<i>Pistacia vera</i> Extract Potentiates the Effect of Melatonin on Human Melatonin MT₁ and MT₂ Receptors with Functional Selectivity

• Main Authors: Nedjma Labani (Author), Florence Gbahou (Author), Marc Noblet (Author), Bernard Masri (Author), Olivier Broussaud (Author), Jianfeng Liu (Author), Ralf Jockers (Author)
• Format: Book
• Published: MDPI AG, 2023-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics15071845; 1999-4923
• Keywords: plant extracts; GPCR; signalling; melatonin; insomnia; depression; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 15, Iss 7, p 1845 (2023)

Melatonin is a tryptophan derivative synthesized in plants and animals. In humans, melatonin acts on melatonin MT₁ and MT₂ receptors belonging to the G protein-coupled receptor (GPCR) family. Synthetic melatonin receptor agonists are prescribed for insomnia and depressive and circadian-related disorders. Here, we tested 25 commercial plant extracts, reported to have beneficial properties in sleep disorders and anxiety, using cellular assays (2─[¹²⁵I]iodomelatonin binding, cAMP inhibition, ERK1/2 activation and β-arrestin2 recruitment) in mock-transfected and HEK293 cells expressing MT₁ or MT₂. Various melatonin receptor-dependent and -independent effects were observed. Extract 18 (<b>Ex18</b>) from <i>Pistacia vera</i> dried fruits stood out with very potent effects in melatonin receptor expressing cells. The high content of endogenous melatonin in <b>Ex18</b> (5.28 ± 0.46 mg/g extract) is consistent with this observation. <b>Ex18</b> contains an additional active principle that potentiates the effect of melatonin on G_i protein-dependent pathways but not on β-arrestin2 recruitment. Further active principles potentiating exogenous melatonin were detected in several extracts. In conclusion, we identified plant extracts with various effects in GPCR-based binding and signalling assays and identified high melatonin levels and a melatonin-potentiating activity in <i>Pistacia vera</i> dried fruit extracts that might be of therapeutic potential.