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.

Piper Species: A Comprehensive Review on Their Phytochemistry, Biological Activities and Applications

“…Recent studies also showed that piperlongumine possess highly potent anti-neuroinflammatory functions. In vitro studies showed that piperlongumine significantly attenuated the production of proinflammatory mediators (NO and PGE 2 ) and some cytokines (TNF-α and IL-6) by suppressing NF-κB signaling pathway in LPS induced BV-2 microglias, primary astrocytes, RAW264.7 macrophages and Jurkat cells [13,397,398]. Some important insights into the anti-neuroinflammatory and neuroprotective effects of piperlongumine have come from recent studies using animal models.…”

“…Some important insights into the anti-neuroinflammatory and neuroprotective effects of piperlongumine have come from recent studies using animal models. Accordingly, piperlongumine inhibited LPS-induced memory impairment, Aβ accumulation and the activities of β- and γ-secretases in murine models [397]. Gu et al [398], reported that the paralytic severity and neuropathology in mice model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein 35–55 immunization were reduced in piperlongumine-treated group in comparison with the EAE model group.…”

Interaction between piperine and genes associated with sciatica and its mechanism based on molecular docking technology and network pharmacology

“…Firstly, based on the strategy of network pharmacology, the interaction network of known sciatica-related genes was constructed, and the key candidate targets of intervention of Piper longum L. on sciatica-related imbalance network were selected. It was found that the key targets of Piper longum L. were significantly enriched in several pathways related to the pathological process of sciatica, among which NF-kB signaling pathway, a member protein of this signaling pathway, especially PPARG and NF-kB1, were closely related to the inflammatory response in the pathological process of sciatica [41].…”

Naturally occurring Piper plant amides potential in agricultural and pharmaceutical industries: perspectives of piperine and piperlongumine

“…Piperlongumine can inhibit amyloidogenesis by inhibiting NF-κB activity. Evidence also suggests that piperlongumine injections inhibited LPS-induced memory [49].…”