Neuroprotective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline on cultured rat mesencephalic neurons in the presence or absence of various neurotoxins.
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous brain amine and its content in parkinsonian brain is decreased compared with that in control brain. There is some evidence that 1MeTIQ protects dopaminergic neurons against dysfunction such as that seen in Parkinson's disease. In this study, we examined the neuroprotective effect of 1MeTIQ against four dopaminergic neurotoxins, 1-methyl-4-phenylpyridinuim ion, 6-hydroxydopamine, rotenone, and l-benzyl-1,2,3,4-tetrahydroisoquinoline, in cultured rat mesencephalic neurons. 1MeTIQ exerted neuroprotective action against all these toxins. Furthermore, (R)-1MeTIQ was neuroprotective, while (S)-1MeTIQ had little effect, indicating that the effect is stereoselective. The protective action of 1MeTIQ was most effective in mesencephalic neurons, especially in tyrosine hydroxylase-positive neurons. 1MeTIQ showed no affinity for dopamine receptors and did not influence the inhibition of mitochondrial respiratory complex I by rotenone, 1-methyl-4-phenylpyridinuim ion, or 1-benzyl-1,2,3,4-tetrahydroisoquinoline. These results raise the possibility that 1MeTIQ indirectly acts as an anti-oxidant such as the induction of anti-oxidative enzymes, because all these four neurotoxins can burden oxidative stress in common. This is the first report to confirm a protective effect of 1MeTIQ at the cultured neuron level, and it may have potential as a lead compound for the development of new agents to treat Parkinson's disease.
Kotake
Yaichiro
Y
Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. yaichiro@hiroshima-u.ac.jp
Taguchi
Ryota
R
Okuda
Katsuhiro
K
Sekiya
Yoko
Y
Tasaki
Yoshikazu
Y
Hirobe
Masaaki
M
Ohta
Shigeru
S
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000633:toxicity; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*
D018696:Neuroprotective Agents; D044005:Tetrahydroisoquinolines; D012402:Rotenone; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D016627:Oxidopamine