Exploring the anti-osteoporosis potential of Petroselinum crispum (Mill.) fuss extract employing experimentally ovariectomized rat model and network pharmacology approach.

One of the most prevalent secondary osteoporosis is ovariectomy-induced osteoporosis. Parsley (Petroselinum crispum) has potent estrogenic and antioxidant properties and was used traditionally in the treatment of amenorrhea and dysmenorrhea. The present study aimed to characterize parsley leaf extract (PLE) employing RP-HPLC-MS-MS/MS-based method and possible protective effect in ovariectomized (OVX)-induced osteoporosis in rats was assessed. Rats were randomly assigned into SHAM group, OVX group, PLE + OVX group (150 mg/kg/day, p.o), and estradiol benzoate (E2) + OVX group (30 μg/kg/day, s.c). After eight weeks following ovariectomy, biomarkers of bone strength, bone resorption, oxidative stress and histopathology were carried out. A network pharmacology approach investigated the key targets and potential mechanisms by of PLE metabolites against osteoporosis using databases: PubChem, BindingDB server, DisGeNET, ShinyGO, and KEGG Pathway. Moreover, FunRich 3.1.3, Cytoscape 3.10.0, and MOE 2019.0102 softwares were used for network pharmacology analysis and molecular docking studies. Flavones and hydroxycinnamic acid derivatives were predominant among 38 metabolites in PLE. It significantly restored bone strength and bone resorption biomarkers, osteocalcin (OST), oxidative stress biomarkers and histopathological alterations. The employed network pharmacology approach revealed that 14 primary target genes were associated with decreasing the severity of osteoporosis. Molecular docking revealed that cGMP-PKG signaling pathway has the highest fold enrichment and its downstream PDE5A. Luteolin, diosmetin, and isorhamnetin derivatives affected mostly osteoporosis targets. PLE exhibited protective action against ovariectomy-induced osteoporosis in rats and may be a promising therapy for premenopausal bone loss. cGMP-PKG signaling pathway could be a promising target for PLE in treating osteoporosis.