MPTP, neurotoxicity

RESPONSE We do not understand all there is to know about the mechanisms of MPTP neurotoxicity, but it seems to involve MPP+, which is potentially cytotoxic to all cells but that attains toxic concentrations after MPTP administration only in cells that concentrate MPP+. Dopamine apparently is not involved in the neurotoxic effects of MPTP. I am attracted to the idea that dopamine itself may be involved in the etiology of Parkinson s disease, that dopamine neurons may be at risk because of the nature of their neurotransmitter. 

Yokoyama, H., Kurolwa, H., and Yano R Araki, T. (2008). Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson s disease. Neurol. Sci. 29, 292-301. 

Feng Z., Li D., Fung P. C., Pei Z., Ramsden D. B., and Ho S. L. (2003). COX-2-deficient mice are less prone to MPTP-neurotoxicity than wild-type mice. NeuroReport 14 1927-1929. 

MPTP decreases glutathione levels and increases the levels of reactive oxygen species and the degree of lipid peroxidation in mouse brain slices in vitro and increases the levels of reactive oxygen species in mouse brain in vivo. MPTP neurotoxicity in vitro is reduced by glutathione. In vitro studies have shown that MPP neurotoxicity can be reduced by vitamin E, vitamin C, coenzyme Q, and mannitol (but not by superoxide dismutase, catalase, allopurinol, or dimethyl sulfoxide). P-Carotene, vitamin C, and /V-acctylcystcine partially protect against the neurotoxic effects of MPTP in mice, as do nicotinamide, coenzyme Q, and the free-radical spin trap A-tert-butyl-a-(sulfophenyl) nitrone. 

Kilboum MR, Sherman P, Abbott LC (1998) Reduced MPTP neurotoxicity in striatum of the mutant mouse tottering. Synapse 30 205-210. 

Gainetdinov RR, Fumagalli F, Jones SR, Caron MG (1997) Dopamine transporter is required for in vivo MPTP neurotoxicity evidence from mice lacking the transporter. J Neurochem 69 1322-1325. 

Gainetdinov RR, Fumagalli F, Wang YM, Jones SR, Levey AI, Miller GW, Caron MG (1998) Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice. J Neurochem 70 1973-1978. 

G, Kaddurah-Douk R, Beal E (1999) Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurology 157(1) 142-149. 

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). 

The relationship of MAO and MPTP has neurobiological relevance beyond MPTP neurotoxicity. Types A and B MAO catalyze the a-carbon oxidative deamination of monoamine neurotransmitters and other aromatic amines. These genetically dissimilar isozymes show differential selectivity for specific substrates and inhibitors (63). Most intraneuro-nal MAO is mitochondrial and type A, and oxidizes primary amines to aldehydes, which are then converted by aldehyde reductases to alcohols or carboxylic acids, including dihy-droxyphenylatic acid (DOPAC) from DA Additional 3-0-methylation yields the majorfmal human metabolite of DA, homovanillic acid (HVA see Fig. 12.4). 

Thus, we have to consider a second hypothesis of MPTP neurotoxicity. Metabolism, transport and storage of MPTP within cells is functionally closely connected with mitochondria. Once created by the MAO in glial cells, MPP+ is suspected to be actively concentrated in mitochondria of astrocytes and of dopaminergic neurons (Ramsay and Singer,... 

Vitamin E supplements fail to protect mice from acute MPTP neurotoxicity. NeuroReport 2 544-546. 

Importantly, the neuropathological and clinical characteristic features of MPTP-induced parkinsonism invariably resemble idiopathic Parkinson s disease rather more intimately than anyother previous human or experimented animal disorder exhibited by toxins, viruses, metals, or other modes. In short, the molecular pathophysiology of the ensuring MPTP neurotoxicity has virtually decephered the mystery surrounding the neurodegenerative mechanisms particularly associated with the idiopathic parkinsonism. 

Fig. 25.5. Chemical conversion of MPPP and probable mechanism of MPTP neurotoxicity.

Accordingiy, understanding the moiecuiar pathophysiology of MPTP neurotoxicity has shed light on the neurodegenerative mechanisms in idiopathic parkinsonism. 

Watanabe H, Muramatsu Y, Kurosaki R et al. Proteotive effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity an immunohistological study. Eur Neuropsychopharmacol 2004 14 93-104. 

Lee CS, Han ES, Jang YY, Han JH, Ha HW, Kim DE (2000) Protective effect of harmalol and harmaline on MPTP neurotoxicity in the mouse and dopamine- induced damage of brain mitochondria and PC12 cell. J Neurochem 75 521-531... 

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