PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “MPTP Poisoning”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 685 records · Page 38Linked to original sources
PubMedDate not supplied

Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We tested the hypothesis that curcumin, a polyphenolic antioxidant, acts as a powerful free radical scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, (MPTP) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We measured the (GSH) reduced glutathione levels, (TBARS) glutathione lipid peroxidation, (CAT) catalase and (SOD) superoxide dismutase activity in the (ST) striatum and (MB) mid brain 3rd day and 7th day following MPTP and curcumin administration. MPTP treatment caused a significant depletion in GSH and increased the specific activity of SOD, CAT and lipid peroxidation in both ST and MB on the 3rd and 7th day. MPTP induced GSH depletion and lipid peroxidation in ST and MB was blocked by curcumin treatment. Curcumin exhibited a synergistic effect on SOD and CAT activities in the ST and MB regions. The present study provides direct evidence for the involvement of curcumin in neuroprotection against oxidative stress.

Animals↗
PubMed1991

In memoriam Richard Heikkila. The MPTP story: irony creeps back in.

Progress in Parkinson's disease research has been rapid in recent years from both a scientific and clinical point of view. The MPTP discovery represented a milestone in the knowledge of the biochemical mechanism underlying degeneration of dopaminergic neurons of the nigrostriatal pathway. Recent life and scientific events have initiated, even ironically, new trends in the mechanism of MPTP toxicity. The role of excitatory amino acids, particularly of NMDA receptors, in this toxicant-induced degenerative process, seems to be crucial. If this new finding is further confirmed by studies on primates, the animal species most sensitive to the neurotoxin, research into Parkinson's disease might move in other directions, useful in both treatment and prevention.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

[Parkinsonism induced by MPTP as an experimental model of Parkinson disease: similarities and differences].

MPTP administration, preferably to mice and primates, induces a selective damage of substantia nigra dopaminergic cells. Intrinsic mechanisms mediating MPTP induced toxicity, remain still under evaluation. There are very few semiological differences between Parkinson's disease (PD) and MPTP parkinsonism, but significant biochemical and neuropathological differences have been reported between these two entities. However, at the moment it represents the best model of Parkinson's disease available for the study of the basal ganglia function. In addition it could be a useful tool for a better understanding of mechanisms involved in neuronal death and regeneration. The present paper, summarize the real knowledge about the mechanism by which MPTP induces neuronal toxicity, the differences reported between PD and MPTP parkinsonism and finally its application for research.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Mechanistic aspects of 1-methyl-4-phenyl pyridinium iodide toxicity in Escherichia coli: the role of oxygen and hydrogen peroxide.

1-Methyl-4-phenyl pyridinium iodide (MPP+) and paraquat (PQ+2) are two structurally analogous and highly toxic pyridinium compounds. The mechanism of PQ+2 toxicity is best understood in the bacterial model system. While numerous studies in a variety of systems have indicated the causative role of free radicals and other oxygen-derived active species in PQ+2 toxicity, this question is yet unresolved in the case of MPP+. In this study we have used the Escherichia coli model and demonstrated that MPP+ is toxic to bacterial cells in dose- and time-dependent modes. Additionally, it is shown that only in the presence of molecular oxygen did bacterial inactivation occur. This requirement for oxygen can be circumvented by adventitious H2O2. The protective effects of the chemical scavenger--mannitol--and of histidine are presented. These results are in complete accord with a free radical mechanism for MPP+ toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Depletion of striatal dopamine by the N-oxide of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The N-oxide of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the major metabolite found in vivo and excreted in urine after the parenteral administration of the neurotoxicant, MPTP. In mice (C57BL/6), stereotaxic injection of MPTP N-oxide (15 micrograms) into the neostriatum produced dopamine (DA) depletion similar to that caused by MPTP. The DA depleting effect of MPTP N-oxide was a direct action, whereas the action of MPTP was mediated by the generation of oxidative metabolites. In the mouse striatal synaptosomal preparation, MPTP, MPP+ and MPTP N-oxide all competed with [3H]DA at its uptake site. In addition, MPP+ and MPTP N-oxide promoted [3H]DA release. In contrast to MPTP and MPDP+, MPTP N-oxide did not alter the electrophysiologically recorded field potential in nigro-striatal slices. These observations suggest that MPTP N-oxide can directly cause the chemical depletion of striatal DA without modifying the characteristics of cortico-striate synaptic transmission.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

A model of chronic neurotoxicity: long-term retention of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) within catecholaminergic neurons.

