Photoreceptor preservation in the S334ter model of retinitis pigmentosa by a novel estradiol analog

Dykens, James A.; Carroll, Amy K.; Wiley, Sandra E.; Covey, Douglas F.; Cai, Zu Yun; Zhao, Lian; Wen, Rong

doi:10.1016/j.bcp.2004.06.042

Cited by 29 publications

(27 citation statements)

References 79 publications

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“…In particular, adamantyl estradiol, also known as ZYC-5 and MX-4565, was demonstrated to lack activity at the classical estrogen receptor, and to provide more robust protection of cortical neurons from death induced by N-methyl-D-aspartate (NMDA) than estradiol [Xia et al, 2002]. Other adamantyl substituted estrogen analogues also have enhanced neuroprotective actions in a variety of in vivo and cell culture models of neuronal cell death [Liu et al, 2002;Simpkins et al, 2004;Kumar et al, 2005;Perez et al, 2005a;Dykens et al, 2004]. Adamantyl estradiol is a more effective free radical scavenger than estradiol , accounting in part for its enhanced neuroprotective actions, although additional factors likely also contribute to the mechanism of action.…”

Section: Introductionmentioning

confidence: 96%

“…The free-radical scavenging property of estradiol has been attributed to its ability to quench lipid hydroperoxy radicals by donation of the hydrogen atom from the hydroxyl group of the phenyl ring, whose aromatic nature stabilizes the resulting oxygen radical [Lacort et al, 1995;Kagan et al, 1990]. In fact, the minimal structural elements required for neuroprotection by estradiol have been identified as the hydroxyl group on the steroid A-ring and planarity of the steroid ring backbone [Dykens et al, 2004;Pike, 1999;Nakamizo et al, 2000;Green et al, 1997Green et al, , 2001. Therefore, estrogens are the focus of an increasing number of therapeutic strategies aimed at alleviating and preventing the devastating consequences of cellular injury implicated in neurodegenerative diseases, including stroke-related brain damage, Alzheimer's disease, Parkinson's disease, glaucoma, and retinitis pigmentosa [Gordon et al, 2005;Simpkins et al, 2005;Wise et al, 2000;Behl and Manthey, 2000;Garcia-Segura et al, 2001].…”

Section: Introductionmentioning

confidence: 98%

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Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR

Cegelski

Rice

O’Connor

et al. 2005

Drug Development Research

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR

Cegelski

Rice

O’Connor

et al. 2005

Drug Development Research

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“…S334ter rhodopsin leads to severe retinal degeneration phenotypes in several animal models. [31][32][33][34][35] By contrast to class II rhodopsins, which bear missense mutations that cause misfolding (e.g., enhanced oligomerization) and ER retention, S334ter rhodopsin lacks the 15 carboxyl-most residues required for proper intracellular trafficking as well as for precise termination of phototransduction signaling. [36][37][38] For these studies, we used the B630N antirhodopsin antibody rather than the 1D4 anti-rhodopsin antibody used in our other experiments, because 1D4 recognized a carboxyl-terminal epitope of rhodopsin that was deleted in the S334ter truncation mutant, whereas B630N recognized an amino-terminal epitope still present in the S334ter mutant rhodopsin (Fig.…”

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confidence: 99%

Selective Activation of ATF6 and PERK Endoplasmic Reticulum Stress Signaling Pathways Prevent Mutant Rhodopsin Accumulation

Chiang¹,

Hiramatsu²,

Messah³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Many rhodopsin mutations that cause retinitis pigmentosa produce misfolded rhodopsin proteins that are retained within the endoplasmic reticulum (ER) and cause photoreceptor cell death. Activating transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) control intracellular signaling pathways that maintain ER homeostasis. The aim of this study was to investigate how ATF6 and PERK signaling affected misfolded rhodopsin in cells, which could identify new molecular therapies to treat retinal diseases associated with ER protein misfolding. METHODS.To examine the effect of ATF6 on rhodopsin, wildtype (WT) or mutant rhodopsins were expressed in cells expressing inducible human ATF6f, the transcriptional activator domain of ATF6. Induction of ATF6f synthesis rapidly activated downstream genes. To examine PERK's effect on rhodopsin, WT or mutant rhodopsins were expressed in cells expressing a genetically altered PERK protein, Fv2E-PERK. Addition of the dimerizing molecule (AP20187) rapidly activated Fv2E-PERK and downstream genes. By use of these strategies, it was examined how selective ATF6 or PERK signaling affected the fate of WT and mutant rhodopsins.RESULTS. ATF6 significantly reduced T17M, P23H, Y178C, C185R, D190G, K296E, and S334ter rhodopsin protein levels in the cells with minimal effects on monomeric WT rhodopsin protein levels. By contrast, the PERK pathway reduced both levels of WT, mutant rhodopsins, and many other proteins in the cell.CONCLUSIONS. This study indicates that selectively activating ATF6 or PERK prevents mutant rhodopsin from accumulating in cells. ATF6 signaling may be especially useful in treating retinal degenerative diseases arising from rhodopsin misfolding by preferentially clearing mutant rhodopsin and abnormal rhodopsin aggregates. (Invest Ophthalmol Vis Sci. 2012; 53:7159-7166) DOI:10.1167/iovs.12-10222 R etinitis pigmentosa (RP) comprises a group of diseases arising from photoreceptor cell death that commonly present with loss of night vision followed by progressive loss of peripheral vision.1,2 The most common causes of autosomal dominant RP (ADRP) are mutations in rhodopsin, the visual pigment of the rod photoreceptor cells. More than 120 distinct rhodopsin mutations have been identified in ADRP (RetNet [Retinal Information Network]; may be accessed at www.sph. uth.tmc.edu/Retnet). Rhodopsin is a membrane glycoprotein of the G-protein-coupled receptor superfamily, with seven transmembrane helices surrounding a retinol-binding pocket buried within the transmembrane portion of the protein. Wild-type (WT) rhodopsin is synthesized and folded in the endoplasmic reticulum (ER) prior to delivery to the outer segment of the photoreceptor cells. Many mutant rhodopsin proteins (''class II mutants'') cannot fold properly and are retained within the ER, where they elicit ER stress and ultimately lead to the death of photoreceptor cells. [4][5][6][7][8][9] Cells respond to ER stress by activating the unfolded protein response (UPR), which i...

