Progesterone as a neuroprotective treatment in the retina Öffentlichkeit
Allen, Rachael Stewart (2014)
Published
Abstract
The neurosteroid progesterone has been shown to have protective effects in a number of injury models, including traumatic brain injury and stroke. Progesterone has been shown to reduce inflammation and infarct size in the brain and improve behavioral outcomes after middle cerebral artery occlusion (MCAO), a stroke model thought to affect the retina as well as the brain. Here, the functional, morphological, and inflammatory responses of the retina after MCAO were examined and compared with responses in the brain. While the retina was found to exhibit similar responses to the brain, it showed a reduced susceptibility to the ischemic injury induced by MCAO. Next, we examined progesterone administration in two models of rodent ocular ischemia: the anterior ischemic optic neuropathy model, which causes monocular optic nerve stroke, and the MCAO model, which we showed caused retinal damage, inflammation, and functional deficits in conjunction with cerebral ischemia. Protective effects with progesterone treatment were observed in the retina following MCAO but not anterior ischemic optic neuropathy. While progesterone treatment was protective in both brain and retina after MCAO, greater reductions in inflammation were observed in the brain versus the retina and greater improvements were observed in brain function-based behavioral tasks than in the retina-based electroretinogram. Levels of progesterone receptor were assessed in retina and brain to confirm expression of progesterone receptor at the protein level in the retina. After MCAO, progesterone receptors were upregulated in brain and downregulated in retina, suggesting a potential mechanism for greater progesterone protection in brain over retina. These results demonstrate the promise of progesterone treatment in retinal ischemia and illustrate the importance of progesterone receptors in how injured tissue responds to progesterone treatment.
Table of Contents
CHAPTER 1: Introduction...1
General Introduction...2
Retinal Anatomy and Visual Processing...2
Anatomy and Structure...2
Neurotransmitters...6
Blood Supply and Blood Barriers in the Brain and Retina...8
Systemic and Brain Diseases that Involve the Retina...12
Ischemic Injury in the Brain and Retina...12
Diabetes and Diabetic Retinopathy...17
Alzheimer's Disease and Age-related Macular Degeneration...18
Parkinson's Disease and the Retina...20
Schizophrenia and the Retina...21
Summary...23
Progesterone as a Neuroprotective Treatment in the Retina...25
Abstract...25
Introduction...26
Ocular Trauma...26
Retinal and Optic Nerve Ischemias...27
Retinal Degenerations such as Retinitis Pigmentosa...27
Glaucoma...28
Few Effective Treatments...28
Ocular Trauma...28
Retinal and Optic Nerve Ischemias.29..
Retinal Degenerations such as Retinitis Pigmentosa...30
Glaucoma...30
The Nature of the Problem...31
Progesterone as a Candidate for Neuroprotective Treatment of the Retina...33
Progesterone's Effectiveness in Non-Ocular Disease Models...33
Progesterone in the Retina...35
Progesterone Research in Models of Ocular Disease and Injury...35
Positive Results...35
Negative Results...37
Evidence of Progesterone, Progesterone Receptors, and Progesterone Synthesis in the Retina...38
Human Studies and Anecdotal Evidence...43
Conclusion...44
Expert Opinion...44
Specific Aims of this Dissertation...48
CHAPTER 2: Retina is less susceptible than brain to ischemic injury caused by middle cerebral artery occlusion...56
Abstract...57
Introduction...59
Material and Methods...63
Animals...63
MCAO surgery...63
Neurological assessment...64
Electroretinogram...65
Retinal morphology and immunohistochemistry...66
Statistical analysis...67
Results...68
Retinal function deficits in MCAO animals are transient and correlate with behavioral deficits...68
Selective apoptosis in retinal ganglion cells from severe MCAO animals...76
Upregulation of GFAP and Glutamine Synthetase (GS) in MCAO retinas...78
Discussion...81
Retinal dysfunction without cell death with moderate MCAO...81
Transient retinal function deficits may be caused by sub-lethal increases in extracellular glutamate...82
The retina is less susceptible to MCAO although early retinal function deficits correlate with deficits in brain function...85
Conclusions...87
CHAPTER 3: Progesterone treatment in two rat models of ocular ischemia...89
Abstract...90
Introduction...91
Material and Methods...93
Animals...93
Progesterone preparation and dosing...94
Methods utilized in rAION experiment...94
rAION surgery...94
Fundus photographs...95
Visual evoked potential (VEP)...95
Immunohistochemistry for Brn3a...96
Methods utilized in MCAO experiment...97
MCAO surgery...97
Electroretinogram (ERG)...98
Neurological assessment...99
Grip Strength.99..
Sticky-tape task...99
TTC staining...99
Retinal morphology and immunohistochemistry...100
Statistical analysis.101..
Results...101
Progesterone treatment was not protective in the rAION model...101
Progesterone treatment protected against retinal ischemia induced by transient MCAO...106
Progesterone reduced ERG deficits in MCAO rats...106
Progesterone reduced upregulation of GFAP and GS in retinas from MCAO rats...111
Progesterone reduced retinal ganglion cell death in retinas from MCAO rats...114
Progesterone treatment protected against cerebral ischemia induced by transient MCAO...116
Progesterone reduced behavioral deficits in MCAO rats...116
Progesterone reduced infarct size in MCAO rats...118
Discussion...120
Progesterone treatment showed protection in MCAO but not rAION...120
Progesterone treatment showed greater protection in brain than retina following MCAO...121
Conclusions.123..
CHAPTER 4: Effect of progesterone on inflammation in brain versus retina in a rat model of middle cerebral artery occlusion...124
Abstract...125
Introduction...127
Material and Methods...129
Animals...129
MCAO surgery...130
Progesterone preparation and dosing...131
Biochemical evaluation...131
Statistical analysis...134
Results...134
NF-κB pathway activation increased in both brain and retina following MCAO and progesterone attenuated this increase...134
IL-6, TNF-α, and CD11b increased in both brain and retina following MCAO and progesterone attenuated these increases...139
Progesterone receptor is upregulated in the brain and downregulated in the retina after MCAO...144
PXR was also upregulated in brain but downregulated in retina after MCAO.. 147
Discussion...150
NF-κB pathway activation after retinal ischemia...150
Greater protection with progesterone was observed in brain vs. retina...153
Differences in PR expression in retina and brain may contribute to differences in responsiveness to progesterone treatment...155
PXR expression in brain vs. retina following transient MCAO...157
Conclusions...158
CHAPTER 5: Conclusions, Discussion, and Future Directions...159
Summary of Results...160
Discussion: Progesterone receptors in brain and retina...161
Expression and function of classical progesterone receptors in the brain...161
Retinal expression of progesterone and its receptors...162
Changes in PR expression with progesterone administration and injury...166
Different types of progesterone receptors in the nervous system...167
Discussion: Progesterone's mechanisms of action post-injury - involvement of PR and other receptors/pathways...169
PR-dependent mechanisms...169
PR-independent mechanisms...171
Allopregnanolone-mediated mechanisms...171
Other receptors/mechanisms...173
Future Directions...174
REFERENCES...176
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