Journal Article

Dual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in lipopolysaccharide-induced RAW 264.7 cells

Rahmawati, Siti Irma, Firdayani, Firdayani, Bayu, Asep, Rosyidah, A’liyatur, Putra, Masteria Yunovilsa, Hardhiyuna, Mutia, Indriani, Dwi Wahyu, Septiana, Eris, Ahmadi, Peni, Dharmayanti, Ni Luh Putu Indi, Ningsih, Febby Nurdiya

2024

Overview

Cyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a pivotal role in producing pro-inflammatory eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs), in the inflammation process. Mitragynine is a primary alkaloid contained in the kratom’s leaves and has been reported to show anti-inflammatory activity by suppressing COX-2 mRNA translation to lowering PGs synthesis. In this study, the Kratom’s alkaloid extract containing ~ 46% mitragynine was found to exhibit dual inhibition activity towards COX-2/5-LOX enzymes at concentrations below 25 ppm in the LPS-induced RAW 264.7 macrophage cells. At these levels, no cell toxicity was observed while the cells became death (e.g., 10–46% viability at 50–100 ppm) and only COX-2 inhibition activity was observed after exposed with more than 25 ppm of alkaloid extract. In contrast, the methanolic-crude extract of Kratom’s leaf containing ~ 5% mitragynine showed no inhibition toward COX-2/5-LOX enzymes and did not toxic onto the cells, even after treated at 100 ppm. The alkaloid extract suppressed several antiinflammation parameters, including ROS (64% reduction at 25 ppm), NO (30% reduction at 25 ppm), TNF-α (~ 50% reduction at 25 ppm), and IL-6 production (60% reduction at 6.25 ppm). In silico molecular studies indicated strong binding affinity of Kratom alkaloids to COX-2 and 5-LOX active sites, supporting the Kratom’s alkaloids to have great potential dual inhibition activity towards COX-2/5-LOX enzymes and to be developed as a safer NSAIDs with fewer side effects.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154 / 631/337 / 631/45 / 631/80 / Alkaloids / Alkaloids - pharmacology / Animals / Anti-inflammatory / Anti-inflammatory agents / Anti-Inflammatory Agents - chemistry / Anti-Inflammatory Agents - pharmacology / Arachidonate 5-Lipoxygenase - metabolism / Cell death / Cell Survival - drug effects / Cellular oxidative stress / Cyclooxygenase 2 - metabolism / Cyclooxygenase 2 Inhibitors - pharmacology / Cyclooxygenase-2 / Dual inhibition COX-2/5-LOX / Eicosanoids / Enzymes / Humanities and Social Sciences / Inflammation / Leukotrienes / Lipopolysaccharides / Lipoxygenase / Lipoxygenase Inhibitors - pharmacology / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Mice / Mitragyna - chemistry / Mitragyna speciosa / Molecular Docking Simulation / mRNA / multidisciplinary / Nonsteroidal anti-inflammatory drugs / Plant Extracts - chemistry / Plant Extracts - pharmacology / Plant Leaves - chemistry / Prostaglandins / RAW 264.7 Cells / Science / Science (multidisciplinary) / Secologanin Tryptamine Alkaloids - pharmacology / Toxicity / Transcription / Tumor necrosis factor-α