Currently, lowering of intra-ocular
pressure (IOP) remains the main therapeutic option for the treatment of
glaucoma. However, studies have shown that despite adequate control of IOP a
large number of patients develop loss of visual function. This has spurred
researchers to look for new options for the management of glaucoma.
According to Dr. Qui N. Cui, Assistant
Professor of Ophthalmology at the Perelman School of Medicine, affiliated to
the University of Pennsylvania, USA, “All available treatments for glaucoma
target IOP control, which is not sufficient to prevent vision loss in a
significant number of patients”.
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| Prof. Qui N. Cui |
Apoptosis, pyroptosis, and necroptosis are classical forms of regulated cell death that play important roles in various diseases. Ferroptosis was a regulated cell death described by Dixon et al. who used elastin to treat cancer cells containing oncogene mutations. They found an iron-dependent and lipid peroxidation-triggered cell death pathway, which relies on iron-generated reactive oxygen species. In the eye, this process can lead to acute retinal degeneration.
There is increasing evidence supporting the
association between ferroptosis and glaucoma. A clinical study involving 17,476
participants showed that a high serum ferritin level was associated with
increased risk and morbidity of glaucoma. Upon facilitated release of ferric
iron by increased ferritin, a redox reaction is triggered. This iron-induced
oxidative stress is suggested to contribute to optic nerve degeneration in
glaucoma.
SEE LINK: https://ourgsc.blogspot.com/search?q=ferroptosis
Also, iron-related genes transferrin,
ceruloplasmin and ferritin were shown to be upregulated in a monkey model of
glaucoma, and in glaucomatous human post mortem eyes, suggesting a role for
iron-induced oxidative stress in glaucoma pathogenesis.
Antioxidant administration has been shown
to rescue rodent RGCs exposed to extended periods of IOP elevation. These
associations suggest iron chelation may slow glaucoma progression.
Deferiprone (DFP), is an
orally-administrated iron chelator approved by the FDA for treating patients
with iron overload. Oral administration of DFP protects against iron-induced
retinal degeneration by reducing retinal iron levels in
ceruloplasmin/hephaestin double-knockout and hepcidin knockout mice, both of
which exhibit age-related retinal iron accumulation and increased oxidative
stress.
In a study performed by Dr. Qui and
colleagues, a mouse model of elevated IOP was used in which one eye had
experimental ocular hypertension and the other was kept as normotensive
control. Half the cohort received oral DFP (1 mg/ml in the drinking water), the
other half did not and served as controls. After 8 weeks, Brn3a immunolabeling
of flat-mounted retinas was used for manual RGC quantification. Axon counts
were obtained from thin sections of optic nerves using the AxonJ plugin for
ImageJ.
DFP administration was found to be protective
against RGC and optic nerve loss in the setting of elevated IOP. These results
suggest that iron chelation by DFP may provide glaucoma neuroprotection.
A side-effect of DFP administration is
reversible agranulocytosis, which requires weekly blood evaluations. Therefore,
the utility of DFP as long-term treatment for a slowly progressive
neurodegenerative condition like glaucoma remains to be seen. Alternatives to
systemic DFP administration may lie in local, targeted ocular administration
and/or other iron chelators.
REFERENCE:
Cui QN, Bargoud AR, Ross AG, Song Y, Dunaief JL. Oral administration of the iron chelator deferiprone protects against loss of retinal ganglion cells in a mouse model of glaucoma. Exp Eye Res. 2020 Apr;193:107961. doi: 10.1016/j.exer.2020.107961. Epub 2020 Feb 8. PMID: 32045598; PMCID: PMC7584350
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012 May 25;149(5):1060-72. doi: 10.1016/j.cell.2012.03.042. PMID: 22632970; PMCID: PMC3367386.
