Neuroprotective function of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, [R-(-)-BPAP], against apoptosis induced by N-methyl(R)salsolinol, an endogenous dopaminergic neurotoxin, in human dopaminergic neuroblastoma SH-SY5Y cells.

Abstract

R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane HCl [R-(-)-BPAP] is one of "catecholaminergic and serotonergic enhancers", which were proposed to improve symptoms through increase in impulse-evoked release of monoamine neurotransmitters for Parkinson's disease. It was reported that (-)-BPAP up-regulated the synthesis of neurotrophic factors in mouse astrocytes, suggesting the neuroprotective potency of (-)-BPAP. In this paper, the neuroprotective function of (-)-BPAP and the related compounds was examined against apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], a possible pathogenic toxin in Parkinson's disease, in human dopaminergic neuroblastoma SH-SY5Y cells. The anti-apoptotic activity was confirmed with some of (-)-BPAP analogues, and the mechanism was found to be due to the direct stabilization of mitochondrial membrane potential and the induction of anti-apoptotic Bcl-2. The studies on structure-activity relationship demonstrated that the potency to stabilize the mitochondrial membrane potential depended on the absolute stereo-chemical structure of BPAP derivatives. The compounds with dextrorotation prevented the mitochondrial permeability transition, whereas those with levorotation did not. The presence of a propargyl or propyl group at the amino residue of R-(-)-1-(benzofuran-2-yl)-2-propylamine increased potency to stabilize the membrane potential and prevent apoptosis. R-FPFS-1169 and R-FPFS-1180 had more potent to induce Bcl-2 and prevent apoptosis than the corresponding S-enantiomers. These results are discussed with the possible application of BPAP derivatives as neuroprotective agents in Parkinson's disease and other neurodegenerative disorders.

• Authors: Wakako Maruyama, Hong Yi, Tsutomu Takahashi, Seiichiro Shimazu, Hironori Ohde, Fumio Yoneda, Kinuko Iwasa, Makoto Naoi
• Journal: Life sciences (Life Sci) Vol. 75 Issue 1 Pg. 107-17 (May 21 2004) ISSN: 0024-3205 [Print] Netherlands
• PMID: 15102525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(benzofuran-2-yl)-2-propylaminopentane
• Benzofurans
• Neuroprotective Agents
• Neurotoxins
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Dopamine
• Salsoline Alkaloids
• Tetrahydroisoquinolines
• salsoline

Topics

• Apoptosis (drug effects)
• Benzofurans (chemistry, pharmacology)
• Electrophoresis, Polyacrylamide Gel
• Flow Cytometry
• Humans
• Neuroblastoma (metabolism, pathology)
• Neuroprotective Agents (chemistry, pharmacology)
• Neurotoxins (toxicity)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Receptors, Dopamine (metabolism)
• Salsoline Alkaloids (toxicity)
• Structure-Activity Relationship
• Tetrahydroisoquinolines (toxicity)
• Tumor Cells, Cultured