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, DeltaPsim, 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 DeltaPsim. 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 DeltaPsim, 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 DeltaPsim 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 DeltaPsim 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.

• Authors: Yukihiro Akao, Wakako Maruyama, Shigeomi Shimizu, Hong Yi, Yoshihito Nakagawa, Masayo Shamoto-Nagai, Moussa B H Youdim, Yoshihide Tsujimoto, Makoto Naoi
• Journal: Journal of neurochemistry (J Neurochem) Vol. 82 Issue 4 Pg. 913-23 (Aug 2002) ISSN: 0022-3042 [Print] England
• PMID: 12358797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indans
• Ion Channels
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Neuroprotective Agents
• Neurotoxins
• Proto-Oncogene Proteins c-bcl-2
• Salsoline Alkaloids
• Tetrahydroisoquinolines
• rasagiline
• Cyclosporine
• salsoline

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Cyclosporine (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Indans (pharmacology)
• Ion Channels (drug effects, metabolism)
• Mitochondria, Liver (chemistry, drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Neuroblastoma (drug therapy, metabolism)
• Neuroprotective Agents (pharmacology)
• Neurotoxins (pharmacology)
• Permeability (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism, pharmacology)
• Rats
• Salsoline Alkaloids (pharmacology)
• Tetrahydroisoquinolines
• Tumor Cells, Cultured