Alkaloids from Piper nigrum Exhibit Antiinflammatory Activity via Activating the Nrf2/HO­1 Pathway

In the present study, ten alkaloids, namely chabamide (1), pellitorine (2), retrofractamide A (3), pyrroperine (4), isopiperolein B (5), piperamide C9:1 (8E) (6), 6,7­dehydrobrachyamide B (7), 4,5‐dihydropiperine (8), dehydropipernonaline (9), and piperine (10), were isolated from the fruits of Piper nigrum. Among these, chabamide (1), pellitorine (2), retrofractamide A (3), isopiperolein B (5), and 6,7­dehydrobrachyamide B (7) exhibited significant inhibitory activity on lipopolysaccharide‐induced nitric oxide (NO) production in RAW264.7 cells, with IC50 values of 6.8, 14.5, 30.2, 23.7, and 38.5 μM, respectively. Furthermore, compound 1 inhibited lipopolysaccharide‐induced NO production in bone marrow‐derived macrophages with IC50 value of 9.5 μM. Consistent with NO inhibition, treatment of RAW264.7 cells with chabamide (1), pellitorine (2), and 6,7­dehydrobrachyamide B (7) suppressed expression of inducible NO synthase and cyclooxygenase‐2. Chabamide (1), pellitorine (2), and 6,7­dehydrobrachyamide B (7) induced heme‐oxygenase‐1 expression at the transcriptional level. In addition, compound 1 induced the nuclear translocation of nuclear factor‐E2‐related factor 2 (Nrf2) and upregulated the expression of Nrf2 target genes, NAD(P)H:quinone oxidoreductase 1 and γ‐glutamyl cysteine synthetase catalytic subunit, in a concentration‐dependent manner in RAW264.7 cells. These findings suggest that chabamide (1) from P. nigrum exert antiinflammatory effects via the activation of the Nrf2/heme‐oxygenase‐1 pathway; hence, it might be a promising candidate for the treatment of inflammatory diseases. Copyright © 2017 John Wiley & Sons, Ltd.