ABSTRACT
The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP; Figure 9.1A) can cause parkinsonism1,2 led to a search for MPTP analogs as possible endogenous or exogenous neurotoxins critical to the neurodegeneration seen in Parkinson’s disease (PD). In the context of identifying other neurotoxins that show some degree of dopaminergic selectively, it is important to remember that (1) MPTP is converted to 1methyl-4-phenyl-pyridinium ion (MPP+) by 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+, and not MPTP, that kills dopaminergic neurons. Isoquinoline (Figure 9.1B) derivatives are one group of neurotoxins that are both substrates for MAO and structurally homologous to MPTP. Several lines of evidence suggest that isoquinoline derivatives may be endogenous and/or exogenous neurotoxins that contribute to dopaminergic cell death in PD.3-5 McNaught et al.6 showed that isoquinoline derivates such as the tetrahydroisoquinolines (TIQs) and dihydroisoquinolines are more potent inhibitors of complex I of the respiratory chain than MPP+. TIQ (Figure 9.1C) is present in several common foods such as cheese, bananas, milk, wine, and cocoa.7-10 TIQ has also been localized to rodent and human brain.7,11 Nagatsu and Yoshida12 stirred interest in TIQ by showing that systemic administration of this molecule to marmosets produced parkinsonism, despite the lack of demonstrable cell death within the substantia nigra, pars compacta (SNpc). TIQ also appears to be a much less potent neurotoxin than MPTP in mice.13 Cell death could have been missed, however, since neither markers of apoptosis nor stereological counting methods were employed. N-methylated derivatives of TIQ (Figures 9.1C through 9.1D and Figure 9.2) and benzyl TIQs (Figures 9.1D and Figure 9.3) may be more neurotoxic than TIQ.5,1421 Although several TIQ derivates have been shown to destroy cultured dopaminergic neurons,22,23 convincing and consistent anatomical proof of cell death in animals exposed to isoquinolines has been lacking.
