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.
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.
Maruyama
Wakako
W
Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan.
Yi
Hong
H
Takahashi
Tsutomu
T
Shimazu
Seiichiro
S
Ohde
Hironori
H
Yoneda
Fumio
F
Iwasa
Kinuko
K
Naoi
Makoto
M
D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011954:Receptors, Dopamine / Q000378:metabolism; D012490:Salsoline Alkaloids / Q000633:toxicity*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000633:toxicity*; D014407:Tumor Cells, Cultured
C404200:1-(benzofuran-2-yl)-2-propylaminopentane; D001572:Benzofurans; D018696:Neuroprotective Agents; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D011954:Receptors, Dopamine; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C032837:salsoline