The mechanism by which 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces lesions in the nigrostriatal dopamine system has been extensively studied. MPTP, a lipophilic molecule, enters the brain rapidly where it is converted to the pyridinium metabolite 1-methyl-4-phenylpyridinium (MPP+), by a two-step reaction that requires the enzyme monoamine oxidase. Following this conversion, which occurs primarily in astrocytes, MPP+ is sequestered within monoaminergic neurons by the energy-requiring monoaminergic transporters. Inside the neuron, MPP+ is thought to act as a mitochondrial toxin, slowly sapping the neuron of its energy-producing potential by blocking the action of NADH dehydrogenase. Much attention has been focused on cell death after MPTP administration, but little attention has been paid to the effects of small subtoxic doses of MPTP (i.e., doses that do not produce overt neuropathologic changes), which might occur during environmental exposure to a nigrostriatal toxin. Low doses of MPTP (as little as 1/25th of a toxic dose) produce long-term (greater than 6 weeks) but reversible changes in catecholamine metabolism. These changes are characterized by a decrease in the products of enzymatic oxidative deamination without a concomitant decrease in the amine concentrations (apparent MAO inhibition). Striatal concentrations of MPP+, which is retained in catecholaminergic terminals for similarly long periods, parallel the metabolic changes. Thus, the long-term storage of the MPTP metabolite, MPP+, correlates with altered catecholamine metabolism. The data on the effects of MPTP have been combined into a working model of how MPP+ exerts its effects following subtoxic or toxic doses. The site of this long-term neuronal storage of MPP+ after exposure to subtoxic doses of MPTP is as yet undetermined, but several studies suggest that monoaminergic vesicles may be the primary site, with mitochondria contributing some storage capacity. This vesicular site could represent a potential brain site for the accumulation of toxins during continual or repeated exposure to low levels of MPTP. Induced release from this site might accelerate the toxic interactions with cellular components such as mitochondria.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces changes in the heme spin state of microsomal cytochrome P-450.

In vitro studies on the nature of interaction of the neurotoxin MPTP with hepatic microsomal cytochrome P-450 were carried out. Spectral perturbation studies showed nitrogenous ligand type binding between MPTP and cytochrome P-450 with a peak at 423 nm and a broad trough at 400 nm. Scatchard analysis of MPTP-cytochrome P-450 binding suggested that MPTP binds to at least 2 species of cytochrome P-450--a high affinity binding species with an apparent spectral dissociation constant (Ks) of 372 microM and a low affinity species with Ks of 37.6 mM. EPR studies confirmed that MPTP is a type II substrate for the forms of cytochrome P-450 with which it interacts and causes a shift from the high spin state of cytochrome P-450 to the low spin state. MPTP is, thus, likely to be an effective inhibitor of cytochrome P-450.

Animals↗
PubMed1990

[Study of an MPTP-induced parkinsonian animal model in the rhesus monkey and the mechanism of the action of MPTP].

In this paper are presented the data of the use of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to create a parkinsonian animal model in rhesus monkey. We studied the mechanism of the action of MPTP through testing monoamine oxidase B (MAO-B) inhibitor, deprenyl and L-prolyl-L-leucyl-glycinamide (PLG) against the neurotoxicity of MPTP. The results indicated that: (1) the use of MPTP can establish a useful parkinsonian animal model in rhesus monkey; (2) pretreatment with deprenyl can effectively prevent the neurotoxicity of MPTP; and (3) whether PLG can prevent or alleviate the neurotoxicity of MPTP requires further study.

Animals↗
PubMed1991

Correlation between the neostriatal content of the 1-methyl-4-phenylpyridinium species and dopaminergic neurotoxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to several strains of mice.

