Selective Androgen Receptor Modulators (SARMs) have attracted significant attention in the realm of performance enhancement and muscle development [1]. These compounds, first identified during drug development trials in the early 1990s, are viewed as a potentially safer and less harmful alternative to anabolic androgenic steroids (AAS) [2]. The perceived safety of SARMs primarily stems from their selective action, which targets specific parts of the body, like striated muscles [1,3] in contrast to AAS (Arnés and Casares, 2022), which exert widespread effects on various tissues, including the central nervous system (CNS) [4,5] and the reproductive system [6].

A compelling example is (17α,20E)-17,20,-[(1-methoxyethylidene)bis-(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester, commonly referred as YK11 [7]. This distinctive compound operates in a manner akin to a SARM and is classified as part of that class, despite possessing the chemical structure and backbone of an AAS [7,8]. YK11, acclaimed for its capacity to stimulate rapid muscle growth, is characterized as a steroid SARM, functioning as a partial Androgen Receptor (AR) agonist [9,10]. Also, it is known to act as an indirect inhibitor of myostatin, a protein that limits muscle mass fast development, thereby fostering a significant enhancement in the hypertrophy and hyperplasia of muscle microfibrils through positive signaling in the synthesis of the follistatin protein [9,11], particularly when coupled with regular exercise [11]. For these reasons, YK11 is often considered the most potent of the SARMs [10,12].

The misuse of these substances, particularly by athletes aiming for performance enhancement, is a significant concern. The intake of high doses, often classified as anabolic, can lead to severe side effects and present considerable health risks [13,14]. While AAS adverse effects are well-documented, the full scope of SARMs effects remains unclear. This knowledge gap is troubling, given the substantial increase in demand, reaching 115 million by 2021 [15]. Significantly, the trend in SARMs usage mirrors that of AAS, with an annual increase of approximately 3.3% [14], exhibiting a higher prevalence among men than women, with a ratio of 2.6:1 concerning the use of ergogenic substances [16]. This escalation in usage raises concerns, particularly among male users, highlighting the pressing need to address the implications of these substances. Despite their appeal for performance enhancement, SARMs are banned by the World Anti-Doping Agency (WADA/USADA) due to their ergogenic potential [17]. Although the Food and Drug Administration (FDA) has not approved SARMs for human use, athletes easily access and often dangerously consume these substances [18].

In this sense, it is crucial to comprehend the potential risks tied to such usage patterns to establish safe practices and regulatory measures, with a specific emphasis on their neurotoxic effects, as observed in AAS side effects [19,20]. In this context, Dahleh et al. [11] have shown that YK11, when administered at high anabolic doses, can escalate oxidative stress, and induce dysfunction in mitochondrial metabolism within the hippocampus. Despite the evident adverse impact on the neurochemistry of the rat hippocampus, a substantial suppression of myostatin was observed in the gastrocnemius, particularly when YK11 was combined with regular exercise. This highlights a clear relation and involvement between anabolic dose and toxic effects, a practice commonly undertaken by both amateur and professional athletes. Of note, this happens irrespective of simultaneous engagement in concurrent exercise, a factor broadly acknowledged as a neuroprotective agent [21,22].

The emergence of SARMs, particularly YK11, has ushered in new possibilities for muscle growth and fat loss, especially when incorporated into regular exercise regimes [1]. However, the dearth of comprehensive research into its metabolism and potential side effects, including neurotoxicity, necessitates a prudent approach to its usage. To address these concerns, we employed a systematic approach utilizing in silico, in vivo, and ex vivo models. This comprehensive strategy was chosen as data obtained from these three models converge to yield consistent results regarding the primary effects of YK11 on the CNS. Physiologically Based Pharmacokinetic (PBPK) modeling was chosen in our study for its capacity to predict the remarkable brain permeability of YK11, shedding light on potential interactions between drugs and the CNS [23]. Also, molecular docking and dynamics were utilized to explore YK11 inhibitory effects on 5-alpha-reductase type II (5αR2), providing insights into its cellular bioavailability [24], as well as its investigation into the affinity for AR in the hippocampus, along with its impact on memory mechanisms and related-behaviors, inflammation, and apoptosis, remarkable effects on CNS by AAS abuse [19,25]. This broadened our understanding of YK11 potential selectivity for the hippocampal AR and its implications for tissue metabolism. In this context, our aim was to clarify the potential neurotoxic mechanisms linked to the metabolism of YK11, to understand how the presence of this compound in the CNS can influence and modify the intricate neurochemical mechanisms inherent to the hippocampus.