Investigation of central versus peripheral effects of estradiol in ovariectomized mice

Andersson, Niklas; Islander, Ulrika; Egecioglu, Emil; Löf, Elin; Swanson, Charlotte; Movérare‐Skrtic, Sofia; Sjögren, Klara; Lindberg, Mattias F.; Carlsten, Hans; Ohlsson, Claes

doi:10.1677/joe.1.06181

Cited by 22 publications

(22 citation statements)

References 28 publications

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“…20 Ovariectomy was performed 2 weeks before injury and E2-PLGA, saline-PLGA, or E2 pellets (Innovative Research of America, Sarasota, FL, USA) were administered at the designated injury sight one week later (i.e., 1 week before injury); E2-PLGA and saline PLGA were administered via subcutaneous injection, and the E2 pellets were subcutaneously implanted. Cyclopamine (50 mg/kg per day) and the estrogen receptor antagonist ICI 182,780 21 (8.3 mg/kg per day; Tocris Cookson Ltd, Bristol, UK) were intraperitoneally injected once daily from 2 days (cyclopamine) or 3 days (ICI) before injury until sacrifice. Serum E2 levels were determined with an E2-ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) as directed by the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein

Sekiguchi

Masaaki

Jujo

et al. 2012

Laboratory Investigation

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Both estradiol (E2) and Sonic Hedgehog (Shh) contribute to angiogenesis and nerve regeneration. Here, we investigated whether E2 improves the recovery of injured nerves by downregulating the Shh-inhibitor Hedgehog-interacting Protein (HIP) and increasing Shh-induced angiogenesis. Mice were treated with local injections of E2 or placebo one week before nerve-crush injury; 28 days after injury, nerve conduction velocity, exercise duration, and vascularity were significantly greater in E2-treated mice than in placebo-treated mice. E2 treatment was also associated with higher mRNA levels of Shh, the Shh receptor Patched-1, and the Shh transcriptional target Gli1, but with lower levels of HIP. The E2-induced enhancement of nerve vascularity was abolished by the Shh inhibitor cyclopamine, and the effect of E2 treatment on Shh, Gli1, and HIP mRNA expression was abolished by the E2 inhibitor ICI. Gli-luciferase activity in human umbilical-vein endothelial cells (HUVECs) increased more after treatment with E2 and Shh than after treatment with E2 alone, and E2 treatment reduced HIP expression in HUVECs and Schwann cells without altering Shh expression. Collectively, these findings suggest that E2 improves nerve recovery, at least in part, by reducing HIP expression, which subsequently leads to an increase in Shh signaling and Shh-induced angiogenesis.

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Section: Methodsmentioning

confidence: 99%

Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein

Sekiguchi

Masaaki

Jujo

et al. 2012

Laboratory Investigation

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“…Rats receiving either EE or ICI treatment alone were also administered vehicle at the appropriate time points. Statistically significant changes in TST were observed among treatment groups [F (5,45) ϭ 13.43; P Ͻ 0.0001] (Fig. 3A).…”

Section: Ici Blocks Estrogenic Actions In the MD Model Of Hot Flush Bmentioning

confidence: 99%

“…Reportedly, the compound does not cross the blood-brain barrier (BBB) (1)(2)(3), and has been used in preclinical studies to understand the biological roles of estrogen receptor (ER) signaling and distinguish peripheral vs. central effects of estrogens (1)(2)(3)(4)(5). Results from clinical studies suggest that ICI (fulvestrant) may be useful in treating advanced, hormone receptor-positive breast cancer in postmenopausal women (6,7).…”

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confidence: 99%

ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing

Alfinito¹,

Chen²,

Atherton³

et al. 2008

Endocrinology

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Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg.d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 alpha-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg.d) dose dependently inhibited this effect. ICI (3.0 mg/kg.d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg.d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg.d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.

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“…However, indirect actions are also evident. Namely, a recent study demonstrated that estrogen signaling in the brain contributes to the regulation of the skeleton, with intracerebroventricular estrogen replacement in mice providing at least 1/3 of the total cancellous bone formation stimulated by estrogen supplementation [79]. Part of this regulation could conceivably take place via modulation of central NPY expression.…”

mentioning

confidence: 99%

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

Zengin

Zhang

Herzog

et al. 2010

Trends in Endocrinology & Metabolism

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The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity. Neuroendocrine control of bone and fatOsteoporosis and excess central adiposity, increasingly prevalent in ageing populations, increase the risk of fractures and diseases such as type-2 diabetes mellitus, and adversely affect both quality of life and survival. The regulation of bone and adipose tissue mass has traditionally been studied independently, but osteoblasts and adipocytes are derived from the same mesenchymal precursor cells, and recent findings that the bone-or fat-derived hormones, osteocalcin and leptin, have significant effects on energy homeostasis and bone [1], respectively, now suggest that bone and adipose tissue share common regulatory pathways. The hypothalamus acts as a pivotal regulator of homeostasis in bone and adipose tissue via regulation of hypothalamopituitary axes. For instance, activation of the hypothalamo-pituitary-adrenal axis, or inhibition of the hypothalamo-pituitary-somatotropic or -gonadotropic axes (as in stress or negative energy balance), can affect circulating concentrations of cortisol, insulin like growth factor-1 (IGF-1) and sex steroids that inhibit bone formation while promoting conservation of fat mass, particularly central adiposity 2, 3 and 4. Sex hormones -a major focus of this review -influence bone and fat via direct actions on osteoblasts or adipocytes 2, 3, 5, 6, 7 and 8. Recently, however, it has been recognized that sex hormones can influence these tissues via the neuropeptide Y (NPY) system (Box 1) 9, 10, 11 and 12, that also regulates bone and adipocyte homeostasis via actions in the hypothalamus and peripheral tissues 9, 13 and 14. In this review we examine the role of sex hormones in skeletal and energy homeostasis, with particular focus on their interaction with NPY. Whereas research into the isolated effects of sex hormones or the NPY system on bone and adipose tissue homeostasis has led to identification of potential novel drug targets for the treatment of osteoporosis or central obesity, emerging research into the interaction of these systems could pave the way for even better treatments for these conditions, particularly in the context of reduced circulating concentrations of sex hormones, as in menopause or ageing in women and in men. Zenging et al.: Trends in Endocrinology & Metabolism, 2(7): 4...

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Investigation of central versus peripheral effects of estradiol in ovariectomized mice

Cited by 22 publications

References 28 publications

Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein

Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein

ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

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