The Suppression Effect Of 18β-glycyrrhetic Acid On Prolactin Hyperactivity And Its Related Mechanism

Prolactin(PRL),a polypeptide hormone,is mainly synthesized and secreted from lactotroph cells of the anterior pituitary gland,the major functions of which are to regulate reproduction,lactation,and maternal behavior.Hyperprolactinemia(hyperPRL),a clinical hypothalamichypophysis disorder,is defined as an abnormally high level of PRL in the blood(>25 ng/ml for women and >20 ng/ml for men)and is a notable adverse side effect of antipsychotic therapies.Amenorrhoea,galactorrhea,sexual impairment,and infertility have also been observed in patients with hyper PRL.The antipsychotic-induced elevation of PRL secretion is related to acute and chronic dopamine inhibition.Although some dopamine agonists such as bromocriptine(BMT)can be administered if high PRL conditions do not improve after the reduction of antipsychotic doses,the associated adverse side effects are a greater risk than hyperPRL itself.There is a need for the development of new treatment strategies aimed at reducing the risk of hyperPRL.Natural products have become among the most promising alternative therapies because they have therapeutic potency and fewer adverse effects than standard therapies.Liquorice and its components are widely used as a conditioning and flavoring agent in treatments for various inflammatory diseases.The major active ingredient is 18β-glycyrrhetinic acid(GA),which has anti-inflammatory,anti-ulcer,anti-viral,antioxidant,and hepatoprotective effects.For example,GA exerts hepatoprotective effects against cyclophosphamide via the activation of Nrf2 and PPAR.We successfully confirmed that GA induces apoptosis in pituitary adenoma cells via ROS/MAPKs dependent mitochondria mediated pathways.The encouraging results obtained in clinical studies and animal models showed that Peony-Glycyrrhiza Decoction made from Paeonia and Glycyrrhiza radices suppresses PRL hyperactivity associated with D2 receptors,DAT,and other sexual hormones.Except for the hypothalamic dopaminergic neuronal system,other neuromodulators are considered to be involved in the regulation of PRL secretion.As reported previously,serotonin(5-HT),acts directly on pituitary PRL-secreting cells orindirectly at the hypothalamic level by disinhibiting the dopaminergic tone.It is known that serotonin affects prolactin levels through the action of prolactin-releasing factors(PRFs),including oxytocin and vasoactive intestinal peptide(VIP).Serotoninergic stimulation of forebrain c-aminobutyric acid(GABA)interneurons,which express the 5HT1 A membrane receptor,results in an inhibition of tuberoinfundibular dopaminergic(TIDA)neurons,releasing the tonic inhibition of PRL secretion.The serotoninergic neurons project from the dorsal raphe nucleus to the medial basal hypothalamus,exerting their action via 5-HT1 A and 5-HT2A/C receptors(5-HT2A/CR).GA treatment for 24 h inhibited PRL synthesis and secretion in MMQ cells and cultured pituitary cells in a dose-dependent fashion;but this effect was not reproduced in GH3 cells that lack the expression of functional dopamine D2 receptors.GA suppressed elevated PRL level and growth hormone,and normalized several sex hormones in a rat model of hyperPRL,produced by repeated injection of the dopamine blocker metoclopramide.GA also modulated the expression 5-HT1 A and5-HT2 A receptors in both in vivo and in vitro models.These results indicate that GA is effective in suppressing PRL hyperactivity caused by the blockade of dopamine D2 receptors.This suppressive effect of GA may be related to its modulation of the serotonergic system.The results provide psychopharmacological evidence for the anti-hyperPRL effects of GA as a potential therapeutic agent for hyperPRL,and offer new insight into the mechanisms associated with the central regulation of PRL secretion.