Researchers at the University of California, Irvine (UCI) have found that the absence of adiponectin receptor 1 (AdipoR1) protein, one of the key enzymes regulating ceramide homeostasis in the retina, leads to an accumulation of ceramides in the retina, leading to photoreceptor cell death and ultimately loss of vision.
According to a university press release, 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 improved 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 UCI statement noted that study results show that ceramide imbalance damages the neural retina and retinal pigmented epithelium, accompanied by a significant reduction in electroretinogram amplitudes, a decrease in retinoid content in the retina, reduced conical opsin expression and 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 UCI 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. Krzysztof Palczewski, PhD, Donald Bren Professor of Ophthalmology at the UCI Faculty of Medicine and co-corresponding author, said in the press release, “The results of our study highlight the importance of the ceramides AdipoR1 in the retina and show that the pharmacological inhibition of the generation of ceramides may provide a therapeutic strategy for patients with retinitis pigmentosa or AdipoR1-related retinopathies.”
According to the university, regeneration 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.
The UCI press release noted that ceramides are essential for eukaryotic cell membrane stability and act as potent signaling molecules in inflammation, cell cycle arrest, cell death and pathways. response to thermal shock. 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 the UCI School of Medicine in the press release. “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.