C20D3-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model.

Purpose: This study aimed to evaluate the contribution of vitamin A dimerization to retinal pigment epithelium (RPE) atrophic changes. Leading causes of irreversible blindness, including Stargardt disease and age-related macular degeneration (AMD), occur as a result of atrophic changes in RPE. The cause of the RPE atrophic changes is not apparent. During the vitamin A cycle, vitamin A dimerizes, leading to vitamin A cycle byproducts, such as vitamin A dimers, in the RPE. Methods: To study the consequence of vitamin A dimerization to RPE atrophic changes, we used a rodent model with accelerated vitamin A dimerization, Abca4-/-/Rdh8-/- mice, and the vitamin A analog C20D3-vitamin A to selectively ameliorate the accelerated rate of vitamin A dimerization. Results: We show that ameliorating the rate of vitamin A dimerization with C20D3-vitamin A mitigates pathological changes observed in the prodromal phase of the most prevalent retinal degenerative diseases, including fundus autofluorescence changes, dark adaptation delays, and signature RPE atrophic changes. Conclusions: Data demonstrate that the dimerization of vitamin A during the vitamin A cycle is sufficient alone to cause the prerequisite RPE atrophic changes thought to be responsible for the leading causes of irreversible blindness and that correcting the dimerization rate with C20D3-vitamin A may be sufficient to prevent the RPE atrophic changes. Translational Relevance: Preventing the dimerization of vitamin A with the vitamin A analog C20D3-vitamin A may be sufficient to alter the clinical course of the most prevalent forms of blindness, including Stargardt disease and age-related macular degeneration (AMD).

Vitamin A cycle byproducts impede dark adaptation.

Impaired dark adaptation (DA), a defect in the ability to adjust to dimly lit settings, is a universal hallmark of aging. However, the mechanisms responsible for impaired DA are poorly understood. Vitamin A byproducts, such as vitamin A dimers, are small molecules that form in the retina during the vitamin A cycle. We show that later in life, in the human eye, these byproducts reach levels commensurate with those of vitamin A. In mice, selectively inhibiting the formation of these byproducts, with the investigational drug C20D3-vitamin A, results in faster DA. In contrast, acutely increasing these ocular byproducts through exogenous delivery leads to slower DA, with otherwise preserved retinal function and morphology. Our findings reveal that vitamin A cycle byproducts alone are sufficient to cause delays in DA and suggest that they may contribute to universal age-related DA impairment. Our data further indicate that the age-related decline in DA may be tractable to pharmacological intervention by C20D3-vitamin A.

Activation of Wnt signaling reduces ipsilaterally projecting retinal ganglion cells in pigmented retina.

In mammalian albinism, disrupted melanogenesis in the retinal pigment epithelium (RPE) is associated with fewer retinal ganglion cells (RGCs) projecting ipsilaterally to the brain, resulting in numerous abnormalities in the retina and visual pathway, especially binocular vision. To further understand the molecular link between disrupted RPE and a reduced ipsilateral RGC projection in albinism, we compared gene expression in the embryonic albino and pigmented mouse RPE. We found that the Wnt pathway, which directs peripheral retinal differentiation and, generally, cell proliferation, is dysregulated in the albino RPE. Wnt2b expression is expanded in the albino RPE compared with the pigmented RPE, and the expanded region adjoins the site of ipsilateral RGC neurogenesis and settling. Pharmacological activation of Wnt signaling in pigmented mice by lithium (Li+) treatment in vivo reduces the number of Zic2-positive RGCs, which are normally fated to project ipsilaterally, to numbers observed in the albino retina. These results implicate Wnt signaling from the RPE to neural retina as a potential factor in the regulation of ipsilateral RGC production, and thus the albino phenotype.

Predator-based psychosocial stress model of PTSD differentially influences voluntary ethanol consumption depending on methodology.

Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder typified by diagnostic symptom clusters including hyperarousal, avoidance, negative cognitions and mood, and intrusive re-experiencing of the traumatic event. Patients with PTSD have been reported to self-medicate with alcohol to ameliorate hyperarousal symptoms associated with the disorder. Research utilizing rodent models of PTSD to emulate this behavioral phenomenon has thus far yielded inconsistent results. In the present study, we examined the effects of a predator-based psychosocial stress model of PTSD on voluntary ethanol consumption. In the first of two experiments, following exposure to a 31-day stress or control paradigm, rats were singly housed during the dark cycle with free access to 1% sucrose solution or 10% ethanol, which was also sweetened with 1% sucrose. Over the course of a 20-day period of ethanol access, stressed rats consumed significantly less ethanol than non-stressed rats. These counterintuitive results prompted the completion of a second experiment which was identical to the first, except rats were also exposed to the two-bottle paradigm for 20 days before the stress or control paradigm. In the second experiment, after the stress manipulation, stressed rats exhibited significantly greater ethanol preference than non-stressed rats. These findings suggest that prior exposure to ethanol influences the subsequent effect of stress on ethanol intake. They also validate the use of the present model of PTSD to examine potential mechanisms underlying stress-related changes in ethanol-seeking behavior.

Sequestration of ubiquitous dietary derived pigments enables mitochondrial light sensing.

Animals alter their physiological states in response to their environment. We show that the introduction of a chlorophyll metabolite, a light-absorbing pigment widely consumed in human diets, to Caenorhabditis elegans results in animals whose fat mass can be modulated by exposure to light, despite the worm consuming the same amount of food. In the presence of the chlorophyll metabolite, exposing the worms to light increased adenosine triphosphate, reduced oxidative damage, and increased median life spans, without an effect on animal reproduction. Mice fed a dietary metabolite of chlorophyll and exposed to light, over several months, showed reductions in systemic inflammation as measured by plasma α-macroglobulin. We propose that dietary chlorophyll metabolites can enable mitochondria to use light as an environmental cue, by absorbing light and transferring the energy to mitochondrial coenzyme Q.