Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes.
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 microM) 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.
Choi
Jae-Hyuck
JH
Department of Pharmacology, Korea University College of Medicine, 126-1, 5-Ga, Anam-Dong, Sungbuk-Gu, Seoul 136-705, Republic of Korea.
Kim
Dong-Hoon
DH
Yun
In-Jin
IJ
Chang
Jun-Hee
JH
Chun
Boe-Gwun
BG
Choi
Sang-Hyun
SH
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002402:Cathepsin D / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D019610:Cytoprotection; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007425:Intracellular Membranes / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D013110:Sphingosine / Q000633:toxicity; D013873:Thionucleotides / Q000494:pharmacology; D014475:Uncoupling Agents / Q000633:toxicity
D010726:Phosphodiesterase Inhibitors; D020011:Protective Agents; D011688:Purinones; D017382:Reactive Oxygen Species; D013873:Thionucleotides; D014475:Uncoupling Agents; D012402:Rotenone; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D017869:Cyclic GMP-Dependent Protein Kinases; D002402:Cathepsin D; C011145:zaprinast; D006152:Cyclic GMP; D003676:Deferoxamine; D013110:Sphingosine