Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology.

ABSTRACT

BACKGROUND: Traumatic Brain Injury (TBI) has long-term devastating effects for which there is no accurate and effective treatment for inflammation and chronic oxidative stress. As a disease that affects multiple signalling pathways, the search for a drug with a broader spectrum of pharmacological action is of clinical interest. The fact that endocrine disruption (e.g hypogonadism) has been observed in TBI patients suggests that endogenous therapy with testosterone, or its more androgenic derivative, dihydrotestosterone (DHT), may attenuate, at least in part, the TBI-induced inflammation, but the underlying molecular mechanisms by which this occurs are still not completely clear. AIMS AND METHODS: In this study, the main aim was to investigate proteins that may be related to the pathophysiological mechanism of TBI and also be pharmacological targets of DHT in order to explore a possible therapy with this androgen using network pharmacology. RESULTS AND CONCLUSIONS: We identified 2.700 proteins related to TBI and 1.567 that are potentially molecular targets of DHT. Functional enrichment analysis showed that steroid (p-value 2.1-22), lipid metabolism (p-value 2.8-21) and apoptotic processes (p-value 5.2-21) are mainly altered in TBI. Furthermore, being mitochondrion an organelle involved on these molecular processes we next identified that out of 32 mitochondrial-related proteins 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), peroxisome proliferator activated receptor gamma (PPGARG) and prohibitin are those found highly regulated in the network and potential targets of DHT in TBI. In conclusion, the identification of these cellular nodes may prove to be essential as targets of DHT for therapy against post-TBI inflammation.