Synthesis and Anti-Neuroinflammatory Activity of 1,7-diphenyl-1,4-heptadien-3-ones in LPS-Stimulated BV2 Microglia Via Inhibiting NF-κB/MAPK Signaling Pathways

Abstract

A series of 1,7-diphenyl-1,4-heptadien-3-ones with various substituents (HO-, CH3O-, CH3-, Cl-) on the phenyl rings were synthesized and evaluated for anti-neuroinflammatory effects in LPS-stimulated BV2 microglia. The pharmacological results showed that the target compounds bearing methoxy groups greatly inhibited LPS-induced NO release, and that the active compounds CU-19 and CU-21 reduced the level of NO, TNF-α, IL-6 and PGE-2, downregulated the expression of COX-2 and iNOS in LPS-stimulated BV2 cells. A study of the mechanism of action revealed that CU-19 and CU-21 inhibited the nuclear translocation of NF-κB and phosphorylation of MAPKs (ERK, JNK, and p38). A preliminary pharmacokinetic study in rats revealed that the pharmacokinetic properties of CU-19 and CU-21 were dramatically ameliorated in comparison with the pharmacokinetic properties of curcumin.

Evaluation of Anti-Neuroinflammatory Activity of Isatin Derivatives in Activated Microglia

“…1 H-NMR was in agreement with those reported in the literature [29]. 1-butyl-1H-indole-2,3-dione (12) Compound 12 was prepared as described in 4.2.1 using isatin (1 g, 6.8 mmol) and 1-bromobutane (876 µL, 8.16 mmol) to obtain the desired product (1.33 g, 96%) as an orange crystal. HPLC Rt: 14.26 min.…”

“…The release of proinflammatory cytokines, including IL-6 and TNF-α, as well as the production of NO, is increased. This is a suitable cell model of murine microglia inflammation since 90% of the genes induced by LPS in BV2 microglia cells are also induced in primary microglia and it has been applied previously as murine neuroinflammation cell model as an alternative to animal experimentation [ 9 , 10 , 11 , 12 ].…”