Melatonin-sulforaphane hybrid ITH12674 attenuates glial response in vivo by blocking LPS binding to MD2 and receptor oligomerization. (February 2020)

• Record Type: Journal Article
• Authors: Michalska, Patrycja; Buendia, Izaskun; Duarte, Pablo; FernandezMendivil, Cristina; Negredo, Pilar; Cuadrado, Antonio; López, Manuela G.; Leon, Rafael
• Is Part Of: Pharmacological research. Volume 152(2020)
• Publication Date: 2020-02
• Subjects: AD Alzheimer's disease -- Aβ amyloid- -- ALS amyotrophic lateral sclerosis -- AP-1 Activator protein 1 -- ARE Antioxidant response element -- BBB Blood brain barrier -- dsDNA double-stranded DNA -- GCLc glutamate cysteine ligase catalytic subunit -- GST Glutathione S-transferase -- HMGB1 high-mobility group protein 1 -- HO-1 heme oxygenase-1 -- HSPs heat shock proteins -- IL1β interleukin 1β -- IKK IκB kinase -- iNOS Inducible nitric oxide synthase -- i.p. intra peritoneal -- IRAKs IL1 receptor-associated kinases -- JNK c-Jun N-terminal kinases -- KEAP1 Kelch-like ECH-associated protein 1 -- MD2 Myeloid differentiation factor-2 -- Mel Melatonin -- MS multiple sclerosis -- MyD88 myeloid differentiation primary response gene 88 -- NAC N-Acetyl-L-Cysteine -- NDDs neurodegenerative diseases -- NLRP3 NLR family pyrin domain containing 3 -- NOX NADPH oxidase -- NRF2 nuclear factor erythroid 2–related factor 2 -- NRF2−/− NRF2 knock-out -- NRF2+/+ NRF2 wild type OxPL oxidized phospholipid -- PD Parkinson's disease -- P-p38 P38 mitogen-activated protein kinase -- PRRs pattern recognition receptors -- p65 nuclear factor NF-kappa-B p65 subunit -- RAC1 RAS-related C3 botulinum substrate 1 -- RNS reactive nitrogen species -- ROS reactive oxygen species -- SFN Sulforaphane -- SnPP tinprotoporphyrin -- TAK1 transforming growth factor β-activated kinase-1 -- TIR Toll/interleukin-1 receptor -- TLR Toll-like receptor; ITH12674 -- Sulforaphane (CID: 5350) -- Melatonin (CID:896) -- SnPP (CID: 73755113) -- N-acetyl-L-cysteine (CID: 12035); ITH12674 -- Neuroinflammation -- Neurodegenerative diseases -- Antiinflammatory properties -- MD2 antagonist -- TLR4 inhibitor -- NRF2 -- Nuclear factor (erythroid-derived 2)-like 2 -- Multi-target; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2019.104597
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Neuroinflammation is increasingly associated to the onset and progression of neurodegenerative diseases. Furthermore, several lines of evidence have demonstrated the capacity of aberrant protein aggregates to activate the immune response, accelerating the advance of the disease. Compound ITH12674 is a melatonin-sulforaphane hybrid designed to exert a dual drug-prodrug mechanism of action that combines potent NRF2 induction and free radical scavenger activity. ITH12674 also showed neuroprotective properties in oxidative stress related models, that were dependant on its NRF2 inducing properties. Given the high impact of neuroinflammation in the pathogenesis of neurodegeneration, we foresaw to study the anti-inflammatory properties of ITH12674. ITH12674 reduced inflammatory markers in glial cell cultures and hippocampal tissue after LPS administration. The anti-inflammatory effect was related to inhibition of TLR4 receptors due to a direct interaction with the TLR4/MD2 complex at the hydrophobic cavity of MD2. ITH12674 is endowed with anti-inflammatory properties, that are complementary to the NRF2 inducing activity and neuroprotective properties. Thus, ITH12674 could be of potential interest for the treatment of diseases with chronic neuroinflammation.