Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Abstract

The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stressinduced damage in an established RPE cell line . Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K + channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD.preconditioning | oxidative stress | sulindac | retinal pigmented epithelial cells | age-related macular degeneration O xidative damage, resulting from excess production of reactive oxygen species (ROS), has been implicated in the progression of key ocular disorders such as cataracts, glaucoma, and age-related macular degeneration (AMD). Death of retinal pigmented epithelial (RPE) cells has been shown to be an important contributor to AMD pathophysiology. RPE cells are known to be highly metabolically active, and there is strong evidence that the RPE cells are sensitive to oxidative stress (1). It has been reported that the pathophysiology of AMD is due to cumulative oxidative damage to RPE cells resulting from an imbalance between the generation of ROS and the ability of these cells to destroy and/or protect against ROS damage to macromolecules (2, 3). Hence, strategies for protecting RPE cells against oxidative damage may be particularly important in maintaining retinal function and preventing the development or progression of AMD.Sulindac was one of the first nonsteroidal antiinflammatory drugs (NSAIDs) used to treat inflammation. It is a prodrug, composed of R and S epimers, whose NSAID activity is dependent on the reduction of the epimers to sulindac sulfide, the active cyclooxygenase (COX) inhibitor (4). This reduction is catalyzed by two members of the methionine sulfoxide reductase (Msr) family, MsrA and MsrB,...

A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cellsin vitro

“…We are not the firsts to point out the potential importance of NRs and particularly, PPARs in controlling several AMD-pathogenic pathways (46)(47)(48)(49)(50)(51). Indeed, it has been shown that PPAR-a agonists protect RPE cells from an oxidative stress insult in vitro (52) and reduce angiogenesis in mouse models of neovascular AMD (53). PPAR-b/d modulation seems to play different roles in dry AMD and neovascular AMD models.…”

Identification of activators of methionine sulfoxide reductases A and B

“…The two mechanisms that have been of interest to us are a protective pharmacological preconditioning response [31, 32]and the Msr protein repair system. The present studies describe for the first time activators of recombinant MsrA and MsrB that are derivatives of the naturally occurring antibiotic fusaricidin A [28].…”

“…We are particularly interested in studying oxidative damage in the retina, where we have recently shown that sulindac, a substrate for the Msr enzymes, initiates a pharmacological preconditioning response that protects retinal pigmented epithelial (RPE) cells against oxidative damage [32]. MsrA is found in high concentrations in RPE cells [34], and the retina is very sensitive to oxidative damage which can lead to loss of the photoreceptor cells that are involved in diseases including age related macular degeneration, diabetic retinopathy, and the genetic disease, retinitis pigmentosa.…”

Integrated Approaches to Drug Discovery for Oxidative Stress‐Related Retinal Diseases

“…For example, peroxisome proliferator-activated receptor α (PPARA, Figure 3(c)) is the pharmacological target of fibrates such as fenofibrate, clofibrate, and bezafibrate [35]. PPARA is associated with both antioxidant and anti-inflammatory activities and has previously been suggested as a therapeutic target in AMD [95–97]. In fact, several clinical trials have revealed that fenofibrate can improve diabetic retinopathy [98, 99], which shares some pathophysiological mechanisms with AMD, including OS [100, 101].…”