Manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, a superoxide dismutase mimetic, reduces disease severity in in vitro and in vivo models for dry-eye disease

Ziniauskaite, Agne; Ragauskas, Symantas; Ak, Ghosh; Thapa, Rubina; Roessler, Anne; Koulen, Peter; Kalesnykas, Giedrius; Hakkarainen, Jenni J.; Kaja, Simon

doi:10.1016/j.jtos.2019.02.006

Cited by 21 publications

(35 citation statements)

References 35 publications

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“…Ten mice were assigned to the healthy control group, the other thirty mice were placed in a controlled environmental room (CER) for 14 days (temperature: 20-24°C; relative humidity: 27 ± 2%; airflow: 15 L/min) ( Figure 1), and treated with transdermal scopolamine patch administration (0.5 mg/72 h, Scopoderm® TTS, Novartis, Rueil-Malmaison, France) starting on day 0, and changed every other day, following a procedure as previously described. [24][25][26][27] The thirty mice were then randomly assigned to the three DED groups (n = 10 per group) based on the corneal fluorescein staining (CFS) values obtained after 3 days of controlled environmental conditions (before any treatment): the DED baseline group (group 1; DED control group) received no treatment, and two treatment groups treated with cyclosporine A emulsions. The treatment with both CsA emulsions covered 10 days and started after a 3-day dry eye induction period (Figure 1).…”

Section: Methodsmentioning

confidence: 99%

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Daull

Nagano

Gros³

et al. 2021

Current Eye Research

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Purpose/Aim: Dry eye (DE) disease is a multifactorial disease in which uncontrolled inflammation can lead to corneal epithelium lesions and symptoms of discomfort. The aim of the present study was to evaluate the efficacy of two cyclosporine emulsions in a mouse model of DE with corneal epithelium lesions. Materials and Methods: Six-to 9-week-old female C57BL/6 N mice were housed in a controlledenvironment room to induce DE. Following DE development, mice were instilled with: QD 0.1%CsA cationic emulsion (CaEm), BID 0.05%CsA anionic emulsion (AEm), or left untreated. Aqueous tear production and corneal epithelium lesions were assessed throughout the experiment. At the end of the treatment period, left eyes were sampled, fixed, and stained for histology, while the cornea, conjunctiva, and lacrimal gland of right eyes were sampled for transcriptomic analysis. Results: Corneal lesion scores were reduced by 10.4%, 18.4%, and 10.9% at day 6, 10, and 14, respectively, with CaEm (QD), and by 2.6%, 3.0%, and 5.5% at day 6, 10, and 14, respectively, with AEm (BID). Histology demonstrated that 7 out of 10 DE mice presented moderate to severe ocular lesions, while only 2 and 5 out of 10 mice presented slight to moderate ocular lesions when treated with the CaEm (QD) and AEm (BID), respectively. The transcriptomic profile analysis suggests that a different set of inflammatory genes are modulated in the cornea, conjunctiva, and lacrimal gland upon DE development. In addition, the two emulsions distinctively modulate the gene expression profile. Conclusions: This study demonstrates that both emulsions were effective at reducing corneal lesions, with the CaEm (QD) being slightly better than the AEm (BID). Interestingly, this study suggests that ocular tissues may not respond similarly to a dry environment and that a different set of genes is modulated by the two formulations in the ocular tissues.

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Section: Methodsmentioning

confidence: 99%

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Daull

Nagano

Gros³

et al. 2021

Current Eye Research

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“…Typically, the endogenous antioxidant system responds within a few hours to environmental changes. While resveratrol and Mn-TM-2-PyP both led to similar increases in Nrf2 expression, the ability of Mn-TM-2-PyP to sustain the significant upregulation of SOD2 at 24 h after Mn-TM-2-PyP treatment may explain its potent glioprotective and cytoprotective effects (present study; [19]).…”

Section: Discussionmentioning

confidence: 54%

“…Specifically, astrocytes were treated with 0.005% Mn-TM-2-PyP or PBS vehicle, 50 µM resveratrol or 0.1% DMSO vehicle, 100 µM Trolox or 0.1% ethanol vehicle, or 5 µM xanthohumol or 0.01% DMSO vehicle for 24 h. Concentrations were determined based on previous studies [5,6,19], the published literature [23,29,30] and cytotoxicity studies in optic nerve head astrocytes ( Figure S1). Quantitative immunoblotting was performed to determine NOX4, SOD2, and Nrf2 protein expression.…”

