Differential Mechanisms of Neuroprotection by 17 β-Estradiol in Apoptotic versus Necrotic Neurodegeneration

Harms, Christoph; Lautenschlager, Marion; Bergk, A.; Katchanov, Juri; Freyer, Dorette; Kapinya, Krisztián; Herwig, Ulrike; Megow, Dirk; Dirnagl, Ulrich; Weber, Joerg R.; Hörtnagl, Heide

doi:10.1523/jneurosci.21-08-02600.2001

Cited by 147 publications

(100 citation statements)

References 68 publications

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“…Estrogens are lipophilic, readily traversing the blood-brain barrier, with the potential to be directly neuroprotective (Brinton, 2001;Garcia-Segura et al, 2001;Wise et al, 2001). Estrogenmediated protection of neurons has been demonstrated in a variety of in vitro models of neurodegeneration including those induced by excitotoxicity and oxidative stress (Behl et al, 1995(Behl et al, , 1997Goodman et al, 1996;Harms et al, 2001). Estrogens have also been shown to decrease glutamate-induced apoptosis and preserve electrophysiologic function in primary cortical neurons (Sribnick et al, , 2004.…”

Section: Discussionmentioning

confidence: 99%

Treatment with an Estrogen Receptor Ligand Is Neuroprotective in Experimental Autoimmune Encephalomyelitis

Morales

Loo

Liu

et al. 2006

Journal of Neuroscience

140

132

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Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms. Here we investigated whether treatment with an estrogen receptor ␣ (ER␣) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms. EAE was induced in wild-type, ER␣-, or ER␤-deficient mice, and each was treated with the highly selective ER␣ agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ER␣ ligand treatment ameliorated clinical disease in both wild-type and ER␤ knock-out mice, but not in ER␣ knock-out mice, thereby demonstrating that the ER␣ ligand maintained ER␣ selectivity in vivo during disease. ER␣ ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNF␣, interferon-␥, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuNϩ (neuronal-specific nuclear protein)/␤3-tubulinϩ/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3ϩ) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1-2 d after the onset of clinical signs. Treatment with either estradiol or the ER␣ ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ER␣ ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.

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Section: Discussionmentioning

confidence: 99%

Treatment with an Estrogen Receptor Ligand Is Neuroprotective in Experimental Autoimmune Encephalomyelitis

Morales

Loo

Liu

et al. 2006

Journal of Neuroscience

140

132

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“…It is well known that adult neurogenesis can be triggered by estrogen (56), yet the ER responsible for these effects has not been identified. In addition, estrogen exposure can promote or deter apoptosis (57), with the identity of the ER responsible for neuroprotection under debate (58,59). Regardless of whether ER␤ acts to reduce estrogen-related synaptogenesis, glia concentrations, prevent cell death and͞or stimulate neurogenesis, any or some of these effects may impact learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Disruption of estrogen receptor β gene impairs spatial learning in female mice

