TY - JOUR
T1 - Zaprinast inhibits hydrogen peroxide-induced lysosomal destabilization and cell death in astrocytes
AU - Choi, Jae Hyuck
AU - Kim, Dong Hoon
AU - Yun, In Jin
AU - Chang, Jun Hee
AU - Chun, Boe Gwun
AU - Choi, Sang Hyun
N1 - Funding Information:
This work was supported by a Korea University Grant to SHC.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/10/1
Y1 - 2007/10/1
N2 - 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.
AB - 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.
KW - Astrocyte
KW - Desferrioxamine
KW - Hydrogen peroxide
KW - Lysosomal stability
KW - Mitochondrial potential
KW - Oxidative stress
KW - Rotenone
KW - Sphingosine
KW - Zaprinast
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U2 - 10.1016/j.ejphar.2007.06.042
DO - 10.1016/j.ejphar.2007.06.042
M3 - Article
C2 - 17643412
AN - SCOPUS:34548598647
VL - 571
SP - 106
EP - 115
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 2-3
ER -