Estradiol protects dopaminergic neurons in a MPP+Parkinson’s disease model

Sawada, Hideyuki; Ibi, Masakazu; Kihara, Takeshi; Honda, Kazuo; Nakamizo, Tomoki; Kanki, Rie; Nakanishi, Miki; Sakka, Noriko; Akaike, Akinori; Shimohama, Shun

doi:10.1016/s0028-3908(02)00049-7

Cited by 108 publications

(71 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The present results suggest that ER␤ affects neural development in the midbrain during embryogenesis. Consistent with these results, it has been demonstrated that ER␤ is the predominant ER in dopaminergic neurons of the substantia nigra, an important structure in the midbrain (7), and that estrogen protects dopaminergic neurons from injury (30)(31)(32)(33).…”

Section: Discussionsupporting

confidence: 61%

Estrogen receptor β expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons

Fan

Warner

Gustafsson

2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Our previous studies with estrogen receptor ␤ knockout (ER␤ ؊/؊ ) mice demonstrated that ER␤ is necessary for embryonic development of the brain as early as embryonic day 14.5 (E14.5) and is involved in neuronal migration. Such early effects of ER were unexpected because estradiol synthesis and action in the brain occur at E18.5. In the present study, we examined the distribution of ER␤ in the developing brain and identified a population of ER␤-regulated interneurons. ER␤ appears in the brain at E12.5, mainly localized in the wall of the midbrain, neuromere, hypothalamus, thalamus, and basal plate of pons. At E15.5 and E16.5, ER␤ expression increased in the hypothalamus, thalamus, and midbrain and appeared in the limbic forebrain. At E18.5, ER␤ expression was strongly expressed throughout the brain, including the cerebellum and striatum, whereas there were very few positive cells in the ventricular region. In the paraventricular thalamic nucleus and parafascicular nucleus, most of the calretinin-immunopositive interneurons expressed ER␤. In ER␤ ؊/؊ mice, calretinin expression was markedly lower than in WT mice in the hippocampus, thalamus, and amygdala both at E16.5 and at E18.5. Epidermal growth factor receptor expression was lower in the cortex of ER␤ ؊/؊ than in WT mice at E15.5 and, unlike WT mice, was absent from the superficial marginal zone. These findings suggest that ER␤ in the embryonic brain is necessary for the development of calretininimmunoreactive GABAergic interneurons and for neuronal migration in the cortex through modulating epidermal growth factor receptor expression at middle and later embryonic stages.cortex ͉ EGF receptor ͉ striatum ͉ thalamus E strogen is important during brain development, influencing the maturation of neural systems and affecting the sexual differentiation of brain structures and functions (1, 2). Sexual differentiation in the brain occurs in male rodents at day 18.5 when aromatase is induced in the brain and catalyses the synthesis of estradiol from testosterone secreted from the embryonic testis. At this time, estrogen imprints the neuroendocrine control of gonadal function, reproductive behavior, and the sexual differences in the secretion of growth hormone.Estrogen actions now are recognized to occur via two distinct estrogen receptors (ER), ER␣ and ER␤, that reside in cell nuclei (3, 4). In the brain, ER␣ plays a critical role in regulating reproductive neuroendocrine function, whereas ER␤ may be more important in regulating nonreproductive functions (5-8).In ER␣ knockout mice, no gross brain abnormalities have been reported, whereas ER␤ plays a prominent role during embryogenesis and there are significant morphological abnormalities in the embryonic brains of ER␤ knockout (ER␤ Ϫ/Ϫ ) mice (9). Studies have revealed that ER␤ also is expressed in fetal human brain and may mediate effects of estrogen in the developing nervous system (10). Lemmen et al. (11) reported that ER␤ mRNA is detectable in brains of mouse embryo at embryonic day 10.5 (E10.5), but there is no i...

show abstract

Section: Discussionsupporting

confidence: 61%

Estrogen receptor β expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons

Fan

Warner

Gustafsson

2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…This may use PI3K/Akt signaling, which may involve CREB as a downstream effector (Morissette et al, 2008a;Quesada et al, 2008), with possible effects on expression of genes for antiapoptotic, growth factor, and antioxidant activity. These might be considered nonspecific effects on processes common to neuroprotection against many forms of injury in different brain regions and are known to require concentrations of estradiol that are orders of magnitude greater than levels in the circulation, even at proestrus (Sawada et al, 1998(Sawada et al, , 2002Green and Simpkins, 2000;Behl, 2002;Callier et al, 2002;Garcia-Ovejero et al, 2005). It remains to be determined whether these responses are sexually dimorphic.…”