Rissman

Heck

Leonard

et al. 2002

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

225

136

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Here we provide the first evidence, to our knowledge, that estradiol (E 2) affects learning and memory via the newly discovered estrogen receptor ␤ (ER␤). In this study, ER␤ knockout (ER␤KO) and wild-type littermates were tested for spatial learning in the Morris water maze after ovariectomy, appropriate control treatment, or one of two physiological doses of E 2. Regardless of treatment, all wild-type females displayed significant learning. However, ER␤KOs given the low dose of E 2 were delayed in learning acquisition, and ER␤KOs administered the higher dose of E2 failed to learn the task. These data show that ER␤ is required for optimal spatial learning and may have implications for hormone replacement therapy in women.T he steroid hormone estradiol (E 2 ) either is required for or significantly modulates many behaviors, including cognitive behaviors (1-9). Learning tasks that involve reference memory tend to be impaired by E 2 (1,7,8). In contrast, low levels of E 2 may facilitate working memory (5, 9). In women, changes in ability on visuospatial tasks and memory recall over the menstrual cycle have been documented (10, 11). Also, beneficial effects of estrogen replacement on cognition have been noted in normally aging women (12, 13) and in women suffering from dementia associated with Alzheimer's disease (14,15).How estrogen acts on learning and memory is not clear. Estrogen binding has been reported throughout the rodent brain, including the hippocampus and cortex (16). Both characterized nuclear estrogen receptors (ER␣ and -␤) are present in extrahypothalamic regions (17,18). In addition, in vitro work suggests that estrogen acts in a nongenomic fashion in hippocampal tissues (19,20). Mice lacking functional ER␣ have severe deficits in several aspects of reproduction, including behavior (21-24). On the other hand, ER␤ knockout mice (ER␤KO) are subfertile, and sexual behavior is normal (25, 26). Thus, there has been speculation that ER␤ regulates estrogen's nonreproductive functions in the central nervous system (21, 27, 28).Here we describe our work on spatial learning in female ER␤KO mice. When treated with doses of E 2 that do not affect learning in wild-type (WT) littermates, ER␤KO mice had impaired ability to escape from the Morris water maze. Interactions between ER␣ and -␤ may contribute to the learning response; to test the hypothesis that lack of ER␤ influences the level of ER␣ protein, mouse brains were examined for ER␣ immunoreactivity (ER␣-ir), with emphasis on the hippocampus (HIPP). MethodsAnimals. Female mice (ages 5-7 mos) were of mixed 129͞J and C57BL͞6J background. Subjects were generated by crossing heterozygotic mating pairs carrying a single copy of the disrupted ER␤ gene (25). The resulting offspring were genotyped by PCR amplification of tail DNA. WT and ER␤ disrupted (ER␤KO) littermates were used in these studies. The ER␤ gene disruption was created by Neo insertion into exon 3 (25), thus the following three primers were used: one from intron 2 (5Ј-GGAGTAGAAACAAGCAATCCAGACATC-3Ј), a...

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“…Primary rat neuronal cultures were prepared from the cerebral cortex of embryonic day 18 rat embryos according to a previously published protocol (15). Following dissociation, 150,000 cells/cm 2 were seeded into 24-well plates pretreated with poly-L-lysine (0.5% w/v in PBS, 1 h at room temperature) and coating medium (dissociation medium with 0.03‰ w/v collagen G, 1 h at 37°C).…”

Section: Generation Of Primary Neuronal and Glial Cell Culturesmentioning

confidence: 99%

TLR2 Mediates Neuroinflammation and Neuronal Damage

Hoffmann¹,

Braun²,

Becker³

et al. 2007

The Journal of Immunology

Self Cite

130

107

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Innate immunity relies on pattern recognition receptors to detect the presence of infectious pathogens. In the case of Gram-positive bacteria, binding of bacterial lipopeptides to TLR2 is currently regarded as an important mechanism. In the present study, we used the synthetic bacterial lipopeptide Pam3CysSK4, a selective TLR2 agonist, to induce meningeal inflammation in rodents. In a 6-h rat model, intrathecal application of Pam3CysSK4 caused influx of leukocytes into the cerebrospinal fluid (CSF) and induced a marked increase of regional cerebral blood flow and intracranial pressure. In wild-type mice, we observed CSF pleocytosis and an increased number of apoptotic neurons in the dentate gyrus 24 h after intrathecal challenge. Inflammation and associated neuronal loss were absent in TLR2 knockout mice. In purified neurons, cytotoxicity of Pam3CysSK4 itself was not observed. Exposure of microglia to Pam3CysSK4 induced neurotoxic properties in the supernatant of wild-type, but not TLR2-deficient microglia. We conclude that TLR2-mediated signaling is sufficient to induce the host-dependent key features of acute bacterial meningitis. Therefore, synthetic lipopeptides are a highly specific tool to study mechanisms of TLR2-driven neurodegeneration in vivo.

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Differential Mechanisms of Neuroprotection by 17 β-Estradiol in Apoptotic versus Necrotic Neurodegeneration

Cited by 147 publications

References 68 publications

Treatment with an Estrogen Receptor Ligand Is Neuroprotective in Experimental Autoimmune Encephalomyelitis

Treatment with an Estrogen Receptor Ligand Is Neuroprotective in Experimental Autoimmune Encephalomyelitis

Disruption of estrogen receptor β gene impairs spatial learning in female mice

TLR2 Mediates Neuroinflammation and Neuronal Damage

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