutic effects and mechanisms of a potent and selective GPR40 agonist TAK-875 on the APPswe/PS1dE9 mice.
Results: The results showed that intracerebroventricular administration of TAK-875 significantly rescued cognitive deficits in APPswe/PS1dE9 mice, and these effects may be mediated by the regulation of phospholipase C/protein kinase C signaling pathway, which enhanced α-secretase ADAM10 activity, promoted amyloid precursor protein non-amyloidogenic processing pathway, and reduced β-amyloid production.
Conclusions: These results suggest that GPR40 may be a potential therapeutic target for AD, and GPR40 agonists may become promising AD drugs in the future.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s00213-021-05837-4 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Recent Developments in Drug Design of Oral Synthetic Free Fatty Acid Receptor 1 Agonists.
Drug Des Devel Ther
December 2024
Tasly Academy, Tasly Pharma Co., Ltd., Tianjin, People's Republic of China.
Over the past two decades, synthetic FFAR1 agonists such as TAK-875 and TSL1806 have undergone meticulous design and extensive clinical trials. However, due to issues primarily related to hepatotoxicity, no FFAR1 agonist has yet received regulatory approval. Research into the sources of hepatotoxicity suggests that one potential cause lies in the molecular structure itself.
View Article and Find Full Text PDFLower hepatotoxicity risk in Xelaglifam, a novel GPR40 agonist, compared to Fasiglifam for type 2 diabetes therapy.
Biomed Pharmacother
December 2024
College of Pharmacy, Dongguk University-Seoul, Goyang-si, Kyeonggi-do 10326, Republic of Korea. Electronic address:
Fasiglifam, a candidate targeting GPR40, showed efficacy in clinical trials for type 2 diabetes but exerted liver toxicity. This study investigated the drug-induced liver injury (DILI) risk of Xelaglifam, a new GPR40 agonist, based on the potential toxicity mechanism of Fasiglifam; transporter inhibition, mitochondrial dysfunction, reactive metabolite formation, and covalent binding to proteins. In the hepatobiliary transporter assay, Xelaglifam showed a broader safety margin (>10-fold) against bile acid transporters, suggesting its less likelihood to cause bile acids accumulation, unlike Fasiglifam (<10-fold safety margin).
View Article and Find Full Text PDFEnteroendocrine cell-derived peptide YY signalling is stimulated by pinolenic acid or Intralipid and involves coactivation of fatty acid receptors FFA1, FFA4 and GPR119.
Neuropeptides
December 2024
King's College London, Wolfson Sensory, Pain and Regeneration Centre, Hodgkin Building, Guy's Campus, London SE1 1UL, UK. Electronic address:
Long chain fatty acids are sensed by enteroendocrine L cells that express free-fatty acid receptors, including FFA1, FFA4 and the acylethanolamine receptor GPR119. Here we investigated the acute effects of single or multiple agonism at these G protein-coupled receptors in intestinal mucosae where L cell-derived peptide YY (PYY) is anti-secretory and acts via epithelial Y receptors. Mouse ileal or colonic mucosae were mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (I) recorded continuously.
View Article and Find Full Text PDFOral administration of linoleic acid immediately before glucose load ameliorates postprandial hyperglycemia.
Front Pharmacol
July 2023
Department of Anatomy and Cell Biology, Graduate School of Medicine, Wakayama Medical University, Wakayama, Japan.
Fatty acids are a major nutrient in dietary fat, some of which are ligands of long-chain fatty acid receptors, including G-protein-coupled receptor (GPR) 40 and GPR120. Pretreatment with GPR40 agonists enhanced the secretion of insulin in response to elevating blood glucose levels after glucose load in a diabetes model, but pretreatment with GPR120 agonist did not ameliorate postprandial hyperglycemia. This study examined whether oral administration of linoleic acid (LA), a GPR40 and GPR120 agonist, immediately before glucose load would affect the elevation of postprandial blood glucose levels in rats.
View Article and Find Full Text PDFMolecular mechanism of fatty acid activation of FFAR1.
Proc Natl Acad Sci U S A
May 2023
Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
FFAR1 is a G-protein-coupled receptor (GPCR) that responds to circulating free fatty acids to enhance glucose-stimulated insulin secretion and release of incretin hormones. Due to the glucose-lowering effect of FFAR1 activation, potent agonists for this receptor have been developed for the treatment of diabetes. Previous structural and biochemical studies of FFAR1 showed multiple sites of ligand binding to the inactive state but left the mechanism of fatty acid interaction and receptor activation unknown.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!