A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy

Abstract

Beneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.

Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

“…EE treatment at this high dose (1 mg/kg body weight), on the other hand, produced an approximate 50% decrease in TST increase at this time point compared to the control group upon Nlx challenge, while an approximate 25% decrease was observed in this measure Importantly, no increase in circulating E 2 concentrations were detected from serum samples (also collected after the animals were sacrificed) compared to the untreated control levels that were at or below our assay's ≥10 pg/mL limit of detection. These findings confirmed that DHED administration to ORDX rats also produced central formation of E 2 without peripheral hormonal liability, similar to OVX rats [16][17][18][19]. In contrast, the clinically used synthetic estrogen (EE, employed here as positive control) produced serum levels reaching a maximum concentration of 840 ± 230 pg/mL EE even after a single 100 µg/kg p.o.…”

“…To overcome these obstacles, we have developed a CNS-selective estrogen therapy and unequivocally showed the target-selective formation of E 2 from a unique bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), as shown in Figure 1 [16][17][18][19]. Therein, DHED treatment efficiently ameliorated tail skin temperature (TST) elevation in an ovariectomized (OVX) rat model of hot flushes without the increase in circulating serum E 2 level and associated adverse estrogenic effects in the periphery [16,17].…”

17β-Estradiol Delivered in Eye Drops: Evidence of Impact on Protein Networks and Associated Biological Processes in the Rat Retina through Quantitative Proteomics

“…Many potential associations and pathways captured by Figures 1 and 2, as well as by the additional protein interaction networks of Figures S2-S17 have not been explored by research specifically addressing the retinal milieu. However, we anticipate that systems insights made possible by our results will guide future hypothesis-driven experiments focusing on the "estrogenic retina" [17,18], including potential therapeutic application of estrogens as topically delivered broad-spectrum retina neuroprotectants [20,69].…”

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

“…In particular, from our point of view, such research will lead toward novel treatments of neurodegeneration, as related to brain disease and brain injury. On a more general base, the various genomic and non-genomic functional pathways, and mechanisms under estrogen control, appear to make estrogens and SERMs potential broad-spectrum agents for treatment of brain injury and brain disease [ 6 ].

Figure 3 A generalized scheme of pathways, whereby SERMs, including raloxifene, may provide neuroprotection and curation in response to brain disease and brain injury.

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“…Furthermore, raloxifene acts as an estrogen agonist on bone and lipid metabolism and as an estrogen antagonist for reproductive tissues [ 2 , 3 ]. Animal studies suggest that raloxifene may affect brain function as well, although the effects of raloxifene on the human brain remain to be established in more detail [ 4 , 5 , 6 ].…”