Tetrahydroisoquinolines and Parkinson’s disease


The risk of developing Parkinson’s disease (PD) is due to the nonorthogonal effects of numerous genetic and environmental risk factors. Aging is the major risk factor for PD. The effects of certain genetic and environmental factors are binary. For instance, exposure to sufficient amounts of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; Figure 8.1A) causes parkinsonism in humans and mice. Discovery that MPTP can cause parkinsonism [1,2] led to a search for MPTP analogues as possible endogenous or exogenous neurotoxins critical to the neurodegeneration seen in PD. In the context of identifying other neurotoxins that show relative dopaminergic selectively, it is important to review the cellular mechanisms of MPTP neurotoxicity: (1) MPTP is converted to 1-methyl-4-phenylpyridinium ion [MPP+] by glial monoamine oxidase [MAO]-B, (2) MPP+ is actively transported into presynaptic dopaminergic nerve terminals through the plasma membrane dopamine transporter [DAT], and (3) it is MPP+, not MPTP, that kills dopaminergic neurons via inhibition of mitochondrial complex I.

Publication Title

Parkinson's Disease, Second Edition