• Cause, develop pharmacological treatment

    From ScienceDaily@1:317/3 to All on Thu Jan 27 21:30:48 2022
    Cause, develop pharmacological treatment for reducing retinitis
    pigmentosa vision loss
    Inhibiting ceramide accumulation in retina protects photoreceptors,
    improves vision

    Date:
    January 27, 2022
    Source:
    University of California - Irvine
    Summary:
    Researchers 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.



    FULL STORY ========================================================================== 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 inAdipoR1-/- mice increases photoreceptor survival and improves vision," was published
    this month in the Journal of Clinical Investigation Insight.

    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 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,
    PhD, 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 Dominik 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 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.

    ========================================================================== Story Source: Materials provided by
    University_of_California_-_Irvine. Note: Content may be edited for style
    and length.


    ========================================================================== Journal Reference:
    1. Dominik Lewandowski, Andrzej T. Foik, Roman Smidak, Elliot H. Choi,
    Jianye Zhang, Thanh Hoang, Aleksander Tworak, Susie Suh, Henri
    Leinonen, Zhiqian Dong, Antonio F.M. Pinto, Emily Tom, Jennings
    C. Luu, Joan Y.

    Lee, Xiuli Ma, Erhard Bieberich, Seth Blackshaw, Alan Saghatelian,
    David C. Lyon, Dorota Skowronska-Krawczyk, Marcin Tabaka, Krzysztof
    Palczewski.

    Inhibition of ceramide accumulation in AdipoR1-/- mice increases
    photoreceptor survival and improves vision. JCI Insight, 2022;
    DOI: 10.1172/jci.insight.156301 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/01/220127104205.htm

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