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1.
Horm Behav ; 164: 105594, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38917776

RESUMO

Menopause is an endocrine shift leading to increased vulnerability for cognitive impairment and dementia risk factors, in part due to loss of neuroprotective circulating estrogens. Systemic replacement of estrogen post-menopause has limitations, including risk for estrogen-sensitive cancers. A promising therapeutic approach therefore might be to deliver estrogen only to the brain. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in ovariectomized mice (a surgical menopause model). We treated mice with the prodrug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17ß-estradiol only in the brain. Young and middle-aged C57BL/6 J mice received ovariectomy and subcutaneous implant containing vehicle or DHED and underwent cognitive testing to assess memory after 1-3.5 months of treatment. Low and medium doses of DHED did not alter metabolic status in middle-aged mice. In both age groups, DHED treatment improved spatial memory in ovariectomized mice. Additional testing in middle-aged mice showed that DHED treatment improved working and recognition memory in ovariectomized mice. These results lay the foundation for future studies determining if this intervention is as efficacious in models of dementia with comorbid risk factors.


Assuntos
Encéfalo , Cognição , Menopausa , Camundongos Endogâmicos C57BL , Ovariectomia , Pró-Fármacos , Animais , Feminino , Pró-Fármacos/farmacologia , Camundongos , Cognição/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Menopausa/efeitos dos fármacos , Estrogênios/farmacologia , Estradiol/farmacologia
2.
Am J Physiol Regul Integr Comp Physiol ; 322(4): R319-R325, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35107023

RESUMO

Hypertension is a primary risk factor for the development of cardiovascular disease. Mechanisms controlling blood pressure (BP) in men and women are still being investigated; however, there is increasing evidence supporting a role for the innate immune system. Specifically, Toll-like receptors (TLRs), and TLR4 in particular, have been implicated in the development of hypertension in male spontaneously hypertensive rats (SHR). Despite established sex differences in BP control and inflammatory markers in hypertensive males and females, little is known regarding the role of TLR4 in hypertension in females. Our hypotheses were that male SHR have greater TLR4 expression compared with females, and that sex differences in TLR4 contribute to sex differences in BP and the T cell profile. To test these hypotheses, initial studies measured renal TLR4 protein expression in 13-wk-old male and female SHR. Additional SHR were implanted with telemetry devices and randomized to treatment with either IgG or TLR4 neutralizing antibodies. Untreated control male SHR have greater TLR4 protein expression in the kidney compared with females. However, treatment with TLR4 neutralizing antibody for 2 wk did not significantly alter BP in either male or female SHR. Interestingly, neutralization of TLR4 increased renal CD3+ T cells in female SHR, with no alteration in CD4+ T cells or CD8+ T cells in either sex. Taken together, our data indicate that although male SHR have greater renal TLR4 expression than females, TLR4 does not contribute to the higher BP and more proinflammatory renal T cell profile in males versus females.


Assuntos
Hipertensão , Caracteres Sexuais , Animais , Pressão Sanguínea/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Receptor 4 Toll-Like/metabolismo
3.
J Alzheimers Dis ; 101(4): 1177-1194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39302361

RESUMO

Background: About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods: First, 3-month-old AppNL-F and WT female mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.


Assuntos
Doença de Alzheimer , Dieta Hiperlipídica , Modelos Animais de Doenças , Menopausa , Camundongos Transgênicos , Animais , Doença de Alzheimer/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Camundongos , Menopausa/metabolismo , Compostos de Vinila , Camundongos Endogâmicos C57BL , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Obesidade/metabolismo , Cicloexenos
4.
bioRxiv ; 2023 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-37609180

RESUMO

Menopause is a major endocrinological shift that leads to an increased vulnerability to the risk factors for cognitive impairment and dementia. This is thought to be due to the loss of circulating estrogens, which exert many potent neuroprotective effects in the brain. Systemic replacement of estrogen post-menopause has many limitations, including increased risk for estrogen-sensitive cancers. A more promising therapeutic approach therefore might be to deliver estrogen only to the brain thus limiting adverse peripheral side effects. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in post-menopausal mice. We modeled surgical menopause via bilateral ovariectomy (OVX). We treated mice with the pro-drug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17ß-estradiol only in the brain. Young (2.5-month) and middle-aged (11-month-old) female C57BL/6J mice received ovariectomy and a subcutaneous implant containing vehicle (cholesterol) or DHED. At 3.5 months old (young group) and 14.5 months old (middle-aged group), mice underwent behavior testing to assess memory. DHED did not significantly alter metabolic status in middle-aged, post-menopausal mice. In both young and middle-aged mice, the brain-specific estrogen DHED improved spatial memory. Additional testing in middle-aged mice also showed that DHED improved working and recognition memory. These promising results lay the foundation for future studies aimed at determining if this intervention is as efficacious in models of dementia that have comorbid risk factors.

5.
Hypertension ; 75(6): 1615-1623, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32336228

RESUMO

Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt-induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.


Assuntos
Acetato de Desoxicorticosterona/farmacologia , Hipertensão , Rim , Fatores Sexuais , Linfócitos T Reguladores/imunologia , Animais , Pressão Sanguínea/imunologia , Fatores de Risco Cardiometabólico , Contagem de Células/métodos , Feminino , Aromatizantes/farmacologia , Hipertensão/imunologia , Hipertensão/fisiopatologia , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Rim/imunologia , Rim/patologia , Masculino , Mineralocorticoides/farmacologia , Fatores de Proteção , Ratos , Cloreto de Sódio na Dieta/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do Tratamento
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