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News — Irvine, Calif., Jan. 26, 2022 — Researchers from the University of California, Irvine have discovered that the absence of Adiponectin receptor 1 protein (AdipoR1), one of the principal enzymes regulating ceramide homeostasis in the retina, leads to an accumulation of ceramides in the retina, resulting in progressive photoreceptor cell death and ultimately vision loss. The team also found that a combination of desipramine and L-cycloserine reduced lowered ceramide levels, which protected photoreceptors, helped preserve the retina’s structure and function, and improved vision.

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

Study findings show that ceramide imbalance damages the neural retina and retinal pigmented epithelium, accompanied by a significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, reduced cone opsin expression and massive inflammatory response. A buildup of ceramides in the retina, likely due to insufficient ceramidase activity, led to photoreceptor death. When treated with the desipramine and L-cycloserine combination, ceramide levels were lowered, which helped preserve photoreceptors in mice. The team also observed improved daylight vision in the L-cycloserine treated mice, and that prolonged treatment significantly improved electrical responses of the primary visual cortex to visual stimuli.

“Although AdipoR1is 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 , Donald Bren Professor of Ophthalmology at the 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 only minimally effective 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. Ceramide imbalance has also been found in cancer, Alzheimer’s disease, type 2 diabetes, multiple sclerosis, cardiovascular disease and non-alcoholic fatty liver disease.

“Noninvasive pharmacological treatment is more easily achieved in humans than gene therapy,” said first and co-corresponding author Dominick Lewandowski, PhD, 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 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.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. 麻豆传媒 & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit .

About the UCI School of Medicine: Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and master’s students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit .

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