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“…The cytoprotective effects of both 17a-E2 and 17b-E2 have now been confirmed in many cell models (see the other articles in this issue), including excitotoxicity where cell death is due to mitochondrial failure and ensuing oxidative stress [Dykens, 1994[Dykens, , 1995[Dykens, , 1997Dykens et al, 2003Dykens et al, , 2004. For example, 17a-E2 and 17b-E2 are equipotent in their ability to moderate neuronal toxicity resulting from gp120 exposure, a pathology induced by a combination of N-methyl-D-aspartate (NMDA) receptor activation, accumulation of intracellular calcium, and downstream degenerative events including generation of reactive oxygen species and lipid peroxidation.…”

Section: Introductionmentioning

confidence: 93%

17β‐ and 17α‐estradiol are non‐competitive inhibitors of dopamine uptake: implications for Parkinson's disease models and therapeutics

Dykens¹,

Wersinger

Sidhu

2005

Drug Development Research

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Despite compelling literature documenting the cyto-and neuro-protective activities of various estrogens in a wide variety of cell and animal models, several large clinical trials of hormone replacement therapies have failed to detect such beneficial responses in humans. To some degree, this failure stems from profound hormonal responses that counterbalance the protective effects. This limitation could be circumvented by the development of less hormonally active estrogen analogs that retain the cytoprotective activities of the parental hormones. For example, 17a-estradiol (17a-E2) is at least 200-fold less active than 17b-estradiol (17b-E2) as a transactivating hormone, yet it is equipotent as a cytoprotectant in many cell types exposed to a variety of stressors, such as amyloid toxicity, serum withdrawal, oxidative stress, and glutamate excitotoxicity. Both estradiol isomers stabilize mitochondrial function under pathogenic conditions, and both have shown efficacy in animal models of stroke. The results for models of Parkinson's disease differ, and 17b-E2, but not 17a-E2, has been reported previously to provide neuroprotection against MPTP toxicity. However, such findings must be regarded in light of reports that 17b-E2 impedes cellular uptake of MPTP by the dopamine transporter (DAT), thereby forestalling development of the lesion rather than providing authentic cytoprotection. We report here that both 17a-E2 and 17b-E2 show classical, non-competitive, inhibition of dopamine uptake by the human DAT (hDAT) transfected into Ltk À mouse fibroblasts, HEK293 human embryonic kidney cells, and SH-SY5Y human neuroblastoma cells. IC 50 values vary slightly with cell type, but are 400 and 70 nM for 17a-E2 and 17b-E2, respectively, in SH-SY5Y cells. We also evaluated 17a-E2 in the 6-OH-dopamine (6-OHDA) model of PD, where toxin uptake occurs via the DAT. In these studies, treatment with estrogen was delayed for 6 hr after unilateral intrastriatal 6-OHDA injection to allow for toxin uptake. After 6 hr, a loading dose of 17a-E2 (100 mg/kg in sesame oil) was injected s.c., accompanied by implanting of a sustained release silastic device. After 21 days, animals treated with 17a-E2 showed significant improvements in both gait asymmetry and apo-morphine induced rotational defects. These positive results encourage evaluation of 17a-E2 in a host of neurodegenerative diseases. Drug Dev.

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Photoreceptor preservation in the S334ter model of retinitis pigmentosa by a novel estradiol analog

Cited by 29 publications

References 79 publications

Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR

Mapping the locations of estradiol and potent neuroprotective analogues in phospholipid bilayers by REDOR

Selective Activation of ATF6 and PERK Endoplasmic Reticulum Stress Signaling Pathways Prevent Mutant Rhodopsin Accumulation

17β‐ and 17α‐estradiol are non‐competitive inhibitors of dopamine uptake: implications for Parkinson's disease models and therapeutics

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