Section: Different Classes Of Antioxidants Elicit Specific Changes Inmentioning

confidence: 99%

“…Mn-TM-2-PyP is a superoxide dismutase (SOD) mimetic that belongs to the metalloporphyrin group and possesses broad antioxidant specificity, which includes scavenging O 2 • -, H 2 O 2 , ONOO -, NO•, and lipid peroxyl radicals [12]. Manganese porphyrins are well characterized and offer protection in a variety of oxidative stress injuries such as stroke, diabetes, radiation injury, dry eye disease and ischemia [13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants

et al. 2020

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Optic nerve head astrocytes are the specialized glia cells that provide structural and trophic support to the optic nerve head. In response to cellular injury, optic nerve head astrocytes undergo reactive astrocytosis, the process of cellular activation associated with cytoskeletal remodeling, increases in the rate of proliferation and motility, and the generation of Reactive Oxygen Species. Antioxidant intervention has previously been proposed as a therapeutic approach for glaucomatous optic neuropathy, however, little is known regarding the response of optic nerve head astrocytes to antioxidants under physiological versus pathological conditions. The goal of this study was to determine the effects of three different antioxidants, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), resveratrol and xanthohumol in primary optic nerve head astrocytes. Effects on the expression of the master regulator nuclear factor erythroid 2-related factor 2 (Nrf2), the antioxidant enzyme, manganese-dependent superoxide dismutase 2 (SOD2), and the pro-oxidant enzyme, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), were determined by quantitative immunoblotting. Furthermore, efficacy in preventing chemically and reactive astrocytosis-induced increases in cellular oxidative stress was quantified using cell viability assays. The results were compared to the effects of the prototypic antioxidant, Trolox. Antioxidants elicited highly differential changes in the expression levels of Nrf2, SOD2, and NOX4. Notably, Mn-TM-2-PyP increased SOD2 expression eight-fold, while resveratrol increased Nrf2 expression three-fold. In contrast, xanthohumol exerted no statistically significant changes in expression levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) uptake and lactate dehydrogenase (LDH) release assays were performed to assess cell viability after chemically and reactive astrocytosis-induced oxidative stress. Mn-TM-2-PyP exerted the most potent glioprotection by fully preventing the loss of cell viability, whereas resveratrol and xanthohumol partially restored cell viability. Our data provide the first evidence for a well-developed antioxidant defense system in optic nerve head astrocytes, which can be pharmacologically targeted by different classes of antioxidants.

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“…Hyperosmolar conditions, inflammatory and matrix-remodeling factors stimulate ocular oxidative stress. These pathogenic factors are also related to the production of reactive oxygen species (ROS), to the decrement of antioxidant enzymes, such as glutathione peroxidase-1 and superoxide dismutase1 (SOD1), and to the increment of heme oxygenase-1 and cycloxygenase2 activity, thus disrupting the physiological balance between antioxidative enzymes and ROS [ 28 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Evidence of Polyphenols Efficacy against Dry Eye Disease

et al. 2021

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Dry eye disease is a multifactorial pathology compromising the quality of life of patients, resulting in significant damage of the ocular surface and discomfort. The current therapeutical strategies are not able to definitively resolve the underlying causes and stop the symptoms. Polyphenols are promising natural molecules that are receiving increasing attention for their activity/effects in counteracting the main pathologic mechanisms of dry eye disease and reducing its symptoms. In the present review, a deep literature search focusing on the main polyphenols tested against dry eye disease was conducted, analyzing related in vitro, in vivo, and clinical studies to provide a comprehensive and current review on the state of the art. Polyphenols present multiple effects against dry eye diseases-related ocular surface injury. In particular, the observed beneficial effects of polyphenols on corneal cells are the reduction of the pathological processes of inflammation, oxidative stress, and apoptosis and modulation of the tear film. Due to numerous studies reporting that polyphenols are effective and safe for treating the pathological mechanisms of this ocular surface disease, we believe that future studies should confirm and extend the evidence of polyphenols efficacy in clinical practice against dry eye disease and help to develop new ophthalmic drug(s).

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Manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, a superoxide dismutase mimetic, reduces disease severity in in vitro and in vivo models for dry-eye disease

Cited by 21 publications

References 35 publications

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants

Evidence of Polyphenols Efficacy against Dry Eye Disease

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