Photoreceptor preservation in the S334ter model of retinitis pigmentosa by a novel estradiol analog.
The cytoprotective activity of MITO-4565, a novel, non-hormonal, estradiol derivative, was evaluated in the S334ter transgenic model of retinitis pigmentosa (RP). Progressive blindness in RP is due to apoptotic death of the photoreceptors, a process mimicked by the animal models [Portera-Cailliau C, Sung C-H, Nathans J, Adler R. Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA 1994;91:974-8]. On postnatal day 9, 10 transgenic S334ter rats received a single intraocular injection of MITO-4565 in the left eye, and vehicle in the right eye. By postnatal day 20, the thickness of the outer nuclear layer (ONL) in the superior retina of the untreated eyes was 5.76 +/- 1.12 microm (N = 10), versus 10.72 +/- 1.52 microm (N = 10) for eyes treated with MITO-4565 (P < 0.0001, ANOVA F = 1671). Comparable cytoprotection was also observed for the inferior retina. Cytoprotection by MITO-4565 was also observed in primary cultures of rat retinal ganglion cells against NMDA excitotoxicity. Data from studies of hexose monophosphate shunt flux, mitochondrial stability, and in vitro lipid peroxidation, are in accord with previous reports [Green PS, Gridley KE, Simpkins JW. Nuclear estrogen receptor independent neuroprotection by estratrienes: a novel interaction with glutathione. Neuroscience 1997;84:7-10]; a likely mechanism of action entails moderation of membrane lipid peroxidation in a redox couple with glutathione. Such preservation of membrane integrity is particularly crucial to mitochondria, where collapse of membrane potential precipitates cell death, and where GSH is maintained at mM concentrations. Indeed, exposure to MITO-4565, but not a methoxy substituted negative control, allowed mitochondria to retain membrane potential (DeltaPsi(m)) under conditions of Ca(2+) overload that would normally induce complete mitochondrial failure. Mitochondrial interventions offer a novel therapeutic approach for RP, and other degenerative diseases of the retina.
Dykens
James A
JA
MitoKor Inc., 11494 Sorrento Valley Road, San Diego, CA 92121, USA. dykensj@mitokor.com
Carroll
Amy K
AK
Wiley
Sandra
S
Covey
Douglas F
DF
Cai
Zu Yun
ZY
Zhao
Lian
L
Wen
Rong
R
D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010786:Photoreceptor Cells / Q000187:drug effects* / Q000502:physiology; D011309:Preservation, Biological; D051381:Rats; D020318:Rats, Long-Evans; D012162:Retinal Degeneration; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D012174:Retinitis Pigmentosa / Q000473:pathology*
D004958:Estradiol