In the present study we observed pronounced differences in the capacity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce dopaminergic neurotoxicity in several strains of mice. For example, there was no MPTP-induced decrement in neostriatal dopamine content in Ace Swiss-Webster mice and a 92% decrement in Taconic Farms C57 bl mice. Several parameters which could possibly explain this differential sensitivity to MPTP were studied. These include: 1) neostriatal monoamine oxidase-B (MAO-B) activity; 2) the capacity of neostriatal synaptosomes prepared from the mouse strains to accumulate 1-methyl-4-phenylpyridinium (MPP+), the major metabolite of MPTP formed via oxidation by MAO-B; and 3) the neostriatal MPP+ content after MPTP administration to the mice. There were no significant differences in the Km values for MAO-B in the neostriatum among the strains of mice examined. Neostriatal Vmax values for MAO-B differed somewhat among the strains, with a low of 2915 +/- 172 nmol/g of tissue per hr (CD-1 mice from Charles River) and a high of 3884 +/- 203 nmol/g of tissue per hr (C57 bl mice from Taconic Farms). However, Vmax values for MAO-B in the mouse strains did not correlate significantly with the relative sensitivity of the strains to MPTP. There were no significant differences in the capacity of neostriatal synaptosomes prepared from the mouse strains to accumulate MPP+. Studies on the metabolism of MPTP after peripheral administration revealed that there was a significant (P less than .01) positive correlation between the relative sensitivity of the mouse strains to MPTP and their neostriatal MPP+ content after MPTP administration.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

MPTP-induced duodenal ulcers in rat. Prevention by reuptake blockers for serotonin and norepinephrine, but not dopamine.

Abnormal activity of dopamine, serotonin, and norepinephrine may contribute to the pathophysiology of duodenal ulcers. We therefore studied the effects of neuropharmacological manipulations on 1-methly-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced duodenal ulcers. Duodenal ulcers were produced in rats by 12 subcutaneous injections of a neurotoxin, MPTP, over 4 days. At an MPTP dose of 20 mg.kg. injection, duodenal ulcers developed in 91% (43 of 47) of animals with low mortality. When neuropharmacological agents were preadministered before MPTP, the following effects on duodenal ulcers incidence were obtained. MAO-B inhibitors (pargyline [55%], deprenyl [43%]) but not MAO-A inhibitors (clorgyline [91%]) significantly decreased the frequency of duodenal ulcers suggesting that, like MPTP-induced parkinsonism, formation of a toxic metabolite, probably 1-methyl-4-phenyl-pyridinium is involved. Reuptake blockers for serotonin (fluoxetine [18%], indalpine [25%]) also decreased the frequency of duodenal ulcers. Reuptake blockers for norepinephrine (desmethylimipramine [17%], tomoxepine [31%], but not amfonelic acid [82%]) decreased the frequency of duodenal ulcers. Reuptake blockers for dopamine (benztropine [73%], amfonelic acid [82%], GBR-12909 [80%]) did not protect against duodenal ulcers. However, GBR-12909 significantly decreased the severity of those duodenal ulcers that were produced. These data suggest that abnormally low levels of synaptic transmission in serotonergic and possibly noradrenergic neurons play an important role in the pathogenesis of duodenal ulcer while the role of dopamine may be limited to modulation of ulcer severity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Neurochemical and toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridine to rat serotonin neurons in dissociated cell cultures.

Dissociated cell cultures from the pontine area of embryonic rat brain were used to study the sensitivity of serotonin (5-hydroxy-tryptamine (5-HT)) neurons to the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP+). Treatment with MPTP (up to 100 microM) for 7 days did not cause degeneration of 5-HT neurons. A 50% inhibition of [3H]5-HT uptake caused by 100 microM MPTP was a direct effect on the 5-HT uptake carrier, reversed by washing for 7 days. Incubation of cultures with MPTP increased the intraneuronal levels of 5-HT and reduced the levels of 5-hydroxyindoleacetic acid, suggesting a reduction in 5-HT metabolism. MPTP reduced monoamine oxidase activity in the cultures, which probably led to the reduction in 5-HT metabolism. Exposure to MPP+ (0.5-10 microM) for 4 to 7 days decreased [3H]5-HT uptake and induced loss of neurons stained with antibodies against 5-HT. Comparison between 5-HT and dopamine (DA) neurons indicated a differential sensitivity to MPP+ toxicity with DA neurons being more susceptible. Analysis of the competition of MPP+ with the natural substrates for uptake sites of 5-HT and DA neurons demonstrated higher affinity of MPP+ for DA compared to 5-HT neurons. The lower affinity of MPP+ for 5-HT neurons could be responsible for the accumulation of lower MPP+ levels observed in pontine cultures and explain the resistance of 5-HT neurons to this toxin.

