After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-DHT, a metabolite that is not converted to estrogens, as already mentioned, and blocked by the androgen receptor antagonist flutamide. In demyelinating disorders such as MS and its experimental models, the neuroprotective effects of androgens have been well documented 31,134,135,136. In its target cells, testosterone can bind directly to AR or is converted by the 5α-reductase enzymes to 5α-DHT, which has a greater activity at the receptor level and cannot be converted to estrogens. Androgens, especially testosterone and its metabolite 5α-DHT, play a critical role in sexual development and function. Using cerebellar slice cultures from postnatal day seven rats and mice, we demonstrated the role of progesterone in oligodendrocyte maturation and developmental myelination 19,108.
There was also a marked increase in the relapse rate during the first three months after delivery, after the drop in sex steroid levels . These observations suggest that differences in circulating sex hormones could play a role in its development. Interestingly, the enzyme 5 alpha-reductase, involved in the metabolism of testosterone to its more potent form dihydro-testosterone, is mainly concentrated in the white matter. However, more in-depth studies and comparisons between species are needed to better define this concept. Therefore, immediate and active therapeutic interventions that inhibit the loss of oligodendrocytes may be crucial to promote remyelination. However, whether spared mature oligodendrocytes contribute to remyelination remains a topic of debate.
Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well. Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise-induced neurogenesis and improvements in cognitive function. Mice born without the ability to make BDNF have developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development. • Using brain stimulation techniques such as Transcranial Magnetic Stimulation (TMS) or Deep Brain Stimulation (DBS) to treat sexual disorders .
This TSPO ligand was also able to exert a beneficial effect on morphological parameters of the sciatic nerve of aged male rats by increasing the total number of myelinated fibers and decreasing the percentage of fibers with myelin decompaction . Beneficial effects by midazolam on behavior deficits have been also reported in an experimental model of post-traumatic stress disorder . Indeed, TSPO ligands, like for instance XBD 173 or etifoxine, increase neurosteroidogenesis and exert anxiolytic effects without causing the classical side effects (i.e., sedation or tolerance) of benzodiazepines . As reported in the CNS, activation of TSPO or liver X receptor (LXR) may be considered the basis for therapeutic strategy in the neurodegenerative and psychiatric field. Moreover, DHEA prevents not only neuronal but also vascular dysfunction in this experimental model . Interestingly, DHEA exerts sex-depending neuroprotective actions, with more potent effects in female animals . Similar neuroprotective effects are also exerted by treatment with T or its derivatives as well as by DHEA .
One of the primary ways BDNF can modulate NMDA receptor activity is through phosphorylation and activation of the NMDA receptor one subunit, particularly at the PKC Ser-897 site. Following exposure to an enriched environment, BDNF and NR1 phosphorylation levels are upregulated simultaneously, probably because BDNF is capable of phosphorylating NR1 subunits, in addition to its many other effects. NMDA receptor activation is essential to producing the activity-dependent molecular changes involved in the formation of new memories.
Besides providing lipids for the synthesis of myelin sheaths during development, astrocytes contribute to the development of oligodendrocytes as well as to myelination and remyelination processes. The different developmental stages of the oligodendrocyte lineage have been well characterized based on the following expression of lipid and protein antigens 3,4,18. Transitioning from OPCs to mature oligodendrocyte is mainly a later embryonic or early postnatal event; the process is complete by P60 in mice and by adulthood in humans. A rough estimate shows that an adult brain consists of 5–10% of these OPCs distributed throughout the brain 13,14.
As for astrocytes, microglia/macrophages play a crucial role in both developmental and repairing oligodendrogenesis and myelination. Astrocytes contribute to the formation and functioning of the blood–brain barrier (BBB) and the disruption of BBB seems to be an essential step in triggering CNS inflammation and subsequent tissue injury . They produce several growth factors, such as platelet-derived growth factor, brain-derived neurotrophic factor or ciliary neurotrophic factor to promote OPC development and CNS myelination and they aid in the removal of myelin debris 20,21,22,23,24,25. Astrocytes form stellate cells with multiple processes and occupy about 25% to 50% of brain volume.
Thus, lipids are essential for the structure of myelin and the change in their composition, during the course of diseases such as MS, leads to the destabilization and the breakdown of myelin . In a pioneering study, Kahn and Morell have reported that the majority of brain polyphosphoinositides are related to myelin metabolism . While the protein composition differs substantially in peripheral and central nervous system myelin, lipid species are remarkably similar. In the CNS, cells that synthesize myelin are oligodendrocytes and the major myelin proteins are MBP and PLP, which contribute to the compaction of myelin.
Numerous observational studies have linked anti-androgen therapy, commonly used in prostate cancer, with an elevated risk of AD and other neurodegenerative diseases, like Parkinson disease . Overall, the connection between androgens, ARs, and ALS remains complex and unclear, with evidence suggesting that sex-based differences might play a role 30–32. However, experiments with neural AR deletion or overexpression in SOD1-G93 A mice showed no significant impact on disease progression. Therefore, studies have explored androgen antagonists as a potential therapeutic strategy to modify disease progression. It fully manifests in men, typically in their third to fifth decades of life, while women with homozygous mutation have a subclinical disease course, indicating a role of androgen in pathogenesis as opposed to solely the mutant AR . The following section highlights our current understanding of the role of androgens in certain CNS disorders and their potential therapeutic role across neurological domains.

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