Section: Sex-specific Estrogen Actions In the Brainmentioning

confidence: 99%

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

2010

View full text Add to dashboard Cite

“…Early JNK activation is found in various culture models following 1-methyl-4-phenylpyridinium (MPP ϩ ) treatment (9 -11). Blockade of JNK in cultures has also been shown to be neuroprotective (12,13). Although its role is less defined, p38 activation has been investigated following treatment with dopamine, MPTP, or MPP ϩ (14 -16).…”

mentioning

confidence: 99%

Phosphorylation of p38 MAPK Induced by Oxidative Stress Is Linked to Activation of Both Caspase-8- and -9-mediated Apoptotic Pathways in Dopaminergic Neurons

Choi

Eom

Han

et al. 2004

Journal of Biological Chemistry

204

141

View full text Add to dashboard Cite

We evaluated the contribution of p38 mitogen-activated protein kinase and the events upstream/downstream of p38 leading to dopaminergic neuronal death. We utilized MN9D cells and primary cultures of mesencephalic neurons treated with 6-hydroxydopamine. Phosphorylation of p38 preceded apoptosis and was sustained in 6-hydroxydopamine-treated MN9D cells. Cotreatment with PD169316 (an inhibitor of p38) or expression of a dominant negative p38 was neuroprotective in death induced by 6-hydroxydopamine. The superoxide dismutase mimetic and the nitric oxide chelator blocked 6-hydroxydopamine-induced phosphorylation of p38, suggesting a role for superoxide anion and nitric oxide in eliciting a neurotoxic signal by activating p38. Following 6-hydroxydopamine treatment, inhibition of p38 prevented both caspase-8-and -9-mediated apoptotic pathways as well as generation of truncated Bid. Consequently, 6-hydroxydopamine-induced cell death was rescued by blockading activation of caspase-8 and -9. In primary cultures of mesencephalic neurons, the phosphorylation of p38 similarly appeared in tyrosine hydroxylase-positive, dopaminergic neurons after 6-hydroxydopamine treatment. This neurotoxin-induced phosphorylation of p38 was inhibited in the presence of superoxide dismutase mimetic or nitric oxide chelator. Co-treatment with PD169316 deterred 6-hydroxydopamine-induced loss of dopaminergic neurons and activation of caspase-3 in these neurons. Furthermore, inhibition of caspase-8 and -9 significantly rescued 6-hydroxydopamine-induced loss of dopaminergic neurons. Taken together, our data suggest that superoxide anion and nitric oxide induced by 6-hydroxydopamine initiate the p38 signal pathway leading to activation of both mitochondrial and extramitochondrial apoptotic pathways in our culture models of Parkinson's disease. Parkinson's disease (PD)1 is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Although its precise etiology is unknown, such factors as oxidative stress, impairment of mitochondrial respiration, and abnormal protein aggregation may play roles in its pathogenesis (1, 2). Although the role of apoptosis in the process of dopaminergic neuronal death has been highlighted in studies using postmortem brains and experimental models of PD, other evidence implicates both apoptosis and non-apoptotic death in PD (3). Regardless, it is not clearly understood which signals may be involved in determining the mode of dopaminergic neuronal death.Among the upstream signals leading to neuronal degeneration, one may include the stress-activated protein kinases. These are c-Jun N-terminal kinases (JNK) and p38 kinases, which are activated in response to various stimuli and are potent effectors of neuronal apoptosis (4). Most interesting, the phosphorylated forms of JNK and p38 are expressed in postmortem brains of PD (5). Moreover, evidence from experimental models of PD has implicated JNK in the process of dopaminergic neuronal death. For example, activation ...

show abstract

Estradiol protects dopaminergic neurons in a MPP+Parkinson’s disease model

Cited by 108 publications

References 40 publications

Estrogen receptor β expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons

Estrogen receptor β expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons

Estrogen Actions in the Brain and the Basis for Differential Action in Men and Women: A Case for Sex-Specific Medicines

Phosphorylation of p38 MAPK Induced by Oxidative Stress Is Linked to Activation of Both Caspase-8- and -9-mediated Apoptotic Pathways in Dopaminergic Neurons

Contact Info

Product

Resources

About