Role of Nonfeminizing Estrogen Analogues in Neuroprotection of Rat Retinal Ganglion Cells Against Glutamate-Induced Cytotoxicity

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dc.contributor.advisorAgarwal, Neeraj
dc.contributor.committeeMemberGracy, Robert
dc.contributor.committeeMemberGarner, Margaret
dc.creatorKumar, Domalapalli Maneesh
dc.date.accessioned2019-08-22T21:21:30Z
dc.date.available2019-08-22T21:21:30Z
dc.date.issued2007-05-01
dc.date.submitted2013-10-10T06:30:13-07:00
dc.description.abstractKumar, Domalapalli Maneesh, Role of Nonfeminizing Estrogen Analogues in Neuroprotection of Rat Retinal Ganglion Cells against Glutamate-Induced Cytotoxicity, Doctor of Philosophy (Cell Biology and Genetics), May, 2007, 210 pp., 3 tables, 23 figures, bibliography, 427 titles. Retinal ganglion cell death has been determined to be the final common pathway in glaucoma. Continuous loss of retinal ganglion cells results in irreversible progressive visual field deterioration that culminates in blindness. No effective therapy is currently available to reverse retinal ganglion cell loss. Therefore, preventing the loss of retinal ganglion cells is a logical approach to maintaining vision in effected individuals. Of the methods of investigation, in vivo models of ganglion cell death provide a physiological system in which to study neuroprotective drugs and their effects, but these systems are inefficient for initial screening studies. We have addressed this by utilizing the RGC-5 clonal rat retinal ganglion cell line. Glutamate treatment of RGC-5 cells induces apoptotic death which can be attenuated by pretreatment with the anti-oxidants N-acetyl cysteine and thiourea, implicating oxidative stress as a major component of glutamate’s cytotoxicity. Also antioxidants, estrogens have been demonstrated to be potent neuroprotectants in a variety of in vitro and in vivo models of neurodegeneration. Estrogens’ antioxidant capacity has been attributed to the ability of the phenolic A ring to quench and resonance stabilize oxidative free radicals. It is also known that the estrogen A ring is responsible for binding of these hormones to estrogen receptors, producing feminizing phenotypes. The feminizing effects of estrogens narrow or preclude their use as neuroprotectants in males, and in females that may be predisposed to their deleterious effects. To address these shortcomings we screened 13, non-feminizing, non-receptor binding estrogen analogues in our glutamate-induced RGC-5 model of oxidative stress-induced cell death. The most effective of these drugs was ZYC-3. ZYC-3 was synthesized by the addition of an adamantly group to the C2 position on the A ring of estrone. This modification produced a neuroprotective compound with potency and efficacy at least equal to the prototypical estrogen, 17β-estradiol, but with no appreciable binding affinity for estrogens receptors α or β. Our preliminary findings suggest that ZYC-3 enhances glutathione synthesis and blocks mitochondrial apoptotic pathways. However, as a novel drug we are naïve to its effects on cellular physiology and as to how it affords neuroprotection. Understanding how this drug regulates cellular destructive and protective mechanisms could lead to further innovations in drug design and in methods to prevent retinal ganglion cell degeneration. In vivo studies of this drug may then form the bridge to a better clinical approach to managing ocular disorders in which ganglion cell loss is the culprit for vision loss. Although promising, evidence supporting the application of estrogen analogues in models of ocular neurodegenerative diseases are nearly non-existent. It is our objective to study the neuroprotective effects of ZYC-3 in glaucomatous models with the goal of maintaining retinal ganglion cell viability and preventing vision loss.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29271
dc.language.isoen
dc.provenance.legacyDownloads0
dc.subjectCell and Developmental Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectChemicals and Drugs
dc.subjectComparative and Laboratory Animal Medicine
dc.subjectEye Diseases
dc.subjectLife Sciences
dc.subjectMedical Cell Biology
dc.subjectMedicine and Health Sciences
dc.subjectOphthalmology
dc.subjectOptometry
dc.subjectOther Cell and Developmental Biology
dc.subjectPharmacy and Pharmaceutical Sciences
dc.subjectPhysiology
dc.subjectVision Science
dc.subjectNonfeminizing estrogen analogues
dc.subjectneuroprotection
dc.subjectrat retinal cells
dc.subjectglutamate-induced cytotoxicity
dc.subjectretinal ganglion cell death
dc.subjectglaucoma
dc.subjectvision
dc.subjectcell death
dc.subjectZYC-3
dc.subjectdrug
dc.titleRole of Nonfeminizing Estrogen Analogues in Neuroprotection of Rat Retinal Ganglion Cells Against Glutamate-Induced Cytotoxicity
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineCell Biology and Genetics
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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