Incretin-Based Multi-Agonist Peptides Are Neuroprotective and Anti-Inflammatory in Cellular Models of Neurodegeneration

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 872 - 872

Published: July 19, 2024

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) are widely used to treat type 2 diabetes mellitus (T2DM) obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) glucagon (Gcg) (GcgR), emerged with aim enhancing drug benefits. In this study, we utilized human mouse microglial cell lines, HMC3 IMG, respectively, together neuroblastoma SH-SY5Y line as cellular models neurodegeneration. Using these studied neuroprotective anti-inflammatory capacity several multi-agonists in comparison a single GLP-1 (GLP-1R) agonist, exendin-4. Our data demonstrate that two selected GLP-1R/GIPR dual agonists GLP-1R/GIPR/GcgR triple agonist not only neurotrophic effects but also anti-neuroinflammatory properties, indicated decreased cyclooxygenase (COX2) expression, nitrite production, pro-inflammatory cytokine release. addition, our results indicate potential outperform commercially available GLP-1R neurodegenerative disease treatment.

Language: Английский

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Prostaglandins in the Inflamed Central Nervous System: Potential Therapeutic Targets

Current Drug Targets, Journal Year: 2024, Volume and Issue: 25(13), P. 885 - 908

Published: Aug. 23, 2024

The global burden of neurological disorders is evident, yet there remains limited efficacious therapeutics for their treatment. There a growing recognition the role inflammation in diseases central nervous system (CNS); among numerous inflammatory mediators involved, prostaglandins play crucial role. Prostaglandins are small lipid derived from arachidonic acid via multi-enzymatic pathways. actions varied, with each prostaglandin having specific maintaining homeostasis. In CNS, can have neuroprotective or neurotoxic properties depending on G-protein receptor. These receptors varying subfamilies, tissue distribution, and signal transduction cascades. Further studies into impact CNS-based may contribute to clarification actions, hopefully leading development therapeutic strategies. This review focuses roles played by neural degeneration, focus Alzheimer's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis both preclinical clinical settings. We further discuss current prostaglandin-related agonists antagonists concerning suggestions use as future therapeutics.

Language: Английский

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Bis-chalcones obtained via one-pot synthesis as the anti-neurodegenerative agents and their effect on the HT-22 cell line

Heliyon, Journal Year: 2024, Volume and Issue: 10(17), P. e37147 - e37147

Published: Aug. 30, 2024

Highlights•The bis-chalcones were synthesized and fully characterized by the spectral methods.•The showed high anti-neurodegenerative activities.•Bis-chalcones affect mouse hippocampal neuronal cell line (HT-22).•The most act mainly through AhR molecular pathway.•Computational studies confirmed assumption derived from in vitro tests.AbstractIn area of research on neurodegenerative diseases, current challenge is to search for appropriate methods that would detect these diseases at earliest possible stage, but also new active structures reduce rate disease progression minimize intensity their symptoms experienced patient. The chalcones are considered context candidates drugs dedicated fight against diseases. synthesis bis-chalcone derivatives (3a-3d), as aim molecules was performed. Their established applying 1H NMR, 13C MS, FT-IR UV–Vis spectra. All terephthalaldehyde aromatic ketone substrates Claisen-Schmidt condensation method evaluated biological tests silico analysis. Compounds exerted antioxidant activity using HORAC (3a-3d) decreased activities GPx, COX-2 (3b-3d), GR (3a-3c) CAT (3a,3b). potential all four observed inhibition acetyl- (AChE) butyrylcholinesterase (BChE) a positive effect HT-22 (LDH release PGC-1α, PPARγ GAPDH protein expression). TD-DFT (computing number descriptors associated with HOMO–LUMO electron transition: electronegativity, chemical hardness potential, first ionization affinity) employed study spectroscopic properties. This excited state compounds consistent maximum absorption computed spectra, which good agreement experimental spectrum PBE1PBE functional. Using approach, interactions selected targets (aryl hydrocarbon receptor (AhR) PAS-A Domain, ligand binding domain human PPAR-γ, soman-aged BChE-butyrylthiocholine complex, Torpedo californica AChE:N-piperidinopropyl-galanthamine complex COX-2-celecoxib complex) characterized. Results obtained models experiments.

Language: Английский

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Sertraline as a Multi-Target Modulator of AChE, COX-2, BACE-1, and GSK-3β: Computational and In Vivo Studies

Molecules, Journal Year: 2024, Volume and Issue: 29(22), P. 5354 - 5354

Published: Nov. 14, 2024

Alzheimer's disease (AD) is a neurodegenerative disorder associated with the dysregulation of several key enzymes, including acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2), glycogen synthase kinase 3β (GSK-3β), β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), and caspase-3. In this study, machine learning algorithms such as Random Forest (RF), Gradient Boost (GB), Extreme (XGB) were employed to screen US-FDA approved drugs from ZINC15 database identify potential dual inhibitors COX-2 AChE. The models trained using molecules obtained ChEMBL database, 5039 for AChE 3689 COX-2. Specifically, 1248 3791 classified active inactive AChE, respectively, while 858 2831 three achieved prediction accuracies ranging 92% 95% both Virtual screening identified sertraline (SETL) inhibitor Further docking studies SETL in sites COX-2, well BACE-1, GSK-3β, caspase-3, revealed strong binding affinities all five proteins. vivo validation was conducted lipopolysaccharide (LPS)-induced rat model pretreated 30 days. results demonstrated significant decrease levels (

Language: Английский

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Quantification of COX-2 Level in Alzheimer’s Disease Patients to Develop Potential Blood-Based Biomarker for Early Diagnosis and Therapeutic Target

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 98(2), P. 699 - 713

Published: Feb. 27, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative and symptoms develop gradually over many years. The current direction for medication development in AD focused on neuro-inflammation oxidative stress. Amyloid-β (Aβ) deposition activates microglia leading to neurodegeneration induced by activation of COX-2 via NFκB p50 glioblastoma cells.

Language: Английский

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