3-methyl-1-2-3-4-tetrahydroisoquinoline and Disease-Models--Animal

Selegiline, a therapeutic drug for Parkinson's disease (PD), structurally resembles the endogenous parkinsonism-related compound 1,2,3,4-tetrahydroisoquinoline (TIQ). In the present study, we evaluated the effects of 3-methyl-TIQ (3-MeTIQ) and 3-methyl-N-propargyl-TIQ (3-Me-N-proTIQ), selegiline mimetic TIQ derivatives, for preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism-like symptoms in mice.. We evaluated the preventative effects of 3-MeTIQ and 3-Me-N-proTIQ on MPTP-induced bradykinesia and depletion of striatal dopamine (DA) and nigral tyrosine hydroxylase (TH)-positive cells.. MPTP-induced bradykinesia was not different when mice were pretreated with 3-MeTIQ, except for the high-dose group. However, pretreatment with 3-Me-N-proTIQ significantly prevented the appearance of this akinesic status. MPTP-induced striatal DA and 3,4-dehydroxyphenylacetic acid reduction were significantly prevented by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ, in a dose-dependent manner. On the other hand, levels of serotonin and its metabolite, 5-hydroxyindole acetic acid, in the striatum were increased following treatment with 3-MeTIQ. In addition, the MPTP-induced decrease in TH-positive cells in the substantia nigra was significantly reduced by pretreatment with 3-Me-N-proTIQ, but not 3-MeTIQ.. These results suggest that not only does 3-Me-N-proTIQ have potential as a candidate compound for disease-modifying therapy for PD, but also the N-propargyl functional group plays an important role in neuroprotection.

Topics: Animals; Antiparkinson Agents; Basal Ganglia; Behavior, Animal; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Hydroxyindoleacetic Acid; Hypokinesia; Male; Mice; Mice, Inbred C57BL; Motor Activity; MPTP Poisoning; Neuroprotective Agents; Serotonin; Substantia Nigra; Tetrahydroisoquinolines; Time Factors; Tyrosine 3-Monooxygenase