Neuroprotective and neurotoxic effects of estrogens

Picazo, Ofir Picazo; Azcoitia, Íñigo; Garcia-Segura, Luis Miguel

doi:10.1016/s0006-8993(03)03380-8

Cited by 64 publications

(49 citation statements)

References 67 publications

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“…Although estrogen receptors are known to be involved in the neuroprotective mechanism of estradiol, high pharmacological concentrations of the hormone are necessary to exert neuroprotection in different experimental models of brain injury (Picazo et al, 2003). This suggests that atypical mechanisms of action, such as the activation of membrane-associated signaling, are involved in these estrogen receptor-mediated effects.…”

Section: Discussionmentioning

confidence: 99%

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

D’Astous

Méndez²,

Morissette³

et al. 2006

Mol Pharmacol

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The present experiments sought to determine the implication of estrogen receptors (ER␣ and ER␤) and their interaction with insulin-like growth factor receptor (IGF-IR) signaling pathways in neuroprotection by estradiol against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. C57BL/6 male mice were pretreated for 5 days with 17␤-estradiol, an estrogen receptor ␣ (ER␣) agonist, 4,4Ј,4Љ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT), or an estrogen receptor ␤ (ER␤) agonist, 5-androsten-3␤, 17␤-diol (⌬5-diol). On day 5, mice received MPTP (9 mg/kg) or saline injections, and estrogenic treatments were continued for 5 more days. MPTP decreased striatal dopamine, measured by high-performance liquid chromatography, to 59% of control values; 17␤-estradiol and PPT but not ⌬5-diol protected against this depletion. MPTP increased IGF-IR measured by Western blot, which was prevented by PPT. The phosphorylation of protein kinase B (Akt) (at serine 473), an essential mediator of IGF-I neuroprotective actions, increased after 17␤-estradiol and tended to increase with PPT but not with ⌬5-diol treatments in MPTP mice. Glycogen synthase kinase 3␤ (GSK3␤) phosphorylation (at serine 9) was greatly reduced in MPTP mice; this was completely prevented by PPT, whereas 17␤-estradiol and ⌬5-diol treatments were less effective. The ratio between the levels of striatal Bcl-2 and BAD proteins, two apoptotic regulators, decreased after MPTP treatment. This effect was effectively prevented only in the animals treated with PPT. In nonlesioned mice, 17␤-estradiol and PPT increased phosphorylation of striatal Akt and GSK3␤, whereas the other markers measured remained unchanged. ⌬5-Diol increased GSK3␤ phosphorylation less than the PPT treatment. These results suggest that a pretreatment with estradiol promoted dopamine neuron survival by activating ER␣ and increasing Akt and GSK3␤ phosphorylation.Many studies have demonstrated the neuroprotective effects of estradiol in vivo against neurotoxins of the nigrostriatal dopaminergic system (Callier et al., 2000;Dluzen and McDermott, 2000;D'Astous et al., 2004). The molecular mechanisms implicated in the neuroprotection have yet to be described. The aim of the present experiment was to investigate the possible implication of the insulin-like growth factor (IGF-I) signaling pathway in the neuroprotective effects of estradiol because there is a great interdependence between the actions of estradiol, IGF-I, and their respective receptors. Indeed, these molecules interact with one another, via their receptors, and are involved in cross-talking through different signaling pathways (Kahlert et al., 2000). These molecules interact to positively affect neuronal differentiation, neurogenesis, synaptic plasticity, neuroendocrine regulation, and neuroprotection (Cardona-Gomez et al., 2001;Garcia-Segura et al., 2001 ABBREVIATIONS: IGF-I, insulin growth factor I; ER, estrogen receptor; IGF-IR, insulin growth factor receptor; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PPT, 4,4Ј,4...

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Section: Discussionmentioning

confidence: 99%

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

D’Astous

Méndez²,

Morissette³

et al. 2006

Mol Pharmacol

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“…Our results also are in keeping with evidence that age at menarche may be inversely associated with estrogen levels among both pre-and postmenopausal women 18,19 and that, in animal models, estrogens are neuroprotective, possibly via antioxidant effects or via activation of growth-signaling pathways. 20,21 In addition, estrogen has been shown to reduce glutamate toxicity in glial cells. 22 Exposure to estrogen due to early age at menarche may therefore act to protect against DNA damage to glial cells.…”

