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PubMed1991

Investigation of the possible dopaminergic toxicity of 1-methyl-3-phenyl-1,2,3,6-tetrahydropyridine, an isomer to the neurotoxin MPTP.

1-Methyl-3-phenyl-1,2,3,6-tetrahydropyridine (M-3-PTP) is an analogue to the Parkinson-producing dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), M-3-PTP, and simple analogues thereof, are versatile intermediates in organic synthesis. The present study was undertaken to investigate the possible dopaminergic toxicity of M-3-PTP. Male albino mice were injected with 50 mg/kg of either MPTP or M-3-PTP and dopamine (DA) and its metabolites were determined 2 hr and 7 days after the administration. Two hr after MPTP profound acute changes in brain DA metabolism were found, i.e. an approximately 50% reduction in the concentration of DA together with a 10-fold increase in the level of 3-methoxytyramine. Seven days after MPTP, DA and metabolites were markedly reduced which is consistent with a degeneration of the dopaminergic neurones. In contrast M-3-PTP produced no acute or long-term alterations in the concentrations of DA and its metabolites in mouse brain. Furthermore, in vitro experiments show that M-3-PTP does not inhibit monoamine oxidase B. Thus, the present data show that M-3-PTP is devoid of dopaminergic toxicity in mouse brain and is not likely to produce Parkinson's disease in humans. The lack of toxicity is probably explained by the low affinity of M-3-PTP for monoamino oxidase B.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Depletion of copper and manganese in brain after MPTP treatment of mice.

The mechanism of action of MPTP, a parkinsonism-inducing drug has been related to trace metals as a result of the observed potentiation of the neurotoxic action of the drug when diethyldithiocarbamate is concurrently administered. Diethyldithiocarbamate is a well-known chelator of trace metals, particularly copper. In the present study we analyzed the concentrations of copper and manganese in four brain regions of mice treated with neurotoxic doses of MPTP, in order to further substantiate the relationship between trace metals of MPTP-induced neurotoxicity. Male Swiss albino mice were administered with MPTP (30 mg/kg) for either three or five days. Seven days after the last MPTP administration, they were sacrificed and the content of manganese and copper in the following regions was determined by graphite furnace atomic absorption spectrophotometry: cortex, cerebellum, midbrain and corpus striatum. Results indicate a significant depletion of manganese in corpus striatum (19.5% versus control) in the mice treated with MPTP for 5 days. Copper was also found to be decreased in corpus striatum (17.3% in mice treated for 3 days and 51.3% in mice treated for 5 days). Midbrain copper was depleted by 42.9% in the group of mice treated for 5 days with MPTP. Results indicate that MPTP induced a diminution of both copper and manganese in corpus striatum, suggesting that this alteration could be related to MPTP mechanism of action.

Animals↗
PubMed1997

Comparison of key steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in rodents.

Three steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity were compared with the neurodegenerative effects of the toxin in mice and rats. Firstly, we compared the neurotoxicity of MPTP, mediated by monoamine oxidase (MAO)-B, to that of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP), an analogue oxidized by MAO-A and MAO-B. Both toxins caused degeneration of dopamine terminals in mice but not in rats. In NMRI mice noradrenaline terminals were also affected by both toxins. Pretreatment with deprenyl to prevent MAO-B-mediated oxidation in the capillary endothelium enhanced dopamine toxicity to 2'-CH3-MPTP in nucleus accumbens but no potentiation was seen in striatum and the olfactory tubercle. Secondly, synaptosomal uptake of the 1-methyl-4-phenylpyridinium ion (MPP+) was studied. Uptake in rats was not significantly different from that in the two mice strains. Thirdly, no significant differences were found in MPP(+)-induced lactate production in striatal slices or synaptosomes. We conclude that the lack of effect of MPTP in rats is not due to mechanisms specific for MPTP but probably to the ability of rat catecholamine neurons to cope with, and survive, impaired energy metabolism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro.

