Retigabine (RTG) is an antiepileptic drug approved as an adjunctive treatment for refractory partial-onset seizures in adults. In April 2013, the Food and Drug Administration issued a warning that RTG could cause changes in retinal pigmentation and discoloration of skin, resulting in a blue appearance. As part of a larger preclinical effort to gain a mechanistic understanding as to the origins of retinal pigment changes associated with RTG, we conducted a long-term repeat dosing study in rats. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was used to determine the distribution of RTG and its metabolites in the rat eye following 13 and 39 weeks of dosing. IMS revealed the presence of RTG, a previously characterized N-acetyl metabolite of RTG (NAMR), and several species structurally related through the dimerization of RTG and NAMR. These species were highly localized to the melanin-containing layers of the uveal tract of the rat eye including the choroid, ciliary body, and iris, suggesting that the formation of these dimers occurs from melanin bound RTG and NAMR. Furthermore, several of the RTG-related dimers have UV absorbance which give them a purple color in solution. We propose that the melanin binding of RTG and NAMR effectively concentrates the two compounds to enable mixed condensation reactions to occur when the binding provides the proper geometry in the redox environment of the uveal tissues. High lateral resolution images illustrate that the blood-retinal barrier effectively restricts retinal access to RTG-related compounds. The spatial information provided by MALDI IMS was critical in contextualizing the homogenate concentrations of key RTG-related compounds and helped provide a basis for the mechanism of dimer formation.
Melanin is a polyanionic pigment that colors, e.g., the hair, skin and eyes. The pigment neuromelanin is closely related to melanin and is mainly produced in specific neurons of the substantia nigra. Certain drugs and chemicals bind to melanin/neuromelanin and are retained in pigment cells for long periods. This specific retention is thought to protect the cells but also to serve as a depot that slowly releases accumulated compounds and may cause toxicity in the eye and skin. Moreover, neuromelanin and compounds with high neuromelanin affinity have been suggested to be implicated in the development of adverse drug reactions in the central nervous system (CNS) as well as in the etiology of Parkinson's disease (PD). Epidemiologic studies implicate the exposure to pesticides, metals, solvents and other chemicals as risk factors for PD. Neuromelanin interacts with several of these toxicants which may play a significant part in both the initiation and the progression of neurodegeneration. MPTP/MPP(+) that has been casually linked with parkinsonism has high affinity for neuromelanin, and the induced dopaminergic denervation correlates with the neuromelanin content in the cells. Recent studies have also reported that neuromelanin may interact with α-synuclein as well as activate microglia and dendritic cells. This review aims to provide an overview of melanin binding of drugs and other compounds, and possible toxicological implications, with particular focus on the CNS and its potential involvement in neurodegenerative disorders.
Yes, Your Eyes Can Change Colors — and Here’s Why Search Advertisement Advertisement April 5, 2023 / Health Conditions / Eye Care Can Your Eyes Change Color? If your eyes suddenly take on a different color, it could be a sign of a medical concern Image content: This image is available to view online. View image online ( https://assets.clevelandclinic.org/transform/42d02b3f-e93b-47a8-8083-5dd886e99592/Eye-Color-Change-1419760033-770x533-1_jpg ) Person close up with brown eyes. Did you know that no two people on Earth have the same color eyes? Whether your peepers are brown, blue, green or some other hue, that shade is one-of-a-kind and absolutely unique to you. Advertisement Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy And if that color suddenly changes, it’s worth a visit to an eye doctor. Ophthalmologist Nicole Bajic, MD , explains why. Reasons your eye color might change Eye color rarely shifts after your first few years of life. (More on that childhood process in a bit.) A change in eye color as an adult “can absolutely signify something nefarious going on,” warns Dr. Bajic. Reasons could include: Changes to your iris Your iris (the colored part of your eye) may change through a virus or disease process, leading to a slightly different hue to your eyes. The color may lighten due to a loss of pigmentation in your iris or atrophy when the muscle in your iris grows thinner. Causes could include: Pigment dispersion syndrome. This condition results in pigment releasing from your iris, which causes atrophy of it and can lead to blurred vision and glaucoma . (On a related note, medication for glaucoma also may lead to eye color changes.) Pseudoexfoliation syndrome. This disease can cause a white, flaky material to build up on your iris, lens and other structures in your eye. The age-related condition can clog your eye’s drainage system and
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