Ethnopharmacological relevance: seeds and aerial part of Peganum harmala L. are widely used in Algeria as anti-inflammatory remedies. Aim of the study: The aim of this study was to provide the use of Peganum harmala as an anti-inflammatory treatment by the inhibition of an enzyme key of inflammatory, myeloperoxidase. Materials and methods: Myeloperoxidase inhibition was tested using taurine chloramine test. The inhibition of LDL oxidation induced by MPO was carried out. The Molecular docking analysis of P. harmala alkaloids on MPO was performed using the Glide XP docking protocol and scoring function and the redox potential of alkaloids was determined using an Epsilon potentiostat. The concentration of harmala alkaloids was determined using HPLC analysis. Results: The profiling of active total alkaloids indicates that -carboline e.g. harmine, harmaline, harmane, harmol and harmalol are major components. As β-carbolines resemble tryptamine, of which derivatives are efficient inhibitors of myeloperoxidase (MPO), the harmala alkaloids were tested for their activity on this enzyme. Total alkaloids of the seed and of the aerial parts strongly inhibited MPO at 20 µg/ml (97±5 and 43±4 %, respectively) whereas, at the same concentration, those of the roots showed very low inhibition (15±6 %). Harmine, harmaline and harmane demonstrated a significant inhibition of MPO at IC50 of 0.26, 0.08 and 0.72 µM respectively. These alkaloids exerted a similar inhibition effects on MPO-induced LDL oxidation. Molecular docking analysis of P. harmala alkaloids on MPO showed that all active P. harmala alkaloids have a high affinity on the active site of MPO (predicted free energies of binding up to -3.1 kcal/mol). Measurement of redox potentials versus the normal hydrogen electrode clearly differentiated (i) the high MPO inhibitory activity of harmine, harmaline and harmane (+ 1014, 1014 and 1003 mV, respectively); and (ii) the low activity of harmalol and harmol (+ 629/778 and 532/644 mV, respectively). A fast and reliable reverse phase HPLC method has been developed to determine simultaneously six alkaloids of Peganum harmala L. Seeds contained all five β-carboline derivatives with the main active alkaloids, harmaline and harmine, being up to 3.8 and 2.9 % ,respectively. Up to 3.2 % of harmine was determined in the roots. The four β-carboline derivatives, harmine, harmaline, harmane and harmalol were identified in the aerial parts. The highest inhibitory effect observed in seeds and the moderate effect of aerial parts could be explained by their harmine and harmaline content. In contrast, the much lower inhibition of the root extract, despite the presence of harmine, may tentatively be explained by the high concentration of harmol which can reduce Compound II of MPO to the native form. Conclusion: The inhibition of myeloperoxidase by Peganum harmala β-carboline alkaloids, herein reported for the first time, may explain the anti-inflammatory effect traditionally attributed to its herbal medicines. ; info:eu-repo/semantics/published