Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson's disease.

Abstract

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.

• Authors: K Abe, K Taguchi, T Wasai, J Ren, I Utsunomiya, T Shinohara, T Miyatake, T Sano
• Journal: Brain research bulletin (Brain Res Bull) Vol. 56 Issue 1 Pg. 55-60 (Sep 01 2001) ISSN: 0361-9230 [Print] United States
• PMID: 11604249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dopamine Antagonists
• Isoquinolines
• Neuroprotective Agents
• Neurotoxins
• Tetrahydroisoquinolines
• 3,4-Dihydroxyphenylacetic Acid
• Serotonin
• Levodopa
• 1-methyl-1,2,3,4-tetrahydroisoquinoline
• Hydroxyindoleacetic Acid
• 1,2,3,4-tetrahydroisoquinoline
• Tyrosine 3-Monooxygenase
• 3-methoxytyramine
• Carbidopa
• Dopamine
• Homovanillic Acid

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Animals
• Carbidopa (pharmacology)
• Cell Count
• Disease Models, Animal
• Dopamine (analogs & derivatives, metabolism)
• Dopamine Antagonists (pharmacology)
• Drug Interactions (physiology)
• Homovanillic Acid (metabolism)
• Hydroxyindoleacetic Acid (metabolism)
• Hypokinesia (chemically induced, drug therapy, physiopathology)
• Immunohistochemistry
• Isoquinolines (pharmacology)
• Levodopa (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL (anatomy & histology, metabolism)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Neurotoxins (pharmacology)
• Parkinsonian Disorders (chemically induced, drug therapy, physiopathology)
• Serotonin (metabolism)
• Stereoisomerism
• Substantia Nigra (drug effects, metabolism, pathology)
• Tetrahydroisoquinolines
• Tyrosine 3-Monooxygenase (metabolism)