YK11 induces oxidative stress and mitochondrial dysfunction in hippocampus: The interplay between a selective androgen receptor modulator (SARM) and exercise

Abstract

Our study investigates potential neurochemical effects of (17α,20E)− 17,20-[(1-methoxyethylidene)bis(oxy)]− 3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), a selective androgen receptor modulator (SARM), in the rat hippocampus, with a particular focus on oxidative stress and mitochondrial function, as well as its potential effect when combined with exercise (EXE). To validate YK11's anabolic potential, we performed a molecular docking analysis with the androgen receptor (AR), which showed high affinity with YK11, highlighting hydrogen interactions in Arg752. During the five-week protocol, we divided male Wistar rats into the following groups: Control, YK11 (0.35 g/kg), EXE (swimming protocol), and EXE+YK11. The administration of YK11 resulted in alterations in the endogenous antioxidant system, promoting increased oxidative stress and proteotoxic effects, impairing all mitochondrial function markers in the hippocampus. In contrast, EXE alone had a neuroprotective effect, increasing antioxidant defenses and improving mitochondrial metabolism. When combined, EXE+YK11 prevented alterations in some mitochondrial toxicity markers, including MnSOD/SOD2 and MTT reduction capacity, but did not reverse YK11's neurochemical impairments regarding increased oxidative stress and dysfunction of the mitochondrial respiratory chain and mitochondrial dynamics regulatory proteins in the hippocampus. In summary, our study identifies important pathways of YK11's hippocampal effects, revealing its potential to promote oxidative stress and mitochondrial dysfunction, suggesting that the administration of YK11 may pose potential neurological risks for athletes and bodybuilders seeking to enhance performance. These findings highlight the need for further research to assess the safety and efficacy of YK11 and SARM use in humans.