Abstract Title

Non-Feminizing Estrogens Do Not Exhibit Antidepressant-Like Activity

RAD Assignment Number

1509

Presenter Name

Vien Nguyen

Abstract

Short description:

In this exploratory lead compound evaluation, we aimed at addressing the utility of two non-feminizing estrogens, specifically 2-adamantyl-17β-estradiol (Ada-E2) and 2-adamantylestrone (Ada-E1), in a well-established animal model of depression-like behavior precipitated by estrogen deprivation.

Purpose:

To evaluate non-feminizing estrogens in fulfilling their overall premise for the treatment of climacteric symptoms.

Methods:

Mice were divided into six animals per treatment group. Test agents were dissolved either in corn oil vehicle or in 30% v/v aqueous 2-hydroxypropyl-β-cyclodextrin. The well-known antidepressant amitriptyline, as a reference standard, was used at 15 mg/kg dose, while the estrogen receptor (ER) antagonist fulvestrant was used at 4 mg/kg dose. The control groups received vehicle only. Test compounds in corn oil vehicle were administered subcutaneously (s.c.), while those in HPβCD were given intravenously (i.v.). Each group of animals was treated daily for five consecutive days injecting the test agents 100 µg/kg or 500 µg/kg doses on each day. Antidepressant-like activity were evaluated 30 min after the last injection using the Porsolt swim test (PST). The immobility time (in seconds, defined as the duration of floating motionless after the cessation of struggling and making only movements necessary to keep the head above the water) was recorded for 6 min simultaneously by a trained observer. Drug-likeness was evaluated via the online Osiris Property Explorer. Antioxidant potencies were determined experimentally by the ferric thiocyanate and thiobarbituric acid reactive substances methods.

Results:

Adding the bulky Ada to the already lipophilic E2 and E1 brought about further increase in the lipophilicity (logP) by >2 log units. This increase was probably the most profound contributor to their unfavorable drug-likeness score. In agreement with our earlier quantitative structure–activity relationship study, our experimental assessment also supported that an increase in logP enhances antioxidant effect of estrogen-derived synthetic steroids and their analogs. However, while E2 and E1 did show significant reduction of immobility time in the mice PST, Ada-E2 and Ada-E1 failed to manifest activity in this paradigm (Immobility time is associated with depression-like behavior). Therefore, ERs play a pivotal role in triggering depression-like behavior in estrogen-deprived animals and non-feminizing estrogen offers no remedy for this symptom.

Conclusions:

Our lead evaluation has confirmed that both genomic and non-genomic mechanisms are required for broad-spectrum estrogen neuroprotection and treatment of menopausal symptoms. Therefore, non-feminizing estrogens such as Ada-E2 and Ada-E1 are not appropriate for the management of symptoms that manifest through ERs such as depression.

Presentation Type

Poster

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Non-Feminizing Estrogens Do Not Exhibit Antidepressant-Like Activity

Short description:

In this exploratory lead compound evaluation, we aimed at addressing the utility of two non-feminizing estrogens, specifically 2-adamantyl-17β-estradiol (Ada-E2) and 2-adamantylestrone (Ada-E1), in a well-established animal model of depression-like behavior precipitated by estrogen deprivation.

Purpose:

To evaluate non-feminizing estrogens in fulfilling their overall premise for the treatment of climacteric symptoms.

Methods:

Mice were divided into six animals per treatment group. Test agents were dissolved either in corn oil vehicle or in 30% v/v aqueous 2-hydroxypropyl-β-cyclodextrin. The well-known antidepressant amitriptyline, as a reference standard, was used at 15 mg/kg dose, while the estrogen receptor (ER) antagonist fulvestrant was used at 4 mg/kg dose. The control groups received vehicle only. Test compounds in corn oil vehicle were administered subcutaneously (s.c.), while those in HPβCD were given intravenously (i.v.). Each group of animals was treated daily for five consecutive days injecting the test agents 100 µg/kg or 500 µg/kg doses on each day. Antidepressant-like activity were evaluated 30 min after the last injection using the Porsolt swim test (PST). The immobility time (in seconds, defined as the duration of floating motionless after the cessation of struggling and making only movements necessary to keep the head above the water) was recorded for 6 min simultaneously by a trained observer. Drug-likeness was evaluated via the online Osiris Property Explorer. Antioxidant potencies were determined experimentally by the ferric thiocyanate and thiobarbituric acid reactive substances methods.

Results:

Adding the bulky Ada to the already lipophilic E2 and E1 brought about further increase in the lipophilicity (logP) by >2 log units. This increase was probably the most profound contributor to their unfavorable drug-likeness score. In agreement with our earlier quantitative structure–activity relationship study, our experimental assessment also supported that an increase in logP enhances antioxidant effect of estrogen-derived synthetic steroids and their analogs. However, while E2 and E1 did show significant reduction of immobility time in the mice PST, Ada-E2 and Ada-E1 failed to manifest activity in this paradigm (Immobility time is associated with depression-like behavior). Therefore, ERs play a pivotal role in triggering depression-like behavior in estrogen-deprived animals and non-feminizing estrogen offers no remedy for this symptom.

Conclusions:

Our lead evaluation has confirmed that both genomic and non-genomic mechanisms are required for broad-spectrum estrogen neuroprotection and treatment of menopausal symptoms. Therefore, non-feminizing estrogens such as Ada-E2 and Ada-E1 are not appropriate for the management of symptoms that manifest through ERs such as depression.