Preventative effects of 1,3-dimethyl- and 1,3-dimethyl- N -propargyl-1,2,3,4-tetrahydroisoquinoline on MPTP-induced Parkinson's disease-like symptoms in mice

Abstract 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is well known as an exogenous dopaminergic neurotoxin that induces Parkinson's disease-like symptoms. In addition, 1,2,3,4-tetrahydroisoquinoline (TIQ) derivatives have been investigated as endogenous MPTP mimetic compounds that structurally resemble selegiline, a commercially available drug for treating Parkinson's disease. In the present study, we examined the ability of 1,3-dimethyl-TIQ (1,3-diMeTIQ) and 1,3-dimethyl- N -propargyl-TIQ (1,3-diMe- N -proTIQ) to prevent MPTP-induced Parkinson's disease-like symptoms in mice and to prevent 1-methyl-4-phenylpyridinium ion (MPP+ , an active metabolite of MPTP)-induced cytotoxicity in vitro, including its structural stereoselectivity. Repeated administration of MPTP induced bradykinesia, a symptom of behavioral abnormality; this was prevented by both 1,3-diMeTIQ and 1,3-diMe- N -proTIQ pretreatments. Pretreatment with 1,3-diMeTIQ did not prevent the MPTP-induced decrease in dopamine content in the striatum or the decrease in the number of tyrosine hydroxylase-positive cells in the substantia nigra. On the other hand, 1,3-diMe- N -proTIQ prevented these Parkinson's disease-like symptoms; in particular, the trans -isomer of this agent showed potent protective effects. However, the ability of the trans -1,3-diMe- N -proTIQ isomer to prevent MPP+ -induced PC12 cell death was weaker than that of its cis -isomer. Thus, stereoisomers of 1,3-diMe- N -proTIQ exhibit different effects; cis -1,3-diMe- N -proTIQ inhibits MPP+ -induced cytotoxicity while trans -1,3-diMe- N -proTIQ exhibits neuroprotective effects primarily through MPTP-related biological events in mice. These results also indicate the possibility of utilizing, at least in part, the stereoselective efficacy of 1,3-diMe- N -proTIQ against MPTP and/or MPP+ -induced adverse states.