The phytoestrogen genistein improves hippocampal neurogenesis and cognitive impairment and decreases neuroinflammation in an animal model of metabolic syndrome.

Metabolic syndrome (MS) is the medical term for the combination of at least three of the following factors: obesity, hyperlipidemia, hyperglycemia, insulin resistance, and hypertension. The spontaneously hypertensive rat (SHR) is an accepted animal model for the study of human MS that reveals all the features of the syndrome when fed high-fat, high-carbohydrate diets. The intake of high-fat diets in rats has been shown to produce brain neuropathology.

Beneficial effects of the phytoestrogen genistein on hippocampal impairments of spontaneously hypertensive rats (SHR).

Hippocampal neuropathology is a recognized feature of the spontaneously hypertensive rat (SHR). The hippocampal alterations associate with cognitive impairment. We have shown that hippocampal abnormalities are reversed by 17β-estradiol, a steroid binding to intracellular receptors (estrogen receptor α and β subtypes) or the membrane-located G-protein coupled estradiol receptor.

Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats.

It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17β-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR.

Mineralocorticoid Receptors, Neuroinflammation and Hypertensive Encephalopathy.

Worldwide, raised blood pressure is estimated to affect 35-40% of the adult population and is a main conditioning factor for cardiovascular diseases and stroke. Animal models of hypertension have provided great advances concerning the pathophysiology of human hypertension, as already shown for the deoxycorticosterone-salt treated rat, the Dahl-salt sensitive rat, the Zucker obese rat and the spontaneously hypertensive rat (SHR). SHR has been widely used to study abnormalities of the brain in chronic hypertension.

Mineralocorticoid receptor associates with pro-inflammatory bias in the hippocampus of spontaneously hypertensive rats.

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry.

Spinal Cord Injury Impairs Neurogenesis and Induces Glial Reactivity in the Hippocampus.

The incorporation of newborn neurons with increased synaptic remodeling and activity-dependent plasticity in the dentate gyrus enhances hippocampal-dependent learning performances. Astrocytes and microglial cells are components of the neurogenic niche and regulate neurogenesis under normal and neurophatological conditions leading to functional consequences for learning and memory. Although cognitive impairments were reported in patients after spinal cord injury (SCI), only few studies have considered remote changes in brain structures which are not related with sensory and motor cortex.

Selective Oestrogen Receptor Agonists Rescued Hippocampus Parameters in Male Spontaneously Hypertensive Rats.

Spontaneously hypertensive rats (SHR) show pronounced hippocampus alterations, including low brain-derived neurotrophic factor (BDNF) expression, reduced neurogenesis, astrogliosis and increased aromatase expression. These changes are reverted by treatment with 17β-oestradiol. To determine which oestradiol receptor (ER) type is involved in these neuroprotective effects, we used agonists of the ERα [propylpyrazole triol (PPT)] and the ERβ [diarylpropionitrite (DPN)] given over 2 weeks to 4-month-old male SHR.

Effects of 17β-estradiol on the cytoarchitecture of pyramidal CA1 neurons in normoglycemic and diabetic male spontaneously hypertensive rats.

Previous work has shown a reduction of apical dendritic length and spine density in neurons from the CA1 hippocampus subfield of spontaneously hypertensive rats (SHRs). These abnormalities are prevented by treatment for 2 weeks with 17β-estradiol. In view of the fact that diabetes and hypertension are comorbid diseases, we have now studied the effect of Streptozotocin-induced diabetes on the dendritic tree and spines of CA1 hippocampus neurons, and also compared the regulation of these parameters by 17β-estradiol in diabetic and normoglycemic SHR.

Estrogens are neuroprotective factors for hypertensive encephalopathy.

Estrogens are neuroprotective factors for brain diseases, including hypertensive encephalopathy. In particular, the hippocampus is highly damaged by high blood pressure, with several hippocampus functions being altered in humans and animal models of hypertension. Working with a genetic model of primary hypertension, the spontaneously hypertensive rat (SHR), we have shown that SHR present decreased dentate gyrus neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus of the dentate gyrus, increased basal levels of the estrogen-synthesizing enzyme aromatase, and atrophic dendritic arbor with low spine density in the CA1 region compared to normotensive Wistar Kyoto (WKY) ratsl.

