Topical Ophthalmic Formulation of Trichostatin A and SurR9-C84A for Quick Recovery Post-alkali Burn of Corneal Haze

Kislay Roy; Prasad Neerati; Chun Hei Antonio Cheung; Rupinder K Kanwar; Rajat Sandhir; Jagat R Kanwar

doi:10.3389/fphar.2017.00223

Topical Ophthalmic Formulation of Trichostatin A and SurR9-C84A for Quick Recovery Post-alkali Burn of Corneal Haze

Front Pharmacol. 2017 May 5:8:223. doi: 10.3389/fphar.2017.00223. eCollection 2017.

Authors

Kislay Roy¹, Prasad Neerati, Chun Hei Antonio Cheung², Rupinder K Kanwar¹, Rajat Sandhir³, Jagat R Kanwar¹

Affiliations

¹ Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, Centre for Molecular and Medical Research, School of Medicine, Faculty of Health, Deakin University, GeelongVIC, Australia.
² Department of Pharmacology and Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, Taiwan.
³ Department of Biochemistry, Panjab UniversityChandigarh, India.

Abstract

Alkali burn injury is a true ocular emergency of the conjunctiva and cornea that requires immediate precision. Lack of an immediate therapy can lead to a substantial damage in the ocular surface and anterior segment further causing visual impairment and disfigurement. We explored the regenerative capability of dominant negative survivin protein (SurR9-C84A) and histone deacetylase inhibitor trichostatin-A (TSA) in vivo, in a rat alkali burn model. A topical insult in rat eyes with NaOH led to degradation of the conjunctival and corneal epithelium. The integrity of the conjunctival and corneal tissue was increased by TSA and SurR9-C84A by improving the clathrin and claudin expressions. Wound healing was initiated by an increase in TGF-beta-1 and, increased endogenous survivin which inhibited apoptosis post-TSA and SurR9-C84A treatments. Protein expressions of fibronectin and alpha-integrin 5 were found to increase promoting corneal integrity. The cytokine analysis confirmed increased expressions of IL-1beta, IL-6, IL-12, IL-13, IFN-gamma, TNF-alpha, GMCSF, Rantes, and MMP-2 in injured cornea, which were found to be significantly downregulated by the combined treatment of SurR9-C84A and TSA. The ocular and systemic pharmacokinetic (PK) parameters were measured post-topical ocular administration of TSA and SurR9-C84A. The SurR9-C84A and TSA sustained relatively longer in the cornea, conjunctiva, and aqueous humor than in the tear fluid and plasma. Our results confirmed that a combination of TSA with SurR9-C8A worked in synergy and showed a promising healing and anti-inflammatory effect in a very short time against alkali burn. Therefore, a combination of TSA and SurR9-C84A can fulfill the need for an immediate response to wound healing in alkali burnt cornea. We also synthesized ultra-small chitosan nanoparticles (USC-NPs) targeted with alpha-SMA antibodies that can be used for delivery of TSA and SurR9-C84A specifically to the ocular burn site.

Keywords: cytokines; haze; scarring; survivin; trichostatin-A; wound healing.