The effects of melatonin on the mitochondrial DNA (mtDNA) damage induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine ion (MPP(+)) were investigated both in vivo and in vitro. MPTP (24 mg/kg, s.c.) induced a rapid increase in the immunoreactivity of 8-hydroxyguanine (8-oxoG), a common biomarker of DNA oxidative damage, in the cytoplasm of neurons in the Substantia Nigra Compact of mouse brain. Melatonin preinjection (7.5, 15 or 30 mg/kg, i.p.) dose-dependently prevented MPTP-induced DNA oxidative damage. In SH-SY5Y cells, MPP(+) (1 mm) increased the immunoreactivity of 8-oxoG in the mitochondria at 1 hr and in the nucleus at 3 hr after treatment. Melatonin (200 microm) preincubation significantly attenuated MPP(+)-induced mtDNA oxidative damage. Furthermore, MPP(+) time-dependently increased the accumulation of mitochondrial oxygen free radicals (mtOFR) from 1 to 24 hr and gradually decreased the mitochondrial membrane potential (Psim) from 18 to 36 hr after incubation. At 72 hr after incubation, MPP(+) caused cell death in 49% of the control. However, melatonin prevented MPP(+)-induced mtOFR generation and Psim collapse, and later cell death. The present results suggest that cytoprotection of melatonin against MPTP/MPP(+)-induced cell death may be associated with the attenuation of mtDNA oxidative damage via inhibition of mtOFR generation and the prevention of Psim collapse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Ginsenoside Rg1 reduces MPTP-induced substantia nigra neuron loss by suppressing oxidative stress.

AIM: To investigate the effect of ginsenoside Rg1, an effective ingredient from ginsenoside, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra neuron lesion. METHODS: C57-BL mice were given MPTP to prepare Parkinson disease mice model. Different doses of Rg1 (5, 10, and 20 mg.kg(-1).d(-1)) or N-acetylcystein (NAC) (300 mg.kg(-1).d(-1)) were given 3 d prior to MPTP in the pretreatment groups. Glutathione (GSH) level and total superoxide dismutase (T-SOD) activity in substantia nigra were determined by spectrophotometry. Nissl staining, tyrosine hydroxylase immunostaining, and TUNEL labeling were used to observe the damage and apoptosis of nigral neurons. Western blot analysis was used to detect the phospho-JNK and phospho-c-Jun levels in midbrain homogenates. RESULTS: Pretreatments of C57-BL mice with different doses of Rg1 or NAC were found to protect against MPTP-induced substantia nigra neurons loss. Rg1 or NAC prevented GSH reduction and T-SOD activation in substantia nigra, and attenuated the phosphorylations of JNK and c-Jun following MPTP treatment. CONCLUSION: The antioxidant property of Rg1 along with the blocking of JNK signaling cascade might contribute to the neuroprotective effect of ginsenoside Rg1 against MPTP.

Animals↗
PubMed1992

Midbrain dopaminergic cell loss in Parkinson's disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells.

Computer imaging and immunohistochemical staining techniques were used to determine which midbrain dopaminergic (DA) cells are spared in Parkinson's disease (PD), and in animals treated with the DA neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and whether the spared cells contain the calcium-binding protein, calbindin-D28k (CaBP). The PD patients had more than 55% fewer midbrain DA neurons than age-matched normal subjects. The cell loss occurred within the combined substantia nigra and retrorubral area (greater than 61%; DA nuclei A9 and A8, respectively), and the ventral tegmental area (greater than 42%; DA nucleus A10). The cell loss was greatest within the ventral portion of the nucleus A9. A similar pattern of DA cell loss was observed in MPTP-treated Macaca fascicularis monkeys. The CaBP-containing cells were located specifically in the cell regions spared by PD and by MPTP-treatment in both monkeys and C57BL/6 mice. These data suggest that PD and MPTP both destroy the same population of midbrain DA neurons within nuclei A8, A9, and A10, and that perhaps CaBP protects the DA neurons from cell death caused by both PD and MPTP.

Aged↗
PubMed1994

In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia.

The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