Retinal ganglion cell protection by 17-beta-estradiol in a mouse model of inherited glaucoma.

Abstract

Glaucoma is the second leading cause of blindness in the world. The ultimate cause of vision loss due to glaucoma is thought to be retinal ganglion cell (RGC) apoptosis. Neuroprotection of RGC is becoming an important approach of glaucoma therapy. Several lines of evidence suggest that estrogen has neurotrophic and neuroprotective properties. In this study, we examine the role of estrogen in preventing RGC loss in DBA/2J mouse, an in vivo model of an inherited (pigmentary) glaucoma. Two-month-old female DBA/2J mice were anesthetized and ovariectomized with or without subcutaneous 17beta-estradiol (betaE2) pellet implantation. RGC survival was evaluated from flat-mounted whole retinas by counting retrograde-labeled cells. The loss of nerve fibers and RGC were also evaluated in paraffin-fixed retinal cross sections. Biochemical alterations in the retinas of DBA/2J mice in response to systemic injection of betaE2 were also examined. We have made several important observations showing that: (1) betaE2 treatment reduced the loss of RGC and neurofibers through inhibition of ganglion cell apoptosis, (2) betaE2 activated Akt and cAMP-responsive-element-binding-protein (CREB), (3) betaE2 up-regulated thioredoxin-1 (Trx-1) expression, (4) betaE2 reduced the increased activations of mitogen-activated protein kinases (MAPK) and NF-kappaB, (5) betaE2 inhibited the increased interleukin-18 (IL-18) expression, and (6) treatment with tamoxifen, an estrogen receptor antagonist, blocked betaE2-mediated activation of Akt and inhibition of MAPK phosphorylation in the retinas of DBA/2J mice. These findings suggest the possible involvement of multiple biochemical events, including estrogen receptor/Akt/CREB/thioredoxin-1, and estrogen receptor/MAPK/NF-kappaB, in estrogen-mediated retinal ganglion cell protection.

• Authors: Xiaohong Zhou, Feng Li, Jian Ge, Steven R Sarkisian Jr, Hiroshi Tomita, Alexander Zaharia, James Chodosh, Wei Cao
• Journal: Developmental neurobiology (Dev Neurobiol) Vol. 67 Issue 5 Pg. 603-16 (Apr 2007) ISSN: 1932-8451 [Print] United States
• PMID: 17443811 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2007 Wiley Periodicals, Inc.

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Drug Implants
• Estrogen Antagonists
• Interleukin-18
• NF-kappa B
• Tamoxifen
• Estradiol
• Thioredoxins
• Oncogene Protein v-akt
• Mitogen-Activated Protein Kinases
• Caspase 3
• Digoxigenin

Topics

• Animals
• Blotting, Western
• Caspase 3 (biosynthesis)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Digoxigenin (metabolism)
• Drug Implants
• Electrophoretic Mobility Shift Assay
• Enzyme Activation (drug effects)
• Estradiol (administration & dosage, pharmacology)
• Estrogen Antagonists (pharmacology)
• Female
• Glaucoma (genetics, physiopathology, prevention & control)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Interleukin-18 (biosynthesis)
• Intraocular Pressure (drug effects)
• Mice
• Mice, Inbred DBA
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (drug effects)
• Nerve Fibers (drug effects)
• Oncogene Protein v-akt (metabolism)
• Ovariectomy
• Phosphorylation
• Retinal Ganglion Cells (drug effects, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• Tamoxifen (pharmacology)
• Thioredoxins (biosynthesis)
• Up-Regulation