MPTP toxic activation

Similarly, a crucial role of DAT in the neurotoxic action of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been supported in mice lacking DAT (62,63). In numerous previous studies it had been demonstrated that MPTP neurotoxicity involves selective uptake of its active metabolite, l-methyl-4-phenylpyridinium (MPP+) into the DA neuron via the DAT (6,9). In DAT-KO mice treated with MPTP, markers of striatal neurotoxicity, such as depletion in DA levels and reactive astrogliosis, were virtually absent, whereas in DAT heterozygotes a partial sensitivity was observed (62). In another investigation, no apparent DA cell body loss was found in the substantia nigra of MPTP-treated DAT-KO mice (63). Thus, an absolute requirement of DAT for development of MPTP toxicity in vivo has been firmly established (9,62,63). 

Similarly, abnormalities in the mitochondrial machinery and resulting oxidative stress may also intervene in Parkinson s disease (PD) [31, 32]. The decreased activity of mitochondrial complex I in PD patients [33], and the preferential toxicity of the complex I inhibitor rotenone [34] and MPP+ (the active metabolite of MPTP)... 

MPTP-induced toxicity and monoamine oxidase activity in the mouse brain. 

The enzyme found in the liver will deaminate secondary and tertiary aliphatic amines as well as primary amines, although the latter are the preferred substrates and are deaminated faster. Secondary and tertiary amines are preferentially dealky la ted to primary amines. For aromatic amines, such as benzylamine, electron-withdrawing substituents on the ring will increase the reaction rate. The product of the reaction is an aldehyde (Fig. 4.30). Amines such as amphetamine are not substrates, seemingly due to the presence of a methyl group on the a-carbon atom (Fig. 4.27). Monoamine oxidase is important in the metabolic activation and subsequent toxicity of allylamine (Fig. 4.31), which is highly toxic to the heart. The presence of the amine oxidase in heart tissue allows metabolism to the toxic metabolite, allyl aldehyde (Fig. 4.31). Another example is the metabolism of MPTP to a toxic metabolite by monoamine oxidase in the central nervous system, which is discussed in more detail in chapter 7. 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

Microdialysis allows direct intracerebral administration of the drugs that normally do not cross the blood-brain barrier (BBB) or are metabolized in the circulation. It was demonstrated earlier (Ozaki et al., 1988 Westerink et al., 1990) that MPP+, a toxic metabolite of 1-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine (MPTP), has a biphasic effect on TH activity when infused via the microdialysis probe for 20 minutes. Since, however, this drug does not penetrate the BBB, it was difficult to investigate its effects in vivo. Microdialysis overcomes this problem and has enabled the testing of a range of other modulators that previously could be studied only on in vitro preparations. 

Figure 44.3. T cell-mediated neui oprotecdon in a PD model. In MPTP-intoxicated mice, regulatory T cells infiltrate tire inflamed nigrostiiatal patliway where tliey encounter cross-reactive CNS antigens (such as myelin basic protein or reactive species-modified proteins) presented in tire context of MHC by resident microglial cells. In response, activated T cells secrete anti-inflammatory cytokines such as IL-4, IL-10, and TGF- 3 tliat suppress toxic microglial activities. Neurotrophin expression may occur directly from T cells or T cell-derived IL-4, and IL-10 may induce neurotrophin production in neigliboimg glia. Tliese activities lead to neuroprotection indirectly by suppression of microglial responses and directly tlu ough tire local delivery of neurotropliins.

Figure 12.3. Phenylpiperidine analgesics and metabolic activation of MPTP. In efforts to synthesize the meperidine-like analgesic agent MPPP ("designer heroin,") (4), MPTP (3)can be formed. It is converted selectively by monoamine oxidase type B (MAO-B, inhibited by agents including deprenyl (selegiline)and pargylineto MPDP (7), and thence to MPP" (8)the proposed toxic species that accumulated in dopamine neurons to result in disruption of their cellular respiration and death.

FIGURE 7.30 The metabolic activation and proposed mechanism of toxicity of MPTP in the central nervous system. Thus MPP+ is actively taken into the neurone where it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Qiq). MPTP l-Methyl-4-... 

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