Protective Effect of Carnosic Acid, a Pro-Electrophilic Compound, in Models of Oxidative Stress and Light-Induced Retinal Degeneration

Rezaie, Tayebeh; McKercher, Scott R.; Kosaka, Kunio; Seki, Masaaki; Wheeler, Larry A.; Viswanath, Veena; Chun, Teresa; Joshi, Rabina; Valencia, Marcos; Sasaki, Shunsuke; Tozawa, Terumasa; Satoh, Tsuyoshi; Lipton, Stuart A.

doi:10.1167/iovs.12-10793

Cited by 54 publications

(56 citation statements)

References 49 publications

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“…Moreover, unlike electrophilic compounds, PEDs do not deplete GSH from healthy cells because in the absence of oxidative stress PEDs are not converted to their active electrophilic form (1,37,50,51,66). Our group previously used CA to protect WT albino rats from severe light-induced photoreceptor damage (30). Here, we used transnasal administration of CA to protect photoreceptors from much lower levels of light exposure that would otherwise induce oxidative stress and photoreceptor cell death in Mef2d +/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…Because we found evidence for ROS generation and impaired NRF2 up-regulation in Mef2d +/− retinas exposed to light, we next sought to combat the increased ROS by upregulating the endogenous NRF2 pathway. We have previously shown that CA, a proelectrophilic compound found in the herb rosemary, readily crosses the blood-retina barrier and protects WT photoreceptors in albino rats from prolonged light-induced retinal degeneration related to oxidative stress (30). We showed that CA up-regulates endogenous antioxidant phase II enzymes via the NRF2 transcriptional pathway.…”

Section: Carnosic Acid Confers Neuroprotection In Vivo To Light-exposedmentioning

confidence: 91%

“…S1), we next asked if Mef2d heterozygosity might render photoreceptors more susceptible to environmental stress conditions such as oxidative insult. Generation of ROS has been associated with photoreceptor degeneration, as observed in the dry form of AMD, and has been shown to occur in response to excessive light (30,32). We exposed dark-adapted P45-60 Mef2d +/+ control (WT) mice and Mef2d +/− mice to 5,000 lux (lx) of white light for 2 h in a light box, followed by 7 d under dark conditions.…”

Section: Mef2dmentioning

confidence: 99%

“…We showed that CA up-regulates endogenous antioxidant phase II enzymes via the NRF2 transcriptional pathway. Moreover, this pathway is largely responsible for the mechanism of CA action because silencing Nrf2 significantly abrogated the protective effect (30,(40)(41)(42)(43). Here, we wanted to determine if CA could provide neuroprotection in the Mef2d +/− mice model of LIRD (44).…”

Section: Carnosic Acid Confers Neuroprotection In Vivo To Light-exposedmentioning

confidence: 99%

“…To combat this light-induced oxidative stress, we treat the Mef2d +/− mouse exposed to LIRD with the novel proelectrophilic compound carnosic acid (CA) (29). Proelectrophilic compounds enhance the endogenous antioxidant capacity of retinal cells during light damage (30). We show that this antioxidant ability prevents sulfonation of MEF2D and hence inhibition of its activity, thus preserving photoreceptor function.…”

mentioning

confidence: 98%

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MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...

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Section: Discussionmentioning

confidence: 99%

Section: Carnosic Acid Confers Neuroprotection In Vivo To Light-exposedmentioning

confidence: 91%

Section: Mef2dmentioning

confidence: 99%

Section: Carnosic Acid Confers Neuroprotection In Vivo To Light-exposedmentioning

confidence: 99%

mentioning

confidence: 98%

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MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Protein Carbonylation-Dependent Photoreceptor Cell Death Induced by N-Methyl-N-nitrosourea in Mice

Furukawa

Sugitani

Koriyama

2018

Retinal Degenerative Diseases

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Retinal degenerative diseases, such as retinitis pigmentosa, are characterized by night blindness and peripheral vision loss caused by the slowly progressive loss of photoreceptor cells. A comprehensive molecular mechanism of the photoreceptor cell death remains unclear. We previously reported that heat shock protein 70 (HSP70), which has a protective effect on neuronal cells, was cleaved by a calcium-dependent protease, calpain, in N-methyl-N-nitrosourea (MNU)-treated mice retina. Carbonylated HSP70 is much more vulnerable than noncarbonylated HSP70 to calpain cleavage. However, it was not known whether protein carbonylation occurs in MNU-treated mice retina. In this study, we clearly show protein carbonylation-dependent photoreceptor cell death induced by MNU in mice. Therefore, protein carbonylation and subsequent calpain-dependent cleavage of HSP70 are key events in MNU-mediated photoreceptor cell death. Our data provide a comprehensive molecular mechanism of the photoreceptor cell death.

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Expression and distribution of peroxiredoxins in the retina and optic nerve

et al. 2015

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Oxidative stress is implicated in various pathological conditions of the retina and optic nerve. Peroxiredoxins (Prdxs) comprise a recently characterized family of antioxidant enzymes. To date, little information exists regarding the distribution of Prdxs in the eye. Herein, we employed a combination of qRT-PCR, immunohistochemistry and Western blotting to determine the level of expression and distribution of the six Prdx isoforms in the retina and optic nerve of the rat. In addition, we performed some parallel analyses on the common marmoset (Callithrix Jacchus). In the rat, all of the Prdx transcripts were expressed in relatively high amounts in both retina and optic nerve, with abundances ranging from approximately 3–50 % of the level of the housekeeping gene cyclophilin. With regard to protein expression, each isoform was detected in the retina and optic nerve by either Western blotting and/or immunohistochemistry. Excepting Prdx4, there was a good correspondence between the rodent and primate results. In the retina, Prdx1 and Prdx2 were principally localized to neurons in the inner nuclear layer and cone photoreceptors, Prdx3 and Prdx5 displayed characteristic mitochondrial immunolabeling, while Prdx6 was associated with astrocytes and Müller cells. In the optic nerve, Prdx1 was robustly expressed by oligodendrocytes, Prdx3 and Prdx5 were observed in axons, and Prdx6 was restricted to astrocytes. The present findings augment our understanding of the distribution and expression of the Prdxs in the retina and optic nerve of rodents and primates and lay the foundation for subsequent analysis of their involvement in relevant blinding diseases.

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Protective Effect of Carnosic Acid, a Pro-Electrophilic Compound, in Models of Oxidative Stress and Light-Induced Retinal Degeneration

Abstract: These findings suggest that CA may potentially have clinical application to diseases affecting the outer retina, including age-related macular degeneration and retinitis pigmentosa, in which oxidative stress is thought to contribute to disease progression.

Cited by 54 publications

References 49 publications

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Protein Carbonylation-Dependent Photoreceptor Cell Death Induced by N-Methyl-N-nitrosourea in Mice

Expression and distribution of peroxiredoxins in the retina and optic nerve

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