Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson's disease.
We carried out behavioral, pathological, and biochemical studies in order to determine whether the stereo-structure of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) affects the onset of Parkinson's disease-like symptoms, which are induced by 1,2,3,4-tetrahydroisoquinoline (TIQ) in mice. Pretreatment with (R)-1-MeTIQ or its racemate (RS)-1-MeTIQ prevented the TIQ-induced bradykinesia. Pretreatment with a combination of L-DOPA and carbidopa significantly prevented subsequent TIQ-induced bradykinesia. Furthermore, the pathological study demonstrated that either (R)-1-MeTIQ or its racemate protected against TIQ-induced loss of tyrosine hydroxylase-positive cells of the substantia nigra pars compacta. (R)-1-MeTIQ and its racemate also prevented the TIQ-induced reduction in the levels of dopamine and its metabolites in the striatum. Serotonin and its metabolite were not affected by repeated administration of (RS)-1-MeTIQ or its derivatives. On the other hand, (S)-1-MeTIQ induced moderate but significant bradykinesia, whereas (R)-1-MeTIQ did not induce this behavioral abnormality at all. In addition, (S)-enantiomer prevented the onset of TIQ-induced bradykinesia, though to a lesser extent than did either (R)-enantiomer or its racemate. However, (S)-enantiomer did not prevent the loss of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. We concluded that (R)-1-MeTIQ, and not (S)-enantiomer, plays a crucial role in protection against TIQ-induced parkinsonism, a fact which suggests that enantiomeric biochemical events such as 1-MeTIQ biosynthesis may participate in the pathogenesis of Parkinson's disease.
Abe
K
K
Department of Neuroscience, Showa Pharmaceutical University, Higashitamagawagakuen, Machida, Tokyo, Japan.
Taguchi
K
K
Wasai
T
T
Ren
J
J
Utsunomiya
I
I
Shinohara
T
T
Miyatake
T
T
Sano
T
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002230:Carbidopa / Q000494:pharmacology; D002452:Cell Count; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004347:Drug Interactions / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D018476:Hypokinesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000033:anatomy & histology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D044005:Tetrahydroisoquinolines; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018492:Dopamine Antagonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D009498:Neurotoxins; D044005:Tetrahydroisoquinolines; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007980:Levodopa; C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D006897:Hydroxyindoleacetic Acid; C014843:1,2,3,4-tetrahydroisoquinoline; D014446:Tyrosine 3-Monooxygenase; C001746:3-methoxytyramine; D002230:Carbidopa; D004298:Dopamine; D006719:Homovanillic Acid