In vivo inhibition of l-buthionine-(S,R)-sulfoximine-induced cataracts by a novel antioxidant, N-acetylcysteine amide

Carey, Joshua W.; Pınarcı, Eylem Yaman; Penugonda, Suman; Karacal, Hümeyra; Erçal, Nuran

doi:10.1016/j.freeradbiomed.2010.12.017

Cited by 41 publications

(26 citation statements)

References 59 publications

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“…The protective effects of NACA are probably mediated by a number of pathways, which may include supplying cysteine for GSH biosynthesis, reduction of extracellular cystine to cysteine, and conversion of GSSG to GSH by the action of GR and by non-enzymatic thiol disulfide exchange. 12,[26][27][28] Our results are in agreement with previous studies which reported an increase in GSH levels after NACA incubation and a decrease in GSH levels upon TBHP treatment in an ARPE cell line. 11,14 Importantly, changes in the GR activity were also observed.…”

Section: Discussionsupporting

confidence: 93%

“…It has demonstrated efficacy in numerous in vitro and animal models of other oxidative stress-related conditions, including drug-induced RPE damage and cataracts. [11][12][13][14][15] Our lab has demonstrated that NACA prevented retinal degeneration in vitro and in animal models.14 The immortalized ARPE-19 cell line was used as an in vitro model because primary human RPE cells were not available at the time. ROS generation and lipid peroxidation induced by tert-butyl hydroperoxide (TBHP) were reversed by pretreatment with NACA.…”

mentioning

confidence: 99%

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The role of N-acetylcysteine amide in defending primary human retinal pigment epithelial cells against tert-butyl hydroperoxide- induced oxidative stress

Wang

Huang

Tobwala

et al. 2017

FRA

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INTRODUCTIONAge-related macular degeneration (AMD) accounts for 8.7% of blindness worldwide, and it is a leading cause of blindness in the United States among adults age 60 and older. [1][2][3] Globally, about 1 in 32 visual impairments and 1 in 15 cases of blindness are due to macular disease. 4 Dry AMD is a degenerative condition that begins in Bruch's membrane and progresses to the retinal pigment epithelium (RPE) and the overlying photoreceptors with loss of central vision. The RPE is a single layer of pigment cells lying between the photoreceptors and choriocapillaris. The functions of the RPE include light absorption, epithelial transport, phagocytosis, secretion, and immune modulation. All of these functions are important to maintaining and supporting the photoreceptors. High blood flow rate and high O 2 saturation in the choriocapillaris render the RPE more exposed to oxidative stress. 5Oxidative stress seems to play a major role in the pathogenesis of dry AMD and retinal degeneration, although the pathophysiology of dry AMD is complex. 5,6 The macula is subject to increased levels of photooxidative stress because of its elevated metabolic rate and high proportion of polyunsaturated fatty acids, which are highly susceptible to lipid peroxidation. As the RPE cells of the macula age, oxidation of lipids and other cellular components results in an accumulation of indigestible lipofuscin in the lysosomes. The accumulation of lipofuscin granules closely parallels drusen formation in time course and distribution in the retina. Oxidative damage to the mitochondrial DNA in RPE cells has also been implicated in the development of AMD. Levels of antioxidants in retinal tissue, in particular glutathione (GSH), decrease with aging, making the macula even more vulnerable to progressive oxidative damage. 7,8 Endogenous antioxidants, such as GSH, cannot be replaced directly. Instead, compounds that can easily enter cells and increase intracellular antioxidant levels are preferred. Dietary antioxidants have been shown to slow the progression of retinal degeneration and halt progression of AMD in human clinical trials.9,10 GSH and its amino acid precursors protect RPE cells from oxidative injury and oxidant-induced apoptosis in vitro. N-acetylcysteine amide (NACA), a GSH prodrug, is a promising candidate for use as an antioxidant-based treatment for AMD. It has demonstrated efficacy in numerous in vitro and animal models of other oxidative stress-related conditions, including drug-induced RPE damage and cataracts. [11][12][13][14][15] Our lab has demonstrated that NACA prevented retinal degeneration in vitro and in animal models.14 The immortalized ARPE-19 cell line was used as an in vitro model because primary human RPE cells were not available at the time. ROS generation and lipid peroxidation induced by tert-butyl hydroperoxide (TBHP) were reversed by pretreatment with NACA. NACA also protected against TBHP-induced cell damage by increasing cellular levels of GSH, and maintaining cellular integrity, as measured by tra...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

