Anti-Inflammatory Effects of Veratramine against Lipopolysaccharide-Induced Inflammation

Plant-derived bioactive molecules are increasingly recognized as valuable therapeutic resources for managing diverse pathological conditions, particularly those involving vascular inflammation. This study aimed to determine whether veratramine (VRT), a naturally occurring steroidal alkaloid found in Veratrum species of the Liliaceae family, attenuates LPS-induced vascular and pulmonary inflammation by upregulating heme oxygenase-1 (HO-1) and modulating the Nrf2, nuclear factor (NF)-κB, and signal transducer and activator of transcription (STAT1) signaling pathways.

The study assessed the modulatory effects of VRT on HO-1, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in LPS-activated human umbilical vein endothelial cells (HUVECs), as well as on iNOS, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) expression in LPS-treated mice. The VRT doses (0.06–0.6 mg/kg) in mice were chosen to approximate peripheral concentrations of 2–20 μM, corresponding to the non-cytotoxic, anti-inflammatory range in HUVECs, based on calculations using mouse blood volume and body weight, and no overt acute toxicity was observed at these doses in this model.

Treatment with VRT enhanced HO-1 induction, inhibited NF-κB activation, diminished COX-2/PGE₂ and iNOS/NO production, and attenuated STAT1 phosphorylation. In addition, VRT promoted nuclear translocation of Nrf2 and its binding to antioxidant response elements (AREs), thereby suppressing IL-1β expression in HUVECs. The VRT-mediated inhibition of iNOS/NO was abolished by HO-1 silencing through RNA interference. In vivo, VRT markedly reduced iNOS expression in lung tissue and lowered TNF-α levels in bronchoalveolar lavage fluid.

Altogether, these findings demonstrate that VRT exhibits substantial anti-inflammatory potential and may serve as a promising candidate for managing inflammation-related vascular disorders.