Section: Discussionmentioning

confidence: 99%

Hormonal and reproductive factors and risk of glioma: A prospective cohort study

Silvera

Miller

Rohan

2005

Intl Journal of Cancer

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The etiology of glioma, the most commonly diagnosed malignant brain tumor among adults in the United States, is poorly understood. Given the lower incidence rate of glioma in women than in men, it has been hypothesized that reproductive and hormonal factors may be involved in the etiology of glioma. We conducted a secondary analysis of data from the National Breast Screening Study, which included 89,835 Canadian women, aged 40-59 years at recruitment between 1980 and 1985. Linkages to national cancer and mortality databases yielded data on cancer incidence and deaths from all causes, respectively, with followup ending between 1998 and 2000. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI) for the association between hormonal and reproductive factors and risk of glioma. During a mean of 16.4 years of follow-up, we observed 120 incident glioma cases. Compared with women with a relatively early age at menarche ( 12 years), women who were 13-14 years of age at menarche had a 64% increased risk of glioma (95% CI 5 1.01-2.65), and women who were older than 14 years of age at menarche had a 66% increased risk of glioma (95% CI 5 0.86-3.20, p trend 5 0.06). Age at first live birth, parity, menopausal status, use of oral contraceptive and use of hormone replacement therapy were not associated with altered glioma risk in our study population. Additional prospective studies are needed to confirm our findings. ' 2005 Wiley-Liss, Inc.Key words: brain neoplasms; glioma; cohort; hormones; reproductive factors Glioma is the most commonly diagnosed malignant brain tumor among adults in the United States, 1,2 with an estimated 5-year survival rate of 30%. 2 Currently, ionizing radiation is the only well-established risk factor for glioma. 2,3 Beyond this, few other risk factors for glioma have been established. However, incidence rates of glioma are lower in women than in men. 2 Furthermore, steroid hormone receptors, particularly androgen receptors, are expressed in gliomas, 4,5 and Khalid et al. 6 have demonstrated the expression of estrogen-receptor-related antigen in human glioma cells. As a result, it has been hypothesized that reproductive and hormonal factors may be involved in the etiology of glioma.The epidemiologic literature regarding reproductive and hormonal factors and brain cancer risk is based primarily on case-control studies. [7][8][9][10][11][12] One cohort study, by Lambe et al., 13 has also examined some of these associations. Parity has been examined as a risk factor for glioma in a number of studies, the findings for which have been mixed, with 5 observing no association 7,9-12 and 2 reporting inverse associations. 8,13 Of the 5 studies that have examined the role of age at first birth, [8][9][10]13 3 observed no association 9,10,13 and 1, by Cantor et al., 8 reported a statistically significant positive association, with risk of glioma. Additionally, no association has been found with menopausal status. 7,9,11,12 Few studies have described the associat...

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“…9% NaCl (pH 7 . 4) and were injected at doses that in previous studies resulted in neuroprotective effects (Picazo et al 2003, Ciriza et al 2004.…”

Section: Animals and Experimental Treatmentsmentioning

confidence: 99%

Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs

Tapia-González¹,

Carrero²,

Pernía³

et al. 2008

Journal of Endocrinology

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It has been previously reported that the neuroprotective hormone oestradiol reduces microglia inflammatory activity. The objective of this study was to test whether two selective oestrogen receptor modulators, tamoxifen and raloxifene, modulate in vivo the activation of microglia induced by the peripheral administration of lipopolysaccharide (LPS). Activation of microglia was assessed in the white matter of the cerebellum using immunoreactivity for major histocompatability complex-II. Oestradiol, tamoxifen and raloxifene decreased microglia activation induced by LPS in male and ovariectomized female rats, although the doses of oestradiol that were effective in decreasing microglia reactivity were not the same in both sexes. Tamoxifen reduced microglia activation in all experimental groups at all doses tested (0 . 5-2 mg/kg b.w.) while raloxifene lost its anti-inflammatory activity at the higher dose tested (2 mg/kg b.w). In addition, raloxifene had per se a moderate pro-inflammatory activity in the brain of control female rats and its antiinflammatory activity was partially impaired in female animals after 1 month of deprivation of ovarian hormones. Spots of oestrogen receptor (ER)-a immunoreactivity were detected in the soma and cell processes of microglia. Treatment with LPS, oestradiol or tamoxifen induced an increase of ER-a immunoreactive spots in the perikaryon of microglia, while oestradiol antagonized the effect of LPS. The results indicate that some oestrogenic compounds decrease brain inflammation by a mechanism that may involve ERs expressed by microglia. The findings support the potential therapeutic role of oestrogenic compounds as protective anti-inflammatory agents for the central nervous system.

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Neuroprotective and neurotoxic effects of estrogens

Cited by 64 publications

References 67 publications

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

Hormonal and reproductive factors and risk of glioma: A prospective cohort study

Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs

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