17α-Oestradiol-induced neuroprotection in the brain of spontaneously hypertensive rats.

17β-oestradiol is a powerful neuroprotective factor for the brain abnormalities of spontaneously hypertensive rats (SHR). 17α-Oestradiol, a nonfeminising isomer showing low affinity for oestrogen receptors, is also endowed with neuroprotective effects in vivo and in vitro. We therefore investigated whether treatment with 17α-oestradiol prevented pathological changes of the hippocampus and hypothalamus of SHR.

Estradiol increases dendritic length and spine density in CA1 neurons of the hippocampus of spontaneously hypertensive rats: a Golgi impregnation study.

Increased neuronal vulnerability has been described in the brain of spontaneously hypertensive rats (SHR), models of primary hypertension. Previous data indicate that estradiol treatment corrects several dysfunctions of the hippocampus and hypothalamus of SHR. Considering this evidence we analyzed the dendritic arborization and spine density of the CA1 subfield in SHR and Wistar-Kyoto (WKY) normotensive rats with and without estradiol treatment.

Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy.

Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR).

Increased expression of the mineralocorticoid receptor in the brain of spontaneously hypertensive rats.

The mineralocorticoid receptor (MR) has been considered as both neuroprotective and damaging to the function of the central nervous system. MR may be also involved in central regulation of blood pressure. In the present study, we compared the expression of MR and the glucocorticoid receptor (GR) in the hippocampus and hypothalamus of 16-week-old spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats.

Protective effect of estrogens on the brain of rats with essential and endocrine hypertension.

Estrogen neuroprotection has been shown in pathological conditions damaging the hippocampus, such as trauma, aging, neurodegeneration, excitotoxicity, oxidative stress, hypoglycemia, amyloid-β peptide exposure and ischemia. Hypertensive encephalopathy also targets the hippocampus; therefore, hypertension seems an appropriate circumstance to evaluate steroid neuroprotection. Two experimental models of hypertension, spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats, develop hippocampal abnormalities, which include decreased neurogenesis in the dentate gyrus, astrogliosis, low expression of brain-derived neurotrophic factor (BDNF) and decreased number of neurons in the hilar region, with respect of their normotensive strains Wistar Kyoto (WKY) and Sprague-Dawley rats.

Increased aromatase expression in the hippocampus of spontaneously hypertensive rats: effects of estradiol administration.

There is high incidence of hippocampal abnormalities in spontaneously hypertensive rats (SHR), including decreased neurogenesis in the dentate gyrus, astrogliosis, low expression of brain derived neurotrophic factor and decreased neuronal density in the hilar region, respect of normotensive Wistar Kyoto rats (WKY). Estradiol treatment given for 2 weeks normalized the faulty hippocampal parameters of SHR, without having effects on WKY rats. The present work studied the potential role of local estrogen biosynthesis in the hippocampus of SHR and WKY, by measuring the expression of aromatase, the key enzyme responsible for estrogen biosynthesis and involved in neuroprotection.

Involvement of brain-derived neurotrophic factor and neurogenesis in oestradiol neuroprotection of the hippocampus of hypertensive rats.

The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)-salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17β-oestradiol (E(2) ) for 2 weeks. The present work investigated whether E(2) treatment of SHR and of hypertensive DOCA-salt male rats modulated the expression of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis.

Levonorgestrel antagonism on estrogen-induced pituitary tumors is mediated by progesterone receptors.

Using both IN VITRO and IN VIVO approaches, we studied the antagonism exerted by the synthetic progestin levonorgestrel on estrogen-induced prolactinomas, considering that levonorgestrel shows partial androgenic properties and that androgens inhibit estrogen-induced prolactin synthesis and secretion. In the tumors, binding of estrogens to their receptors was competed neither by progesterone receptor ligands nor by androgen receptor ligands, ruling out direct inhibitory effects of these drugs on tumor development. Progestin binding was competed by the progesterone receptor agonists progesterone and levonorgestrel, by the antagonist mifepristone, and also by the androgen dihydrotestosterone, whereas the androgen receptor antagonist hydroxyflutamide was a weak competitor.

Steroid protection in aging and age-associated diseases.

