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Dopamine-induced toxicity is synergistically potentiated by simultaneous HSP-90 and Akt inhibition in oligodendrocyte progenitors.

Authors
  • 1
  • 1 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada. , (Canada)
Type
Published Article
Journal
Journal of Neurochemistry
1471-4159
Publisher
Wiley Blackwell (Blackwell Publishing)
Publication Date
Volume
105
Issue
4
Pages
1223–1234
Identifiers
DOI: 10.1111/j.1471-4159.2008.05227.x
PMID: 18194434
Source
Medline
License
Unknown

Abstract

Oligodendrocyte progenitors are highly susceptible to various insults. Their limited antioxidant defenses and high levels of apoptotic factors, such as Bax and pro-caspase-3 contribute to their sensitivity. We previously showed that dopamine (DA) is toxic to oligodendrocyte progenitors by inducing superoxide generation, lowering glutathione levels and promoting apoptosis through caspase-3 activation. In contrast, factors that contribute to cell survival and defense against dopamine (DA) toxicity are less studied. Here, we explored the role of two molecules which play important roles in cell survival, namely the heat shock protein 90 (HSP-90) and the protein kinase Akt, using the selective inhibitors, 17-AAG and Akt inhibitor III, respectively. The HSP-90 inhibitor caused a decrease in P-Akt level, induced caspase-3 activation, increased nuclear condensation and caused a loss in cell viability. Furthermore, 17-AAG potentiated DA-induced apoptosis by enhancing caspase-3 activation. In addition, the Akt inhibitor alone exacerbated DA toxicity and in combination with 17-AAG caused synergistic potentiation of DA toxicity by enhancing caspase-3 activation. Together, these results indicate that HSP-90 is essential for oligodendrocyte progenitor survival. Both HSP-90 and Akt play important roles in concert in the defense against DA-induced apoptosis.

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