|Figure 1. Chemical structures of MPTP, its metabolite MPP+, and various MPTP analogues.|
The pathology of Parkinson's disease (PD) involves extensive degeneration and loss of dopamine (DA)-containing neurons in the substantia nigra pars compacta. This results in a dramatic reduction in total DA content within the nigrostriatal region. Although a variety of hypotheses have been proposed, the etiology of PD is unknown. The development of PD may be due to a genetically inherited, vulnerable dopaminergic system or exogenous or endogenous neurotoxins.
Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) displays symptoms indistinguishable from those of idiopathic PD.1,2 Neither MPTP nor its metabolite MPP+ (a potent dopaminergic neurotoxin) is found in humans, however. As a result, the in vivo neurotoxicity associated with PD cannot be attributed to MPTP. This has led to the search for MPTP analogues that are possible endogenous or exogenous neurotoxins in PD and has provided a model for investigating the mechanism of PD.
MPTP analogues, such as beta-carboline and various isoquinoline derivatives, may be responsible for PD. This group of molecules includes 1,2,3,4-tetrahydroisoquinolines (TIQs), 6,7-dihydroxy-1,2,3,4-tetrahydroquinolines, 1(R), 2-dimethyl-6,7dihydroxy-TIQ, N-methyl-6,7-dihydroxy-tetrahydroisoquinoline (N-methyl-norsalsolinol) and
beta-carbolines. The resulting structure of the oxidized isoquinoline (i.e. isoquinolinium ion) is similar to that of MPP+ (see Figure 1).3,4 In contrast to MPP+, TIQ can be found in humans as it is present in a variety of foods and beverages, including cheese, wine, bananas, milk, and cocoa.5-7 It can cross the blood-brain barrier due to its hydrophobicity and can be converted enzymatically to compounds that are neurotoxic. Endogenously, TIQ and its derivatives can be synthesized by the non-enzymatic Pictet-Spengler condensation or by enzymatically induced condensation of catecholamines with aldehydes.8 Salsolinol and norsalsolinol can be formed from endogenous DA with acetaldehyde or formaldehyde and can be converted by a neural N-methyltransferase into N-methyl-salsolinol and N-methyl-norsalsolinol. They can then be oxidized to the corresponding isoquinolinium ions, which do not cross the blood-brain barrier and subsequently accumulate within the brain.
Elevated levels of salsolinol and TIQ derivatives can be found in the urine, cerebrospinal fluid (CSF), and brain tissue from PD patients.9-11 These increased levels of TIQ derivatives may reflect increased DA metabolism or neuronal toxicity. TIQs and their derivatives are known to be toxic to dopaminergic neurons in culture. The mechanisms responsible for this neurotoxicity, however, are not clear. One hypothesis is that TIQ, or a TIQ derivative, is taken up by the DA transporter and accumulates within the nigrostriatal system. Oxidation can then result in the generation of a neurotoxic ion. For example, TIQ is capable of inhibiting mitochondrial respiration and ATP synthesis.12 Cell death of dopaminergic neurons could result from free radical generation, inhibition of mitochondrial ATP synthesis, or by induction of apoptosis.11,13-19
Note: R&D Systems has developed a monoclonal antibody against one of the TIQ derivatives N-methyl-6,7 dihydroxy-TIQ (Catalog # MAB167). This antibody provides a useful tool for immunohistochemical localization and identification of this molecule.