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.