Inhibition of ceramide accumulation in the retina protects photoreceptors and improves vision


Researchers from the University of California at Irvine have found that the absence of adiponectin receptor 1 (AdipoR1) protein, one of the main enzymes regulating ceramide homeostasis in the retina, leads to an accumulation of ceramides in the retina, leading to the progressive death of photoreceptor cells. and ultimately loss of vision. The team also found that a combination of desipramine and L-cycloserine reduced levels of ceramides, which protect photoreceptors, help preserve retinal structure and function, and improve vision.

The study, titled “Inhibition of ceramide accumulation in AdipoR1-/- mouse increases photoreceptor survival and improves vision,” was published this month in the Journal of Clinical Investigation.

The results of the study show that the imbalance of ceramides damages the neural retina and the retinal pigmented epithelium, accompanied by a significant reduction in the amplitudes of the electroretinogram, a decrease in the content of retinoids in the retina, reduced conical opsin expression and a massive inflammatory response. An accumulation of ceramides in the retina, probably due to insufficient ceramidase activity, led to the death of photoreceptors. When treated with the combination of desipramine and L-cycloserine, ceramide levels were lowered, which helped preserve photoreceptors in mice. The team also observed improved daylight vision in mice treated with L-cycloserine, and this prolonged treatment significantly improved the electrical responses of the primary visual cortex to visual stimuli.

“Although AdipoR1 is found in multiple organs, the highest levels are found in the eyes and brain, suggesting its critical importance in these neural tissues. The results of our study highlight the importance of AdipoR1 ceramides in the retina and show that pharmacological inhibition of ceramide generation may provide a therapeutic strategy for patients with retinitis pigmentosa or AdipoR1-related retinopathies.” said Krzysztof Palczewski, PhD, Donald Bren Professor of Ophthalmology at UCI School of Medicine and co-corresponding author.

Degeneration of photoreceptor cells and retinal pigment epithelium is the underlying cause of several progressive retinal diseases. Many of these conditions have minimal effectiveness or no treatment options. New therapeutic approaches are urgently needed to combat these disorders and reduce vision loss.

Ceramides are essential for eukaryotic cell membrane stability and act as potent signaling molecules in inflammation, cell cycle arrest, cell death, and heat shock response pathways. An imbalance of ceramides has also been found in cancer, Alzheimer’s disease, type 2 diabetes, multiple sclerosis, cardiovascular disease, and non-alcoholic fatty liver disease.

“Non-invasive pharmacological treatment is more easily achieved in humans than gene therapy,” said first and corresponding co-author Dominik Lewandowski, PhD, postdoctoral researcher at UCI School of Medicine. “Our proposed pharmacological strategy may become broadly applicable to other neurodegenerative conditions linked to elevated levels of ceramides.”

This work was supported 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 retinal regeneration, under grants P30 014195 and 1S10OD021815- 01, and the Helmsley Center for Genomic Medicine.

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Material provided by University of California – Irvine. Note: Content may be edited for style and length.


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