17β-Estradiol as a Neuroprotective Agent

Prókai-Tátrai, Katalin; Prókai, László

doi:10.5772/intechopen.72682

Cited by 6 publications

(12 citation statements)

References 109 publications

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“…Besides the already-mentioned thermoregulation, estrogens’ numerous beneficial actions in the CNS also include enhancing learning and memory and stabilizing mood, as well as protection against a wide variety of noxious stimuli leading to neurodegenerative processes [26,27,28]. The latter is especially important, as neuroprotection of the CNS is clearly a pressing unmet medical need.…”

Section: Estrogens As Cns Agentsmentioning

confidence: 99%

“…The latter is especially important, as neuroprotection of the CNS is clearly a pressing unmet medical need. The pathophysiology of neurodegeneration is complex and multi-factorial in nature; therefore, development of pleiotropic, broad-spectrum neuroprotective agents impacting multiple mechanisms rather than a single druggable target is highly desired [26]. Estrogens, especially E2, possess such therapeutic properties and, therefore, are ideally suited as broad-spectrum neuroprotectants.…”

Section: Estrogens As Cns Agentsmentioning

confidence: 99%

“…Estrogens, especially E2, possess such therapeutic properties and, therefore, are ideally suited as broad-spectrum neuroprotectants. The beneficial effects of estrogens on neuronal health come from a synergistic combination of genomic and non-genomic actions [26] that are not restricted to the brain but also important in ocular neuroprotection [13]. These benefits are many, and include prevention and reduction of inflammation, stabilization of mitochondrial membrane potential, elimination of free radicals and, thus, reduction of oxidative stress — all are critical contributors to collectively thwart both the initiation and progression of neuronal cell death [26].…”

Section: Estrogens As Cns Agentsmentioning

confidence: 99%

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

Prókai-Tátrai

Prókai

2019

Molecules

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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.

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Section: Estrogens As Cns Agentsmentioning

confidence: 99%

Section: Estrogens As Cns Agentsmentioning

confidence: 99%

Section: Estrogens As Cns Agentsmentioning

confidence: 99%

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

Prókai-Tátrai

Prókai

2019

Molecules

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“…This condition requires chronic treatments, and therefore, considerations for therapeutic safety are especially important [ 10 ]. It has been generally accepted that the broad-spectrum neuroprotection exerted by E2 is owing to a synergistic combination of its non-genomic and genomic actions [ 11 , 12 ]. The latter involves the nuclear estrogen receptors (ERα and ERβ) expressed throughout the eye including the retina [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug

et al. 2020

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The purpose of this study was to explore retina-targeted delivery of 17β-estradiol (E2), a powerful neuroprotectant, by its bioprecursor prodrug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) administered as eye drops in animal models. Compared to the parent hormone, DHED displayed increased transcorneal flux ex vivo both with and without the presence of 2-hydroxypropyl-β-cyclodextrin used as a penetration-enhancing excipient in rat, rabbit, and pig. In vitro, the prodrug also showed facile bioactivation to E2 in the retina but not in the cornea. After topical administration to rats and rabbits, peak DHED-derived E2 concentrations reached 13 ± 5 ng/g and 18 ± 7 ng/g in the retina of female rats and rabbits, respectively. However, the prodrug remained inert in the rest of the body and, therefore, did not cause increase in circulating hormone concentration, as well as wet uterine and anterior pituitary weights as typical markers of E2′s endocrine impact. Altogether, our studies presented here have demonstrated the premise of topical retina-selective estrogen therapy by the DHED prodrug approach for the first time and provide compelling support for further investigation into the full potential of DHED for an efficacious and safe ocular neurotherapy.

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“…It seems that 17β-estradiol, directly and indirectly, decreases the responses to glutamate activation via the receptor or other mediator levels of the signaling pathway (Weiss et al, 2002). Thus, a neuroprotective activity has been suggested for 17β-estradiol, among neurodegenerative conditions (Platania et al, 2005; Prokai-Tatrai & Prokai, 2018).…”

Section: Discussionmentioning

confidence: 99%

Sex Differences and Role of Gonadal Hormones on Glutamate Level, After Spinal Cord Injury in Rats: A Microdialysis Study

Samandari

Hassanpour-Ezatti

Fakhri

et al. 2018

Basic Clin. Neurosci. J.

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Introduction: Sex differences in outcomes of Spinal Cord Injury (SCI) suggest a sex-hormone-mediated effect on post-SCI pathological events, including glutamate excitotoxicity. This study aimed to investigate the importance of gonadal hormones on glutamate release subsequent to SCI in rats. Methods: After laminectomy at T8–T9, an electrolytic lesion was applied to the spinothalamic tracts of male and female rats. Using spinal microdialysis, we assessed glutamate levels at the site of lesion in both intact and gonadectomized rats for 4 hours. In this way, we examined the sex differences in the glutamate concentrations. Results: The peak retention time of glutamate level was 10.6 min and spinal glutamate concentration reached a maximum level 40 min following SCI. In male SCI rats, gonadectomy caused a significant elevation of glutamate level (P<0.001) following injury which was maximum 40 min post-SCI as well. However, no significant alterations were seen in gonadectomized female rats. Conclusion: The significant differences in glutamate levels between both intact and gonadectomized SCI male and female rats show the sex-hormone-related mechanisms underlying the molecular events in the second phase of SCI. It seems that the role of male gonadal hormones to prevent glutamate excitotoxicity is more prominent. The exact mechanisms of these hormones on the functional recovery after SCI should be clarified in further studies.

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17β-Estradiol as a Neuroprotective Agent

Cited by 6 publications

References 109 publications

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

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

Retina-Targeted Delivery of 17β-Estradiol by the Topically Applied DHED Prodrug

Sex Differences and Role of Gonadal Hormones on Glutamate Level, After Spinal Cord Injury in Rats: A Microdialysis Study

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