The spirostenol (22R, 25R)-20alpha-spirost-5-en-3beta-yl hexanoate blocks mitochondrial uptake of Abeta in neuronal cells and prevents Abeta-induced impairment of mitochondrial function.
Abeta(1-42) has been shown to uncouple the mitochondrial respiratory chain and promote the opening of the membrane permeability transition (MPT) pore, leading to cell death. We have previously reported that the spirostenol derivative (22R, 25R)-20alpha-spirost-5-en-3beta-yl hexanoate (SP-233) protects neuronal cells against Abeta(1-42) toxicity by binding to and inactivating the peptide. Picomolar concentrations of Abeta(1-42) decreased the mitochondrial respiratory coefficient in mitochondria isolated from the rat forebrain, and this decrease was partially reversed by SP-233. SP-233 abolished the uncoupling of oxidative phosphorylation induced by carbonyl cyanide 3-chlorophenylhydrazone on isolated mitochondria. These results are consistent with a direct effect of SP-233 on the MPT. Moreover, SP-233 displayed a neuroprotective effect on SK-N-AS human neuroblastoma cells treated with the MPT promoter, phenylarsine oxide. Treatment of SK-N-AS cells with Abeta(1-42) resulted in an accumulation of the peptide in the mitochondrial matrix; SP-233 completely scavenged Abeta(1-42) from the matrix. In addition, SP-233 protected the cells against mitochondrial toxins targeting complexes IV and V of the respiratory chain. These results indicate that Abeta(1-42) and SP-233 exert direct effects on mitochondrial function and SP-233 protects neuronal cells against Abeta-induced toxicity by targeting Abeta directly.
Tillement
Laurent
L
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20057, USA.
Lecanu
Laurent
L
Yao
Wenguo
W
Greeson
Janet
J
Papadopoulos
Vassilios
V
D000251:Adenosine Triphosphatases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects; D002208:Caproates / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D012119:Respiration / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*; D013150:Spirostans / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
C514145:(22R, 25R)-20alpha-spirost-5-en-3beta-yl hexanoate; D016229:Amyloid beta-Peptides; D002208:Caproates; D002352:Carrier Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D013141:Spiro Compounds; D013150:Spirostans; C098994:amyloid beta-protein (1-43); D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D016572:Cyclosporine; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein