Inhibition of brain 17β-estradiol synthesis by letrozole induces cognitive decline in male and female rats

2020 ◽  
Vol 175 ◽  
pp. 107300
Author(s):  
Ladan Marbouti ◽  
Maryam Zahmatkesh ◽  
Esmail Riahi ◽  
Seyed Shahabeddin Sadr
2019 ◽  
Author(s):  
Paula Duarte-Guterman ◽  
Stephanie E. Lieblich ◽  
Wansu Qiu ◽  
Jared E.J. Splinter ◽  
Kimberly A. Go ◽  
...  

AbstractOxytocin regulates social behaviours, pair bonding and hippocampal neurogenesis but most studies have used adult males. Our study investigated the effects of oxytocin on social investigation and adult hippocampal neurogenesis in male and female rats. Oxytocin has poor penetration of the blood-brain barrier, therefore we tested a nanoparticle drug, TRIOZANTM (Ovensa Inc.), which permits greater blood-brain-barrier penetration. Adult male and female rats were injected daily (i.p.) for 10 days with either: oxytocin in PBS (0.5 or 1.0 mg/kg), oxytocin in TRIOZANTM (0.5 or 1.0 mg/kg), or vehicle (PBS) and tested for social investigation. Oxytocin decreased body mass and increased social investigation and number of oxytocin-immunoreactive cells in the supraoptic nucleus (SON) of the hypothalamus in male rats only. In both sexes, oxytocin decreased the number of immature neurons (doublecortin+ cells) in the ventral hippocampus and reduced plasma 17β-estradiol levels in a dose- and delivery-dependent way. Oxytocin in TRIOZANTM reduced sedation observed post-injection and increased some central effects (oxytocin levels in the hypothalamus and ventral hippocampus neurogenesis) relative to oxytocin in PBS indicating that the nanoparticle may be used as an alternative brain delivery system. We showed that oxytocin has sex-specific effects on social investigation, body mass, sedation, and the oxytocin system. In contrast, similar effects were observed in both sexes in neurogenesis and plasma 17β-estradiol. Our work suggests that sex differences in oxytocin regulation of brain endpoints is region-specific (hypothalamus versus hippocampus) and that oxytocin does not promote social investigation in females.


2009 ◽  
Vol 296 (5) ◽  
pp. H1577-H1585 ◽  
Author(s):  
Baojian Xue ◽  
Daniel Badaue-Passos ◽  
Fang Guo ◽  
Celso E. Gomez-Sanchez ◽  
Meredith Hay ◽  
...  

The present study tested the hypotheses that male and female rats respond differently to subcutaneous infusions of aldosterone (Aldo; 1.8 μg·kg−1·h−1, 1% NaCl to drink; 28 days) and that central estrogen plays a protective role against the development of hypertension. In rats with blood pressure (BP) and heart rate (HR) measured by Data Sciences International telemetry, chronic Aldo/NaCl treatment induced a greater increase in BP in males (Δ25.4 ± 2.4 mmHg) than in females (Δ7.1 ± 2.2 mmHg). Gonadectomy augmented Aldo/NaCl-induced hypertension in females (Δ18.2 ± 2.0 mmHg) but had no effect in males (Δ23.1 ± 2.9 mmHg). Immunohistochemistry for Fra-like activity was higher in the paraventricular nucleus of intact males, castrated males, and ovariectomized (OVX) females compared with intact females after 28 days of Aldo/NaCl treatment. In intact males, central 17β-estradiol (E2) inhibited the Aldo/NaCl increase in BP (Δ10.5 ± 0.8) compared with that in central vehicle plus systemic Aldo/NaCl (Δ26.1 ± 2.5 mmHg) rats. Combined administration of E2 and estrogen receptor antagonist ICI182780 (ICI) blocked the protective effect of E2 (Δ23.2 ± 2.4 mmHg). In intact females central, but not peripheral, infusions of ICI augmented the Aldo/NaCl (Δ20.4 ± 1.8 mmHg) BP increase. Finally, ganglionic blockade after Aldo infusions resulted in a smaller reduction in BP in intact females (−23.9 ± 2.5 mmHg) and in central estrogen-treated males (−30.2 ± 1.0 mmHg) compared with other groups (intact males, −39.3 ± 3.4; castrated males, −41.8 ± 1.9; intact males with central E2 + ICI, −42.3 ± 2.1; OVX females, −40.3 ± 3.3; and intact females with central ICI, −39.1 ± 1.3 mmHg). Chronic Aldo infusion produced increases in NaCl intake and decreases in HR that were both similar in all groups. Taken together, the results indicate that central estrogen plays a protective role in the development of Aldo/NaCl-induced hypertension and that this may result from reduced sympathetic outflow.


Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Lianying He ◽  
Yasir Abdul ◽  
Sarah Jamil ◽  
Maria Fatima Falangola ◽  
...  

Diabetes increases the risk of VCID but underlying reasons remain unclear. We reported that diabetes-mediated early cerebrovascular dysfunction facilitates the entrapment of microemboli (ME) and results in demyelination/neurodegeneration 6 weeks after ME injection in male diabetic but not control rats. Cognitive decline became apparent by week 8 and further amplified by week 12 in diabetes. The goals of the current study were to determine whether ME injection 1) mediates demyelination and cognitive decline in females, 2) activates microglia and promotes inflammation, 3) causes gait abnormalities and 4) mediates changes in cerebral blood flow (CBF) and brain structure as determined by diffusion MRI. Diabetes was induced by a high fat diet and low dose streptozotocin (35 mg/kg) injection in male and female Wistar rats. After 8 weeks onset of diabetes, control and diabetic rats received cholesterol crystal ME (40-70 μm) injection. In study 1, histology was done at week 6 after injection (3000 crystals) to determine early structural changes and cognition was assessed by novel object recognition (NOR) test. In Study 2, MRI, gait (stand on catwalk) and NOR tests were done at baseline and week 8 after injection (6000 crystals) in male rats and will be further monitored at weeks 12 and 16. Diabetic animals developed inflammation, demyelination, and neurodegeneration associated with cognitive decline that was greater than that observed in males (TABLE). In Study 2, initial analyses show higher infarct score and lower CBF after ME injection with no gait pattern change in diabetic male rats. Longitudinal measurements at weeks 12 & 16 will demonstrate the disease progression. These data suggest that 1) endothelial dysfunction renders diabetic animals more susceptible to infarction and subsequent cognitive decline caused by ME, and 2) intervention strategies can be tried in this clinically relevant model of VCID.


2020 ◽  
Vol 10 (1) ◽  
pp. 204589401989859 ◽  
Author(s):  
Yuanjun Shen ◽  
Dmitry A. Goncharov ◽  
Theodore Avolio ◽  
Arnab Ray ◽  
Evelyn Okorie ◽  
...  

Pulmonary arterial hypertension (PAH) is a progressive fatal disease with no cure. Inhibition of integrin-linked kinase (ILK) reverses experimental pulmonary hypertension (PH) in male mice, but its effect on severe experimental PH in either male or female animals is unknown. We examined effects of ILK inhibitor Cpd22 on rats with SU5416/hypoxia-induced PH; treatment was performed at six to eight weeks after PH initiation. Five weeks after PH initiation, male and female rats developed similar levels of PH. Eight weeks after PH induction, vehicle-treated male rats had more severe PH than females. Cpd22-treated males, but not females, showed complete suppression of phospho-Akt in small pulmonary arteries (PAs), significantly lower PA medial thickness and percentage of fully occluded arteries, decreased systolic right ventricle (RV) pressure, PA pressure, RV hypertrophy, RV end-diastolic pressure, and improved RV contractility index compared to vehicle-treated group. Cpd22 suppressed proliferation of human male and female PAH pulmonary artery vascular smooth muscle cell (PAVSMC). 17β-estradiol had no effect as a single agent but significantly attenuated Cpd22-dependent inhibition of proliferation in female, but not male, PAH PAVSMC. Taken together, these data demonstrate that male rats develop more severe PH than females but respond better to Cpd22 treatment by reducing pulmonary vascular remodeling, PH, and RV hypertrophy and improving RV functional outcomes. 17β-estradiol diminishes anti-proliferative effect of Cpd22 in female, but not male, human PAH PAVSMC. These findings suggest potential attractiveness of ILK inhibition to reduce established PH in males and suggest that the combination with estrogen-lowering drugs could be considered to maximize anti-proliferative and anti-remodeling effects of ILK inhibitors in females.


1961 ◽  
Vol 38 (1) ◽  
pp. 50-58 ◽  
Author(s):  
N. E. Borglin ◽  
L. Bjersing

ABSTRACT Oestriol (oestra-1,3,5(10)-triene-3,16α,17β-triol) is a weakly oestrogenic substance which, however, in contrast to what was formerly believed, is of physiological significance. Its effect is localized largely to the uterine cervix and vagina. Clinical experience argues both for and against an effect on the pituitary gland. This investigation is concerned with the morphological changes in the pituitary gland and adrenal cortex of gonadectomized male and female rats after the injection of oestriol. It was found that oestriol has the same type of action on these glands as other oestrogens, but under the experimental conditions used, this effect proved much weaker than that produced by oestradiol (oestra-1,3,5(10)-triene-3,17β-diol).


