Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole.

Abstract:

:Recently, it has been shown that release of cytochrome c from the mitochondria to the cytosol is required for activation of the caspase-3-dependent cascade in apoptosis, and also for alpha-synuclein aggregation. In the present study, we examined the effects of talipexole and pramipexole on the release of cytochrome c and alpha-synuclein, their aggregations, and activation of caspases. Treatment of human neuroblastoma SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP(+), 1 mM) induced the first event, which was the release of cytochrome c from the organellar fraction to the cytosolic fraction, then came the DNA fragmentation, and caused the last event, which was the accumulation of alpha-synuclein protein in the cytosolic fraction. Talipexole and pramipexole at low concentration (0.1-1 mM) significantly inhibited the accumulation of cytochrome c or alpha-synuclein in the cytosolic fraction. These drugs at high concentration (3-10 mM) inhibited in vitro aggregation of cytochrome c by hydrogen peroxide or that of alpha-synuclein by cytochrome c and hydrogen peroxide. In addition, in vitro activation of caspase-3 induced by cytochrome c and/or dATP was also inhibited by drugs at high concentration (5-10 mM). These results suggest that talipexole and pramipexole may have protective effects against the neurodegeneration, which is induced by intracellular accumulation of cytochrome c and alpha-synuclein.

journal_name

Eur J Pharmacol

authors

Kakimura J,Kitamura Y,Takata K,Kohno Y,Nomura Y,Taniguchi T

doi

10.1016/s0014-2999(01)00902-5

keywords:

subject

Has Abstract

pub_date

2001-04-06 00:00:00

pages

59-67

issue

1-2

eissn

0014-2999

issn

1879-0712

pii

S0014299901009025

journal_volume

417

pub_type

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