Piperlongumine Improves Lipopolysaccharide-Induced Amyloidogenesis by Suppressing NF-KappaB Pathway.

Abstract

Amyloidogenesis is known to cause Alzheimer's disease. Our previous studies have found that lipopolysaccharide (LPS) causes neuroinflammation and amyloidogenesis through activation of nuclear factor kappaB (NF-κB). Piperlongumine (PL) is an alkaloid amide found naturally in long pepper (Piper longum) isolates; it was reported to have inhibitory effects on NF-κB activity. We therefore investigated whether PL exhibits anti-inflammatory and anti-amyloidogenic effects by inhibiting NF-κB. A murine model of LPS-induced memory impairment was made via the intraperitoneal (i.p.) injection of LPS (0.25 mg/kg/day, i.p.). We then injected PL (1.5 or 3.0 mg/kg/day, i.p.) for 7 days in three groups of mice to observe effects on memory. We also conducted an in vitro study with astrocytes and microglial BV-2 cells, which were treated with LPS (1 µg/mL) or PL (0.5 or 1.0 or 2.5 µM). Results from our behavioral tests showed that PL inhibited LPS-induced memory. PL also prevented LPS-induced beta-amyloid (Aβ) accumulation and inhibited the activities of β- and γ-secretases. The expression of inflammatory proteins also was decreased in PL-treated mice, cultured BV-2, and primary astrocyte cells. These effects were associated with the inhibition of NF-κB activity. A docking model analysis and pull-down assay showed that PL binds to p50. Taken together, our findings suggest that PL diminishes LPS-induced amyloidogenesis and neuroinflammation by inhibiting NF-κB signaling; PL therefore demonstrates potential for the treatment of Alzheimer's disease.

• Authors: Sun Mi Gu, Hee Pom Lee, Young Wan Ham, Dong Ju Son, Hoi Yeong Kim, Ki Wan Oh, Sang-Bae Han, Jaesuk Yun, Jin Tae Hong
• Journal: Neuromolecular medicine (Neuromolecular Med) Vol. 20 Issue 3 Pg. 312-327 (09 2018) ISSN: 1559-1174 [Electronic] United States
• PMID: 29802525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cytokines
• Dioxolanes
• Lipopolysaccharides
• NF-kappa B p50 Subunit
• piperlongumine

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (antagonists & inhibitors, biosynthesis)
• Animals
• Astrocytes (drug effects, metabolism)
• Cell Death (drug effects)
• Cells, Cultured
• Cytokines (antagonists & inhibitors)
• Dioxolanes (administration & dosage, pharmacology, therapeutic use)
• Disease Models, Animal
• Inflammation (chemically induced, drug therapy, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Memory (drug effects)
• Mice
• Microglia (drug effects, metabolism)
• NF-kappa B p50 Subunit (antagonists & inhibitors, metabolism)
• Piper (chemistry)