Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome

Ziniauskaite, Agne; Ragauskas, Symantas; Hakkarainen, Jenni J.; Rich, Cadmus; Baumgartner, Rudolf; Kalesnykas, Giedrius; Albers, David S.; Kaja, Simon

doi:10.1167/iovs.18-24432

Cited by 13 publications

(22 citation statements)

References 32 publications

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“…Neither drug was able to increase the number of conjunctival goblet cells (Fig. 5C, D), in agreement with previous reports [32].…”

Section: Discussionsupporting

confidence: 93%

“…Our mouse model for DED is based on a well-established paradigm that employs low-humidity air flow and concurrent scopolamine administration to induce DED in wild-type mice [36]. The model and its quantitative readouts used to determine DED severity were published by us previously [32] and are of similar magnitude to those reported by us and others using a desiccating stress/ scopolamine model to induce DED in mice [32,36].…”

Section: Discussionmentioning

confidence: 99%

“…Eyes and intraorbital lacrimal glands were dissected and post-fixed overnight in 4% paraformaldehyde. Paraffin sections (5 μm) of lacrimal glands and frozen sections (10 μm) of eyeballs were processed for histological analysis using hematoxilin-eosin staining for quantification of immune cell infiltration into the lacrimal gland and Periodic Acid Schiff (PAS) staining to quantify the number of goblet cells in the inferior conjunctiva, as described by us in detail previously [32].…”

Section: Tissue Collection and Histologymentioning

confidence: 99%

“…DED is characterized by infiltration of immune cells into the lacrimal gland. To determine whether topical administration Mn-TM-2-PyP can attenuate lacrimal gland pathology, we scored immune cell infiltration as described by us previously [32]. Lacrimal glands showed a large number of foci of mononuclear cells, and in some cases, degeneration of parenchymal tissue resulting in a median score of 3 in saline-treated animals (n = 8; Fig.…”

Section: Topical Application Of Mn-tm-2-pyp Attenuates Lacrimal Glandmentioning

confidence: 99%

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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

Ziniauskaite

Ragauskas

et al. 2019

The Ocular Surface

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Purpose: To determine the efficacy of the superoxide dismutase mimetic, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (Mn-TM-2-PyP), in vitro in human corneal epithelial (HCE-T) cells and in vivo in a preclinical mouse model for dry-eye disease (DED). Methods: In vitro, HCE-T cultures were exposed either to tertbutylhydroperoxide (tBHP) to generate oxidative stress or to hyperosmolar conditions modeling cellular stress during DED. Cells were pre-treated with Mn-TM-2-PyP or vehicle. Mn-TM-2-PyP permeability across stratified HCE-T cells was assayed, In vivo, Mn-TM-2-PyP (0.1% w/v in saline) was delivered topically as eye drops in a desiccating stress / scopolamine model for DED. Preclinical efficacy was compared to untreated, vehicle-and ophthalmic cyclosporine emulsion-treated mice. Results: Mn-TM-2-PYP protected HCE-T cells in a dose-dependent manner against tBHPinduced oxidative stress as determined by calculating the IC 50 for tBHP in the resazurin, MTT and lactate dehydrogenase release cell viability assays. Mn-TM-2-PyP did not protect HCE-T cells

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“…Neither drug was able to increase the number of conjunctival goblet cells (Fig. 5C, D), in agreement with previous reports [32].…”

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Tissue Collection and Histologymentioning

confidence: 99%

Section: Topical Application Of Mn-tm-2-pyp Attenuates Lacrimal Glandmentioning

confidence: 99%

See 2 more Smart Citations

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

Ragauskas

et al. 2019

The Ocular Surface

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“…Inhibiting tear secretion by systemic administration of the muscarinic cholinergic antagonist scopolamine produced keratoconjunctivitis sicca that mimics human dry eye. This scopolamine-induced dry eye model is commonly used animal model in DED research [22,[24][25][26][27]. We demonstrated that the oxidation product 8-OHdG accumulated in the corneal epithelial cells of this model.…”

Section: Plos Onementioning

confidence: 74%

NFE2L2 activator RS9 protects against corneal epithelial cell damage in dry eye models

et al. 2020

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Oxidative stress may cause ocular surface damage during the development of dry eye. Mammalian cells have defense systems against oxidative stress. A central regulator of the stress response is nuclear factor-erythroid 2-related factor 2 (NFE2L2). NFE2L2 is activated by the novel triterpenoid RS9 (a biotransformation compound of RTA 402). The purpose of this study was to assess the efficacy of RS9 against dry eye using in vitro and in vivo models. Bioactivity was estimated by the induction of mRNAs for two NFE2L2-targeted genes: NQO1 (prevents radical species) and GCLC (glutathione synthesis), using a corneal epithelial cell line (HCE-T). Protection against oxidation and cell damage was tested in vitro by culturing cells under hyperosmotic stress or by the addition of menadione, a generator of reactive oxygen species (ROS). Dry eye in vivo was induced by the injection of scopolamine into rats. Then, 930 nM of RS9 was applied to both eyes for 2 weeks. Oxidative stress was measured by the accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Corneal wound healing was measured by scoring for superficial punctate keratitis (SPK). Corneal epithelial cell densities were evaluated histologically. RS9 and RTA 402 induced the expression of NQO1 and GCLC mRNAs in HCE-T cells. And both compounds suppressed hyperosmotic-ROS generation and menadione induced cellular damage. However RS9 had a stronger protective effect than RTA 402. Ocular instillation of RS9 also significantly upregulated the expression of Nqo1 mRNA in the corneal epithelium. Accumulation of 8-OHdG, increase of SPK scores and decrement of basal cell density were observed in corneal epithelium from scopolamine-injected rats. These changes were significantly ameliorated by the topical administration of RS9. RS9 induced Nfe2l2 activation and Nfe2l2-targeted genes, reduced oxidation, and ameliorated symptoms of dry eye using in vitro and in vivo models. Thus, RS9 might be a potent candidate agent against dry eye disease.

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Ocular mucins in dry eye disease

Portal

Gouyer

Gottrand

et al. 2019

Experimental Eye Research

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Dry eye disease is a common and multifactorial disease with a high prevalence worldwide. Water loss, reduced expression of glycocalyx mucins, and loss of goblet cells secreting gel-forming mucins are hallmarks of dry eye disease. Mucins are large and complex heavily glycosylated proteins. Their organization in the tear film remains unclear, but they play a key role to protect and maintain integrity of the ocular surface. Mice have been extremely valuable mammalian models with which to study ocular physiology and disease, and to evaluate eye therapies. Genetically modified mice and spontaneously occurring mutants with eye defects have proven to be powerful tools for the pharmaceutical industry, clinicians, and basic researchers investigating dry eye disease. However, ocular mucins remain relatively under-studied and inadequately characterized. This review aims to summarize current knowledge about mucin production at the ocular surface in healthy individuals and in dry eye disease, and to compile an overview of mouse models available for the study of mucins in dry eye disease.

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Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome

Cited by 13 publications

References 32 publications

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

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

NFE2L2 activator RS9 protects against corneal epithelial cell damage in dry eye models

Ocular mucins in dry eye disease

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