Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork

Alberto Izzotti, Sebastiano La Maestra, Rosanna Tindara Micale, Maria Grazia Longobardi, Sergio Claudio Saccà

Research output: Contribution to journalArticle

Abstract

Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3. The efficacy of the preservatives in inhibiting bacterial growth increased the adverse effects in trabecular meshwork in terms of DNA damage and alteration of gene expression. Presented data indicates the delicate balance between efficacy and safety of drug preservatives as not yet optimized.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume772
DOIs
Publication statusPublished - Feb 1 2015

Fingerprint

Trabecular Meshwork
Benzalkonium Compounds
Glaucoma
DNA Damage
Pharmaceutical Preparations
DNA Fragmentation
Gene Expression
Cell Survival
Oxidative Stress
Effector Caspases
Safety
Oligonucleotide Array Sequence Analysis
Caspase 3
polyquaternium 1
Growth

Keywords

  • Drug preservatives
  • Gene expression
  • Glaucoma
  • Microarray
  • Oxidative damage
  • Trabecular meshwork

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis
  • Medicine(all)

Cite this

Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork. / Izzotti, Alberto; La Maestra, Sebastiano; Micale, Rosanna Tindara; Longobardi, Maria Grazia; Saccà, Sergio Claudio.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 772, 01.02.2015, p. 1-9.

Research output: Contribution to journalArticle

Izzotti, Alberto ; La Maestra, Sebastiano ; Micale, Rosanna Tindara ; Longobardi, Maria Grazia ; Saccà, Sergio Claudio. / Genomic and post-genomic effects of anti-glaucoma drugs preservatives in trabecular meshwork. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2015 ; Vol. 772. pp. 1-9.
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AB - Oxidative stress plays an important role in glaucoma. Some preservatives of anti-glaucoma drugs, commonly used in glaucoma therapy, can prevent or induce oxidative stress in the trabecular meshwork. The aim of this study is to evaluate cellular and molecular damage induced in trabecular meshwork by preservatives contained in anti-glaucoma drugs. Cell viability (MTT test), DNA fragmentation (Comet test), oxidative DNA damage (8-oxo-dG), and gene expression (cDNA microarray) have been evaluated in trabecular meshwork specimens and in human trabecular meshwork cells treated with benzalkonium chloride, polyQuad, purite, and sofzia-like mixture. Moreover, antimicrobial effectiveness and safety of preservative contents in drugs was tested. In ex vivo experiments, benzalkonium chloride and polyQuad induced high level of DNA damage in trabecular meshwork specimens, while the effect of purite and sofzia were more attenuated. The level of DNA fragmentation induced by benzalkonium chloride was 2.4-fold higher in subjects older than 50 years than in younger subjects. Benzalkonium chloride, and polyQuad significantly increased oxidative DNA damage as compared to sham-treated specimens. Gene expression was altered by benzalkonium chloride, polyQuad, and purite but not by sofzia. In in vitro experiments, benzalkonium chloride and polyQuad dramatically decreased trabecular meshwork cell viability, increased DNA fragmentation, and altered gene expression. A lesser effect was also exerted by purite and sofzia. Genes targeted by these alterations included Fas and effector caspase-3. The efficacy of the preservatives in inhibiting bacterial growth increased the adverse effects in trabecular meshwork in terms of DNA damage and alteration of gene expression. Presented data indicates the delicate balance between efficacy and safety of drug preservatives as not yet optimized.

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