Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes

Jae Hyuck Choi, Dong Hoon Kim, In Jin Yun, Jun Hee Chang, Boe Gwun Chun, Sang Hyun Choi

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The lysosomal destabilization that precedes mitochondrial apoptotic changes is an important step in cell death, particularly in oxidative cell death. This study describes the novel pharmacological effects of zaprinast, a cGMP-elevating phosphodiesterase inhibitor, on the inhibition of oxidative cell death in astrocyte cultures. H2O2-induced oxidative cytotoxicity was measured grossly by monitoring lactate dehydrogenase (LDH) release, and was found to be associated with lysosomal acridine orange relocation, lysosomal cathepsin D release into cytosol, and reduced mitochondrial potentials. Moreover, zaprinast (100 μM) inhibited all of these cytotoxic phenomena. In addition, H2O2-induced LDH release was not inhibited by 8-pCPT-cGMP, and the inhibition of this release by zaprinast was unaffected by Rp-8-pCPT-cGMP, a protein kinase G inhibitor. Zaprinast was found to inhibit sphingosine-induced lysosomal acridine orange relocation and the induced decrease in mitochondrial potential, but zaprinast had no effect on rotenone-induced mitochondrial collapse, which was not associated with lysosomal destabilization. However, zaprinast did not inhibit the cellular increase of reactive oxygen species induced by H2O2, which suggests that its protective mechanism differs from that of desferrioxamine, which does inhibit such cellular increase of oxygen free radicals. We suggest that the novel protective effect of zaprinast on H2O2-induced oxidative cell death is primarily associated with its inhibition of lysosomal destabilization.

Original languageEnglish
Pages (from-to)106-115
Number of pages10
JournalEuropean Journal of Pharmacology
Volume571
Issue number2-3
DOIs
Publication statusPublished - 2007 Oct 1

Keywords

  • Astrocyte
  • Desferrioxamine
  • Hydrogen peroxide
  • Lysosomal stability
  • Mitochondrial potential
  • Oxidative stress
  • Rotenone
  • Sphingosine
  • Zaprinast

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes'. Together they form a unique fingerprint.

Cite this