Oxidation of N-methyl(R)salsolinol: involvement to neurotoxicity and neuroprotection by endogenous catechol isoquinolines.
1(R), 2(N)-Dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl(R)salsolinol, is a potent dopaminergic neurotoxin to induce parkinsonism in rats. The cytotoxicity of N-methyl(R)salsolinol proved to be ascribed to its oxidation into cytotoxic 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion with generation of hydroxyl radical. The isoquinolinium ion caused massive necrosis in the striatum, whereas N-methyl(R)salsolinol depleted selectively dopaminergic neurons in the substantia nigra without necrotic tissue reaction. N-Methyl(R)salsolinol induced DNA damage to human neuroblastoma SH-SY5Y cells, which could be prevented by anti-oxidants and cycloheximide. These results suggest that oxidative stress through oxidation of N-methyl(R)salsolinol induces apoptotic cell death. On the other hand, (R)salsolinol proved to scavenge hydroxyl radical produced by oxidation of dopamine. The neurotoxicity and neuroprotection of catechol isoquinolines may be ascribed to their oxidation and scavenging of radicals.
Naoi
M
M
Department of Biosciences, Nagoya Institute of Technology, Japan.
Maruyama
W
W
Kasamatsu
T
T
Dostert
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism* / Q000633:toxicity*; D008297:Male; D009336:Necrosis; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000503:physiopathology*; D011187:Posture; D051381:Rats; D017208:Rats, Wistar; D012490:Salsoline Alkaloids / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity*; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D007546:Isoquinolines; D009498:Neurotoxins; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; D015102:3,4-Dihydroxyphenylacetic Acid; D017665:Hydroxyl Radical; D003513:Cycloheximide; C036617:salsolinol; C032837:salsoline; D004298:Dopamine; D006719:Homovanillic Acid