1-Methyl-4-phenylpyridinium↗
PubMed1990

Ultrastructural changes of the substantia nigra, ventral tegmental area and striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice.

The substantia nigra pars compacta (SNc), ventral tegmental area (VTA) and striatum in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated young adult mice were examined for the occurrence of marked ultrastructural changes. In the median SNc dopaminergic neurons, the Golgi apparatus and rough endoplasmic reticulum were dilated and there was a decrease in the number of ribosomes in the rough endoplasmic reticulum (Nissl substance). The mitochondrial cristae were often disarranged. Characteristic electron dense deposits were often observed in the neuronal fibers, many of which were dilated. However, no clear evidence of nuclear degeneration was seen. On the other hand, ultrastructural abnormalities were not seen in the dopaminergic neurons in the VTA. In both the latero-dorsal and latero-ventral striatum, many dilated neuronal fibers, which contained only a few synaptic vesicles and sparse subcellular structures were observed, but no significant ultrastructural changes could be seen in the medial part of the striatum in MPTP-treated mice. Thus, the effect of MPTP treatment is inhomogenous within the mouse striatum, as would be expected from the appearance of ultrastructural changes in only some of the dopaminergic neurons in the SNc.

Animals↗
PubMed1990

Pharmacological correction of CNS functional disorders and parkinsonian syndrome in old animals.

The effects of 2-ethyl-6-methyl-3-hydroxypyridine (3-HP) on age-related and alcohol-induced impairment of memory and learning were studied in rats and mice. 3-HP was found to accelerate the acquisition of the conditioned reflex of active avoidance and to improve the retention of the conditioned reflex of passive avoidance in old (24 months) rats. 3-HP consumption during chronic (5 months) alcoholisation improved learning ability and prevented lipofuscin accumulation in brain of ethanol-treated mice. Extrapyramidal disorders after systemic administration of MPTP and intranigral injection of MPP+ depended on age of animals, dose of MPTP and MPP+, and duration of administration. The beneficial effects of 3-HP on age-related impairment of memory and learning and experimental parkinsonian syndrome may be due to its ability to inhibit the peroxidation of membrane lipids and increase cell resistance to different disturbing actions.

Aging↗
PubMedDate not supplied

[Effect of damage of the nigro-neostriatal dopaminergic system by MPTP on the transmission of corticofugal impulses to the neurons of the caudate nucleus].

It is shown in acute experiments on cats (males) that the induced responses as action potentials (AP) by the latent period (LP) less than 8.0 ms in the caudate nucleus neurons (CN) to a single stimulation of the motor zone of the cortex (MI) are more frequently inhibited than facilitated after specifying single stimulation of the compact part of the black substance (BS) in the intervals between stimuli 10-100 ms. As a result of system multiple injection of MPTP neurotoxin during 5 days per 5 mg/kg the number of CN neurons responding to stimulation of MI, AP, LP less than 8.0 Usec and to stimulation of BS-LP less than 10.0 ms reliably decreases. A conclusion is made that dopaminergic nigro-striatum system exerts a protective action on the impulse transfer on monosynaptic connections from the cortex to striatum.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Maneb enhances MPTP neurotoxicity in mice.

The effects of acute administration of maneb (30 mg/kg, i.p.), an agricultural fungicide, combined with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP 50 mg/kg, i.p.), a dopaminergic neurotoxin, were examined on mouse locomotor activity and catalepsy test. The pretreatment with maneb significantly exacerbated the effects of MPTP on locomotion and catalepsy in mice. These results suggest that exposure to some pesticides might enhance motor dysfunction.

Animals↗