Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan

Yukihiro Akao, Wakako Maruyama, Shigeomi Shimizu, Hong Yi, Yoshihito Nakagawa, Masayo Shamoto-Nagai, Moussa B.H. Youdim, Yoshihide Tsujimoto, Makoto Naoi

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, ΔΨm, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of ΔΨm. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced ΔΨm, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyl-1(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the ΔΨm reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Sal-induced loss of ΔΨm and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline.

Original languageEnglish
Pages (from-to)913-923
Number of pages11
JournalJournal of Neurochemistry
Volume82
Issue number4
DOIs
Publication statusPublished - 01-08-2002

Fingerprint

Neurotoxins
Permeability
Apoptosis
Mitochondria
Cyclosporine
Caspase Inhibitors
Swelling
salsoline
N-propargyl
1-aminoindan
rasagiline
Mitochondrial Membrane Potential
Neuroprotective Agents
Cell death
Cytochromes c
Neuroblastoma
Liver
Parkinson Disease
Rats
Cell Death

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Akao, Yukihiro ; Maruyama, Wakako ; Shimizu, Shigeomi ; Yi, Hong ; Nakagawa, Yoshihito ; Shamoto-Nagai, Masayo ; Youdim, Moussa B.H. ; Tsujimoto, Yoshihide ; Naoi, Makoto. / Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. In: Journal of Neurochemistry. 2002 ; Vol. 82, No. 4. pp. 913-923.
@article{35f64552f61f49f1a2dd3ab0672054f5,
title = "Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan",
abstract = "The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, ΔΨm, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of ΔΨm. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced ΔΨm, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyl-1(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the ΔΨm reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Sal-induced loss of ΔΨm and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline.",
author = "Yukihiro Akao and Wakako Maruyama and Shigeomi Shimizu and Hong Yi and Yoshihito Nakagawa and Masayo Shamoto-Nagai and Youdim, {Moussa B.H.} and Yoshihide Tsujimoto and Makoto Naoi",
year = "2002",
month = "8",
day = "1",
doi = "10.1046/j.1471-4159.2002.01047.x",
language = "English",
volume = "82",
pages = "913--923",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "4",

}

Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. / Akao, Yukihiro; Maruyama, Wakako; Shimizu, Shigeomi; Yi, Hong; Nakagawa, Yoshihito; Shamoto-Nagai, Masayo; Youdim, Moussa B.H.; Tsujimoto, Yoshihide; Naoi, Makoto.

In: Journal of Neurochemistry, Vol. 82, No. 4, 01.08.2002, p. 913-923.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan

AU - Akao, Yukihiro

AU - Maruyama, Wakako

AU - Shimizu, Shigeomi

AU - Yi, Hong

AU - Nakagawa, Yoshihito

AU - Shamoto-Nagai, Masayo

AU - Youdim, Moussa B.H.

AU - Tsujimoto, Yoshihide

AU - Naoi, Makoto

PY - 2002/8/1

Y1 - 2002/8/1

N2 - The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, ΔΨm, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of ΔΨm. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced ΔΨm, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyl-1(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the ΔΨm reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Sal-induced loss of ΔΨm and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline.

AB - The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, ΔΨm, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of ΔΨm. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis. In mitochondria isolated from rat liver, NM(R)Sal induced swelling and reduced ΔΨm, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that NM(R)Sal induced the PT by direct action on the mitochondria. Rasagiline, N-propargyl-1(R)-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the ΔΨm reduction, release of cytochrome c, and apoptosis induced by NM(R)Sal in SH-SY5Y cells. Rasagiline also inhibited the NM(R)Sal-induced loss of ΔΨm and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in NM(R)Sal-induced cell death and the neuroprotective effect of rasagiline.

UR - http://www.scopus.com/inward/record.url?scp=0036677312&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036677312&partnerID=8YFLogxK

U2 - 10.1046/j.1471-4159.2002.01047.x

DO - 10.1046/j.1471-4159.2002.01047.x

M3 - Article

C2 - 12358797

AN - SCOPUS:0036677312

VL - 82

SP - 913

EP - 923

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 4

ER -