Neuroactive steroids are secretory products of peripheral endocrine glands that modulate a variety of brain functions. A close relationship between neuroactive steroid structure and function becomes most evident under pathological circumstances. On one side, overproduction of glucocorticoid and mineralocorticoid neuroactive steroids may be detrimental to the hippocampus, which is enriched in glucocorticoid receptors (GR) and mineralocorticoid receptors (MR).

Protective effects of estradiol in the brain of rats with genetic or mineralocorticoid-induced hypertension.

Abnormalities of hippocampus and hypothalamus are commonly observed in rats with genetic (SHR) or mineralocorticoid/salt-induced hypertension. In the hippocampus, changes include decreased cell proliferation in the dentate gyrus (DG), astrogliosis and decreased neuronal density in the hilus, whereas in the hypothalamus expression of arginine vasopressin (AVP) is markedly elevated. Here, we report that estradiol treatment overturns these abnormalities.

Neuroprotective effects of estradiol in hippocampal neurons and glia of middle age mice.

During aging the hippocampus experiences structural, molecular, and functional alterations. Protection from age-related disorders is provided by several factors, including estrogens. Since aging defects start at middle age, we studied if 17 beta-estradiol (E(2)) protected the hippocampus at this age period.

Estrogens and neuroendocrine hypothalamic-pituitary-adrenal axis function.

The function of the HPA axis is subject to regulation by many factors, which achieve relevance under normal and pathological conditions. In the case of aging, this period of life is associated with disturbances of the HPA axis and signs of hippocampal vulnerability. We examined 20-month-old male rats, in which abnormalities of the HPA axis included altered response to stress, reduced effectiveness of the steroid negative feedback and low expression of hippocampal glucocorticoid receptors (GR).

Abnormalities of the hippocampus are similar in deoxycorticosterone acetate-salt hypertensive rats and spontaneously hypertensive rats.

Hippocampal neuropathology is a recognised feature of the brain in spontaneously hypertensive rats (SHR), but similar studies are lacking in another model of hypertension, the mineralocorticoid-salt-treated rat. The present study aimed to compare changes in hippocampal parameters in 16-week-old male SHR (blood pressure approximately 190 mmHg) and their normotensive Wistar-Kyoto controls, with those of male Sprague-Dawley rats receiving (i) 10 mg deoxycorticosterone acetate (DOCA) every other day during 3 weeks and drinking 1% NaCl solution (blood pressure approximately 160 mmHg) and normotensive controls treated with (ii) DOCA and drinking water, (iii) drinking water only or (iv) 1% NaCl only. In these experimental groups, we determined: (i) cell proliferation in the dentate gyrus (DG) using the 5-bromo-2'-deoxyuridine-labelling technique; (ii) the number of glial fibrillary acidic protein (GFAP) positive astrocytes under the CA1, CA3 and DG; (iii) the number of apolipoprotein E (ApoE) positive astrocytes as a marker of potential neuronal damage; and (iv) the number of neurones in the hilus of the DG, taken as representative of neuronal density in other hippocampal subfields.

Mineralocorticoid treatment upregulates the hypothalamic vasopressinergic system of spontaneously hypertensive rats.

Mineralocorticoid effects in the brain include the control of cardiovascular functions, induction of salt appetite, interaction with the vasoactive neuropeptides arginine vasopressin (AVP) and angiotensin II and development or aggravation of hypertension. In this regard, mineralocorticoids may play a pathogenic role in rats with a genetic form of hypertension (spontaneously hypertensive rats, SHR). Our objective was to compare the response of the hypothalamic vasopressinergic system to mineralocorticoid administration in SHR and control Wistar-Kyoto (WKY) rats.

Gender differences in the expression of galanin and vasoactive intestinal peptide in oestrogen-induced prolactinomas of Fischer 344 rats.

We have previously described a sexual dimorphism in oestrogen-induced anterior pituitary tumorigenesis in Fischer 344 rats, with female tumours averaging twice the size of those of males. Neonatal androgenization of female Fischer 344 rats with 100 micro g of testosterone propionate reverted that effect, causing a 'male-like' phenotype. The peptides galanin and vasoactive intestinal peptide (VIP) are possible mediators of oestrogen effects on the anterior pituitary, including hyperprolactinemia and lactotroph proliferation.

Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease.

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days.