The role of N-acetylcysteine amide in defending primary human retinal pigment epithelial cells against tert-butyl hydroperoxide- induced oxidative stress

Wang

Huang

Tobwala

et al. 2017

FRA

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“…In contrast, N-acetylcysteine amide (NACA), an analog of NAC, has been shown to be more effective than NAC, owing to its neutral amide group, which increases its lipophilicity and, consequently, its penetration into cell membranes. This has been verified in previous studies, as well as its ability to chelate Cu 2+ , scavenge free-radicals, and protect against oxidative stress [29][30][31][32][33][34][35][36]. Our lab has demonstrated NACA's improved antioxidant ability compared to that of NAC [33,37].…”

supporting

confidence: 80%

Prevention and reversal of selenite‐induced cataracts by N‐acetylcysteine amide in Wistar rats

Maddirala

Tobwala

Karacal

et al. 2016

Acta Ophthalmologica

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Background: The present study sought to evaluate the efficacy of N-acetylcysteine amide (NACA) eye drops in reversing the cataract formation induced by sodium selenite in male Wistar rat pups. Methods: Forty male Wistar rat pups were randomly divided into a control group, an N-acetylcysteine amide-only group, a sodium selenite-induced cataract group, and a NACA-treated sodium selenite-induced cataract group. Sodium selenite was injected intraperitoneally on postpartum day 10, whereas N-acetylcysteine amide was injected intraperitoneally on postpartum days 9, 11, and 13 in the respective groups. Cataracts were evaluated at the end of week 2 (postpartum day 14) when the rat pups opened their eyes. N-acetylcysteine amide eye drops were administered beginning on week 3 until the end of week 4 (postpartum days 15 to 30), and the rats were sacrificed at the end of week 4. Lenses were isolated and examined for oxidative stress parameters such as glutathione, lipid peroxidation, and calcium levels along with the glutathione reductase and thioltransferase enzyme activities. Casein zymography and Western blot of m-calpain were performed using the water soluble fraction of lens proteins. Results: Morphological examination of the lenses in the NACA-treated group indicated that NACA was able to reverse the cataract grade. In addition, glutathione level, thioltransferase activity, m-calpain activity, and m-calpain level (as assessed by Western blot) were all significantly higher in the NACA-treated group than in the sodium selenite-induced cataract group. Furthermore, sodium selenite-injected rat pups had significantly higher levels of malondialdehyde, glutathione reductase enzyme activity, and calcium levels, which were reduced to control levels upon treatment with NACA.

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“…NACA acts as a carrier of NAC and its antioxidant and free radical scavenging abilities are equal to or better than those of NAC (Ates et al, 2008;Penugonda et al, 2011;Tobwala et al, 2014). Previous studies have shown that NACA is lipophilic and can cross membranes, chelate Cu 2þ , scavenge free-radicals, and protect against oxidative stress (Banerjee et al, 2009;Carey et al, 2011;Grinberg et al, 2005;Penugonda et al, 2011;Tobwala et al, 2013;Zhang et al, 2009Zhang et al, , 2012. Promising results with NACA in various oxidative stressrelated disorders encouraged us to investigate the ability of NACA to protect against Mn-induced toxicity.…”

Section: Introductionmentioning

confidence: 99%

N-acetylcysteineamide protects against manganese-induced toxicity in SHSY5Y cell line

2015

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In vivo inhibition of l-buthionine-(S,R)-sulfoximine-induced cataracts by a novel antioxidant, N-acetylcysteine amide

Cited by 41 publications

References 59 publications

The role of N-acetylcysteine amide in defending primary human retinal pigment epithelial cells against tert-butyl hydroperoxide- induced oxidative stress

The role of N-acetylcysteine amide in defending primary human retinal pigment epithelial cells against tert-butyl hydroperoxide- induced oxidative stress

Prevention and reversal of selenite‐induced cataracts by N‐acetylcysteine amide in Wistar rats

N-acetylcysteineamide protects against manganese-induced toxicity in SHSY5Y cell line

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