The absence of Adiponectin receptor 1 protein (AdipoR1), one of the main enzymes regulating ceramide homeostasis in the retina, leads to an accumulation of ceramides in the retina, resulting in progressive photoreceptor cell death and eventually vision loss, according to researchers from the University of California, Irvine.
Desipramine and L-cycloserine were also found to lower ceramide levels, which protected photoreceptors, helped retain the structure and function of the retina, and enhanced eyesight.
The study was published in the Journal of Clinical Investigation Insight this month and is titled “Inhibition of ceramide buildup in AdipoR1-/- mice increases photoreceptor survival and improves vision.”
Ceramide imbalance affects the neural retina and retinal pigmented epithelium, resulting in lower electroretinogram amplitudes, decreased retinoid content in the retina, reduced cone opsin expression, and a large inflammatory response, according to the findings.
Photoreceptor death was caused by an accumulation of ceramides in the retina, which was likely caused by insufficient ceramidase activity. Ceramide levels were reduced in mice treated with a combination of desipramine and L-cycloserine, which helped protect photoreceptors.
Noninvasive pharmacological treatment is more easily achieved in humans than gene therapy. Our proposed pharmacological strategy might become broadly applicable to other neurodegenerative conditions related to high ceramide levels.
Dominik Lewandowski
The researchers also noticed the enhanced daytime vision in the L-cycloserine-treated mice, as well as increased electrical responses of the primary visual cortex to visual stimuli after a long period of therapy.
“Although AdipoR1 is found in multiple organs, the highest levels are found in the eye and brain, suggesting its critical importance in these neural tissues. Our study results highlight the significance of AdipoR1 ceramides in the retina, and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for patients suffering from retinitis pigmentosa or AdipoR1-related retinopathies,” said Krzysztof Palczewski, Ph.D., Donald Bren Professor of Ophthalmology at the UCI School of Medicine and co-corresponding author.
Several progressive retinal disorders are caused by photoreceptor cell and retinal pigment epithelium degeneration. Many of these illnesses have treatment choices that are either ineffective or nonexistent. To fight these illnesses and reduce eyesight loss, new therapeutic techniques are urgently needed.
Ceramides are required for the stability of eukaryotic cell membranes and operate as signaling molecules in the pathways of inflammation, cell cycle arrest, cell death, and heat shock response. Cancer, Alzheimer’s disease, type 2 diabetes, multiple sclerosis, cardiovascular disease, and non-alcoholic fatty liver disease have all been linked to ceramide imbalance.
“Noninvasive pharmacological treatment is more easily achieved in humans than gene therapy,” said first and co-corresponding author Dominik Lewandowski, Ph.D., a postdoctoral scholar at the UCI School of Medicine. “Our proposed pharmacological strategy might become broadly applicable to other neurodegenerative conditions related to high ceramide levels.”
This work was supported by by funding from the National Institutes of Health under grants R24EY027283, NEI: F30 EY031566, and T32GM007250; and the Audacious Goals Initiative for Regenerative Medicine, a National Eye Institute program to push the boundaries of vision science and restore vision through regeneration of the retina, under grants P30 014195, and 1S10OD021815-01, and the Helmsley Center for Genomic Medicine.