1973 ◽  
Vol 74 (1) ◽  
pp. 88-104 ◽  
Author(s):  
T. Jolín ◽  
M. J. Tarin ◽  
M. D. Garcia

ABSTRACT Male and female rats of varying ages were placad on a low iodine diet (LID) plus KClO4 or 6-propyl-2-thiouracil (PTU) or on the same diet supplemented with I (control rats). Goitrogenesis was also induced with LID plus PTU in gonadectomized animals of both sexes. The weight of the control and goitrogen treated animals, and the weight and iodine content of their thyroids were determined, as well as the plasma PBI, TSH, insulin and glucose levels. The pituitary GH-like protein content was assessed by disc electrophoresis on polyacrylamide gels. If goitrogenesis was induced in young rats of both sexes starting with rats of the same age, body weight (B.W.) and pituitary growth hormone (GH) content, it was found that both the males and females developed goitres of the same size. On the contrary, when goitrogenesis was induced in adult animals, it was found that male rats, that had larger B.W. and pituitary GH content than age-paired females, developed larger goitres. However, both male and female rats were in a hypothyroid condition of comparable degree as judged by the thyroidal iodine content and the plasma PBI and TSH levels. When all the data on the PTU or KClO4-treated male and female rats of varying age and B.W. were considered together, it was observed that the weights of the thyroids increased proportionally to B.W. However, a difference in the slope of the regression of the thyroid weight over B.W. was found between male and female rats, due to the fact that adult male rats develop larger goitres than female animals. In addition, in the male rats treated with PTU, gonadectomy decreased the B.W., pituitary content of GH-like protein and, concomitantly, the size of the goitre decreased; an opposite effect was induced by ovariectomy on the female animals. However, when goitrogenesis was induced in weight-paired adult rats of both sexes, the male animals still developed larger goitres than the females. Among all the parameters studied here, the only ones which appeared to bear a consistent relationship with the size of the goitres in rats of different sexes, treated with a given goitrogen, were the rate of body growth and the amount of a pituitary GH-like protein found before the onset of the goitrogen treatment. Moreover, though the pituitary content of the GH-like protein decreased as a consequence of goitrogen treatment, it was still somewhat higher in male that in female animals. The present results suggest that GH may somehow be involved in the mechanism by which male and female rats on goitrogens develop goitres of different sizes, despite equally high plasma TSH levels.


1968 ◽  
Vol 58 (4) ◽  
pp. 600-612 ◽  
Author(s):  
Robert Boyd ◽  
Donald C. Johnson

ABSTRACT The effects of various doses of testosterone propionate (TP) upon the release of luteinizing hormone (LH or ICSH) from the hypophysis of a gonadectomized male or female rat were compared. Prostate weight in hypophysectomized male parabiotic partners was used to evaluate the quantity of circulating LH. Hypophyseal LH was measured by the ovarian ascorbic acid depletion method. Males castrated when 45 days old secreted significantly more LH and had three times the amount of pituitary LH as ovariectomized females. Administration of 25 μg TP daily reduced the amount of LH in the plasma, and increased the amount in the pituitary gland, in both sexes. Treatment with 50 μg caused a further reduction in plasma LH in males, but not in females, while pituitary levels in both were equal to that of their respective controls. LH fell to the same low level in partners of males or females receiving 100 μg TP. When gonadectomized at 39 days, males and females had the same amount of plasma LH, but males had more stored hormone. Pituitary levels were unchanged from controls following treatment with 12.5, 25 or 50 μg TP daily, but plasma values dropped an equal amount in both sexes with the latter two doses. Androgenized males or females, gonadectomized when 39 days old, were very sensitive to the effects of TP and plasma LH was significantly reduced with 12.5 μg daily. Pituitary LH in androgenized males was higher than that of normal males but was reduced to normal by small amounts of TP. The amount of stored LH in androgenized females was not different from that of normal females and it was unchanged by any dose of TP tested. Results are consistent with the conclusion that the male hypothalamic-hypophyseal axis is at least as sensitive as the female axis to the negative feedback effects of TP. Androgenization increases the sensitivity to TP in both males and females.


1988 ◽  
Vol 117 (4_Suppl) ◽  
pp. S191-S192
Author(s):  
M. STOPPOK ◽  
H. SCHRIEFERS ◽  
E. R. LAX

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