ABSTRACT
Parkinson’s disease (PD) is a debilitating progressive neurodegenerative disease, primarily of the aged population, that is characterized by severe motor symptoms including resting tremor, muscular rigidity, slowness of movement, and postural imbalance. The redundant pathological hallmarks of this disorder are a severe loss of dopaminergic (DA) neurons in the nigrostriatal region and the appearance of cytoplasmic inclusions known as Lewy bodies (LB) in surviving neurons. It is estimated that more than one and one-half million individuals in North America alone are affected with PD and more than 50,000 new cases are being diagnosed each year (Fahn and Przedborski, 2000). The exact cause for the selective loss of DA neurons in PD is still not known; however, MPTP-like compounds (Langston et al., 1983; Hao et al., 1995a; Nagatsu, 1997; Schapira, 2001; Shavali et al., 2004) are suspected to be involved in the pathogenesis. Further, the presynaptic protein α-synuclein, which is an important component of LB, is also associated with the pathogenesis of PD (Polymeropoulos et al., 1997; Krüger et al., 1998; Spillantini et al., 1998). Tetrahydroisoquinolines (TIQs) are dopamine-derived neurotoxins that are structurally homologous to MPTP that can induce parkinsonism in rodents and humans (Figure 9.1). Several lines of evidence suggest that TIQs are endogenous neurotoxins that may contribute to DA neuron dysfunction and DA neuron death in PD (Nagatsu, 1997). The evidence for this hypothesis came from the studies of Hao et al. (1995a) when they reported the occurrence of low-molecular-weight substances in the CSF of PD patients that severely inhibited the function and growth of rat DA neurons in culture. They
also observed that the inhibition was completely prevented by selegiline, a monoamine oxidase type B inhibitor (Hao et al., 1995b).
