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Introduction: Premenstrual dysphoric disorder (PMDD) is a cyclical mooddisorder that severely affects the daily life of women of reproductive age.Most of the medications being used clinically have limitations such as lowefficacy, side effects, and high cost, so there is an urgent need to discoversafer and more effective medications. Rutin is a natural flavonol glycoside withvarious pharmacological properties including antidepressant. The study of theefficacy and mechanism of action of rutin in PMDD-depressed subtype modelrats plays an important role in the discovery of new drugs for thetreatment of PMDD.

Methods: Binding of rutin to gamma-aminobutyric acid type A receptors (GABAAreceptors) was probed using molecular docking, microscale thermophoresis,radioactive receptor ligand binding assay and cell membrane clamp experiment.Behavioral tests in mice were performed to screen the optimal dose of rutin.Behavioral tests were performed to evaluate the effects of rutin on depressedmood, memory impairment, and social impairment in PMDD-depressed subtypemodel rats. HE staining and Golgi staining were performed to observe theneuronal damage in rat hippocampus. UHPLC-MS/MS targeted metabolomicswas performed to detect the changes of neurotransmitter content in rathippocampus. PCR array to detect the effect of rutin on mRNA expression ofGABAA receptor partial subunits in rat hippocampus.

Results: The docking score of rutin with the GABAA receptor benzodiazepine site was −11.442 and the gliding score was −11.470. The Kd of rutin with the GABAA receptor (α1β2γ2) was 1.17 ± 0.89 μM. Rutin competed with [H3 ]-flunitrazepam for the GABAA receptor benzodiazepine site and inhibited the inward flow of chloride ions (P < 0.05). In PMDD-depressed subtype rats, rutin alleviated depressed mood, memory impairment and social impairment, ameliorated hippocampal neuronal damage and reduces gamma-aminobutyric acid (GABA) and acetylcholine (ACh) levels (P < 0.05). Moreover, we found that rutin did not affect the relative mRNA expression of GABAA receptor subunits in rat hippocampus.

Discussion: Overall, rutin alleviated depressed mood, memory impairment andsocial impairment in PMDD-depressed subtype rats, which may be related tobinding to GABAA receptor benzodiazepine sites, inhibiting chloride ions inwardflow, ameliorating hippocampal neuronal damage and reducing GABA and AChlevels. The results of this study provide an experimental basis and scientificevidence for the development of new drugs for the treatment of PMDD.