Network pharmacology and topological analysis on tibolone metabolites and their molecular mechanisms in traumatic brain injury

Traumatic brain injury (TBI) is a pathology of great social impact, affecting millions of people worldwide.  Despite the scientific advances to improve the management of TBI in recent years, we still do not have a specific  treatment that controls the inflammatory process after mechanical trauma. The discovery and implementation of  new treatments is a long and expensive process, making the repurpose of approved drugs for other pathologies a  clinical interest. Tibolone is a drug in use for the treatment of symptoms associated with menopause and has been  shown to have a broad spectrum of actions by regulating estrogen, androgen and progesterone receptors, whose  activation exerts potent anti-inflammatory and antioxidant effects. In the present study, we aimed to investigate  the therapeutic potential of the tibolone metabolites 3α-Hydroxytibolone, 3β-Hydroxytibolone, and Δ4-Tibolone  as a possible therapy in TBI using network pharmacology and network topology analysis. Our results demonstrate that the estrogenic component mediated by the α and β metabolites can regulate synaptic transmission and  cell metabolism, while the Δ metabolite may be involved in modulating the post-TBI inflammatory process. We  identified several molecular targets, including KDR, ESR2, AR, NR3C1, PPARD, and PPARA, which are known to  play critical roles in the pathogenesis of TBI. Tibolone metabolites were predicted to regulate the expression of  key genes involved in oxidative stress, inflammation, and apoptosis. Overall, the repurposing of tibolone as a  neuroprotective treatment for TBI holds promise for future clinical trials. However, further studies are needed to  confirm its efficacy and safety in TBI patients.