Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase

Chiba, Kazuhiro; Trevor, Anthony J.; Castagnoli, Neal

doi:10.1016/0006-291x(84)91293-2

Cited by 1,067 publications

(393 citation statements)

References 7 publications

Supporting

Mentioning

385

Contrasting

Unclassified

Order By: Relevance

“…Recent data from a transgenic animal model developed by Yue et al that overexpresses APP and lacks the aromatase enzyme, the APP23/Ar +/À mice, show an earlier onset of plaque formation compared to ovariectomized APP23 mice [260]. In this model it was also found that BACE protein expression and activity, as well as Ab 40 and Ab 42 levels, were elevated in the brains of APP23/Ar +/À mice as young as 6 months. Thus, the early-onset AD neuropathology in APP23/Ar +/À mice associated with brain estrogen deficiency may be mediated by increased BACE activity and accelerated Ab production.…”

Section: Estrogens and Alzheimer's Diseasementioning

confidence: 95%

“…MPTP is converted by astrocytes to the metabolite 1 methyl-4-phenylpyridinium [MPP + ], a substrate of the DA transporter ( [40,41]). MPP + thus accumulates in dopaminergic neurons where it inhibits the mitochondrial complex I of the electron transport chain, resulting in ATP depletion and subsequent inability to release sufficient amounts of dopamine and ultimately leading to apoptosis [231].…”

Section: Animal Models Of Parkinson's Diseasementioning

confidence: 99%

See 1 more Smart Citation

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

261

196

View full text Add to dashboard Cite

a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

show abstract

Section: Estrogens and Alzheimer's Diseasementioning

confidence: 95%

Section: Animal Models Of Parkinson's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

261

196

View full text Add to dashboard Cite

show abstract

“…The protective effect of NSAIDs on neuronal death induced by 1-methyl-4-phenyl pyridinium (MPP + ), a toxic metabolite of MPTP (Chiba et al, 1984;Cleeter et al, 1992), was studied using human dopaminergic SH-SY5Y neuroblastoma cells which express COX-2 (Alique et al, 2007). Furthermore, we identified the signal pathway related with the neuroprotective effect exhibited by a certain NSAID (meloxicam), and proposed possible therapeutic application of meloxicam in PD treatment.…”

Section: Introductionmentioning

confidence: 99%

Meloxicam protects cell damage from 1-methyl-4-phenyl pyridinium toxicity via the phosphatidylinositol 3-kinase/Akt pathway in human dopaminergic neuroblastoma SH-SY5Y cells

et al. 2010

View full text Add to dashboard Cite

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuronal death in the substantia nigra pars compacta. There is growing interest in the effects of nonsteroidal antiinflammatory drugs (NSAIDs) against PD progression. In this study, we investigated the neuroprotective effect of NSAIDs on neuronal damage induced by 1-methyl-4-phenyl pyridinium (MPP + ) in human

show abstract

“…review [1] we summarized how the sudden appearance of parkinsonism in relatively young patients in the San Francisco Bay Area in 1982 was traced to their use of a designer drug, 'new heroin', manufactured by a clandestine laboratory, and to the MPTP contained in defective batches of the street drug. Almost immediately following the reports that MPTP is neurotoxic to humans [2], subhuman primates md mice [3][4][5], eliciting damage to dopaminergic aeurons, it was shown that MPP + (1-methyl-4-phenylpyridinium) is the neurotoxic form and that it arises by 4-e oxidation of MPTP in brain mitochondria [6]. Proof that the enzyme responsible for processing MPTP is monoamine oxidase (MAO B) in the glial cells, of which it is an excellent substrate and that MAO A also oxidizes MPTP, albeit more slowly, was reported soon thereafter [7].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the neurotoxicity of MPTP

1990

View full text Add to dashboard Cite

This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.Monoamine oxidase; MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); Neurotoxin; NADH dehydrogenase

show abstract

Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase

Cited by 1,067 publications

References 7 publications

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Meloxicam protects cell damage from 1-methyl-4-phenyl pyridinium toxicity via the phosphatidylinositol 3-kinase/Akt pathway in human dopaminergic neuroblastoma SH-SY5Y cells

Mechanism of the neurotoxicity of MPTP

Contact Info

Product

Resources

About