論文 - 詳細
| RRC ID | 59891 |
|---|---|
| 著者 | Žiniauskaitė A, Ragauskas S, Ghosh AK, Thapa R, Roessler AE, Koulen P, Kalesnykas G, Hakkarainen JJ, Kaja S. |
| タイトル | 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. |
| ジャーナル | Ocul Surf |
| Abstract |
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 tert-butylhydroperoxide (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 tBHP-induced oxidative stress as determined by calculating the IC50 for tBHP in the resazurin, MTT and lactate dehydrogenase release cell viability assays. Mn-TM-2-PyP did not protect HCE-T cells from hyperosmolar insult. Its permeability coefficient across a barrier of HCE-T cells was 1.1 ± 0.05 × 10-6 cm/s and the mass balance was 62 ± 0.6%. In vivo, topical dosing with Mn-TM-2-PyP resulted in a statistically significant reduction of corneal fluorescein staining, similar to ophthalmic cyclosporine emulsion. Furthermore, Mn-TM-2-PyP significantly reduced leukocyte infiltration into lacrimal glands and prevented degeneration of parenchymal tissue. No protective effect against loss of conjunctival goblet cells was observed. Notably, Mn-TM-2-PyP did not produce ocular toxicity when administered topically. DISCUSSION:Our data suggest that Mn-TM-2-PyP, a prototypic synthetic metalloporphyrin compound with potent catalytic antioxidant activity, can improve signs of DED in vivo by reducing oxidative stress in corneal epithelial cells. |
| 巻・号 | 17(2) |
| ページ | 257-264 |
| 公開日 | 2019-4-1 |
| DOI | 10.1016/j.jtos.2019.02.006 |
| PII | S1542-0124(18)30233-7 |
| PMID | 30807830 |
| PMC | PMC6570415 |
| MeSH | Animals Antioxidants Cell Count Disease Models, Animal Dry Eye Syndromes / drug therapy* Dry Eye Syndromes / metabolism Dry Eye Syndromes / pathology Goblet Cells / drug effects Goblet Cells / pathology* Humans Metalloporphyrins / administration & dosage* Mice Mice, Inbred C57BL Ophthalmic Solutions / administration & dosage Oxidative Stress* Severity of Illness Index |
| IF | 12.336 |
| 引用数 | 1 |
| リソース情報 | |
| ヒト・動物細胞 | HCE-T(RCB2280) |