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

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 (Aß) accumulation and inhibited the activities of ß- 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.

Piperlongumine attenuates experimental autoimmune encephalomyelitis through inhibition of NF-kappaB activity.

Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disease in which demyelination sporadically and repeatedly occurs in the central nervous system (CNS). The activity of nuclear factor kappa B (NF-κB), a family of transcription factors, was increased in the cerebrospinal fluid (CSF) and/or the serum and brain and/or spinal cord of MS patients than in a healthy donors. In our study, we investigated whether piperlongumine (PL), which is known to have inhibitory effect on activity of NF-κB, can alleviate an experimental autoimmune encephalomyelitis (EAE). The mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), and then we injected PL (1.5mg/kg/day or 3.0mg/kg/day) into the mice intraperitoneally on every second day from days 2 to 28. For in vitro study, we treated PL (0.5, 1 and 2.5µM) to RAW 264.7 and Jurkat cells with each stimulator. We observed that the paralytic severity and neuropathology of EAE in PL-treated group were decreased compared with the EAE group. PL showed a suppressed effect on demyelination, immune cells infiltration, astrocytes/microglials activation, level of inflammatory cytokines and proteins as well as NF-κB activity. Production of inflammatory cytokines and proteins as well as translocation of NF-κB into nucleus by treatment stimulators in RAW 264.7 and Jurkat cells were reduced by PL. Moreover, treatment of NF-κB inhibitor further inhibited production of inflammatory cytokines and proteins. These results suggest that PL can mitigate MOG-induced EAE symptoms and activation of macrophages and T cells by inhibiting NF-κB signaling. Therefore, PL could be useful for the treatment for MS.