The present experiments sought to determine the implication of estrogen receptors (ERalpha and ERbeta) 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 17beta-estradiol, an estrogen receptor alpha (ERalpha) agonist, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)tris-phenol (PPT), or an estrogen receptor beta (ERbeta) agonist, 5-androsten-3beta, 17beta-diol (Delta5-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; 17beta-estradiol and PPT but not Delta5-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 17beta-estradiol and tended to increase with PPT but not with Delta5-diol treatments in MPTP mice. Glycogen synthase kinase 3beta (GSK3beta) phosphorylation (at serine 9) was greatly reduced in MPTP mice; this was completely prevented by PPT, whereas 17beta-estradiol and Delta5-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, 17beta-estradiol and PPT increased phosphorylation of striatal Akt and GSK3beta, whereas the other markers measured remained unchanged. Delta5-Diol increased GSK3beta phosphorylation less than the PPT treatment. These results suggest that a pretreatment with estradiol promoted dopamine neuron survival by activating ERalpha and increasing Akt and GSK3beta phosphorylation.
"These effects were not observed when raloxifene was administered with G15, suggesting that raloxifene induces Akt phosphorylation and modulation of Bcl-2 and BDNF levels through GPER1. In contrast to 17b-estradiol, raloxifene does not change striatal GSK3b phosphorylation levels (D'Astous et al., 2006). In support of the role of Akt in raloxifene neuroprotection, an in vitro study using cortical neurons demonstrated that the protection induced by raloxifene is abolished in the presence of a PI3K inhibitor (Abdelhamid et al., 2011) showing that Akt is an important mediator of raloxifene beneficial effect. "
[Show abstract][Hide abstract] ABSTRACT: Raloxifene, used in the clinic, is reported to protect brain dopaminergic neurons in mice. Raloxifene was shown to mediate an effect through the G protein-coupled estrogen receptor 1 (GPER1). We investigated if raloxifene neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice is mediated through GPER1 by using its antagonist G15. Striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid to dopamine ratio as well as dopamine transporter and vesicular monoamine transporter 2 showed that raloxifene neuroprotection of dopaminergic neurons was blocked by G15. Protection by raloxifene was accompanied by activation of striatal Akt signaling (but not ERK1/2 signaling) and increased Bcl-2 and brain-derived neurotrophic factor levels; these effects were abolished by coadministration with G15. The effect of raloxifene was not mediated through increased levels of 17β-estradiol. MPTP mice had decreased plasma testosterone, dihydrotestosterone, and 3β-diol levels; this was prevented in raloxifene-treated MPTP mice. Our results suggest that raloxifene acted through GPER1 to mediate Akt activation, increase Bcl-2 and brain-derived neurotrophic factor levels, and protection of dopaminergic neurons and plasma androgens.
Neurobiology of aging 03/2014; 35(10). DOI:10.1016/j.neurobiolaging.2014.03.017 · 5.01 Impact Factor
"The exact mechanisms of neuroprotection , however, are not clear. Studies have shown a role for binding of estrogen to the nuclear estrogen receptor , the ERα subtype,  ERα with a glial contribution,  ERα + ERβ , and ER-independent mechanisms . This has implications for potential therapeutic agents, as some estrogen analogues lack activity at one or both nuclear receptors; while others, such as the " inactive " enantiomer E2, may have no ER binding activity at all. "
[Show abstract][Hide abstract] ABSTRACT: Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT) with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer's disease and improved cognitive functioning of postmenopausal women who use 17β-estradiol. With regards to Parkinson's disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17β-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson's-related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases.
International Journal of Alzheimer's Disease 04/2012; 2012:258454. DOI:10.1155/2012/258454
"ERβ can modulate DATs and D2 receptors in rats.99 ERα is thought to participate in striatal dopamine neuroprotection.100 However, the neuroprotective effects of estrogens are usually seen at much higher than physiological concentrations, and therefore may also act via nonreceptor-mediated mechanisms, such as changing fluidity of membranes surrounding the receptors, in which steroids dissolve readily at these high concentrations. "
[Show abstract][Hide abstract] ABSTRACT: Gender and sex hormones can influence a variety of mental health states, including mood, cognitive development and function, and vulnerability to neurodegenerative diseases and brain damage. Functions of neuronal cells may be altered by estrogens depending upon the availability of different physiological estrogenic ligands; these ligands and their effects vary with life stages, the genetic or postgenetic regulation of receptor levels in specific tissues, or the intercession of competing nonphysiological ligands (either intentional or unintentional, beneficial to health or not). Here we review evidence for how different estrogens (physiological and environmental/dietary), acting via different estrogen receptor subtypes residing in alternative subcellular locations, influence brain functions and behavior. We also discuss the families of receptors and transporters for monoamine neurotransmitters and how they may interact with the estrogenic signaling pathways.
International Journal of Women's Health 08/2010; 2(1):153-66. DOI:10.2147/IJWH.S6907
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