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PubMed1989

In vitro effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on muscarinic cholinergic receptors in mouse striatum.

1. MPTP significantly lowered Kd of the binding of [3H]QNB to muscarine receptor without affecting Bmax values compared with those of control. Hill coefficients (nH) of control and MPTP (250 microM) added group were 1.15 +/- 0.127 and 0.56 +/- 0.202, respectively. 2. Prior addition of pargyline to MPTP did not prevent the decrease of [3H]QNB binding. The patterns of displacement of [3H]QNB by MPTP and MPP+ were similar to those by some muscarinic agonists, such as acetylcholine, carbamyl choline and methacholine. 3. These results suggest that MPTP might be muscarinic agonist and might play a role to produce Parkinsonism through directly affecting the muscarinic cholinergic receptors in vivo.

Animals↗
PubMed1991

New rapid analysis method demonstrates differences in 6-[18F] fluoro-L-dopa plasma input curves with and without carbidopa and in hemi-MPTP lesioned monkeys.

Kinetic modeling of the PET tracer 6-[18F]fluoro-L-dopa ([18F]Dopa), used to measure presynaptic dopamine function, requires the accurate determination of the plasma input curve. We have developed a new method that uses alumina extraction preceded by cation and anion exchange resins to determine the parent compound, [18F]Dopa and its critical metabolite 3-O-methyl-6-[18F]fluoro-L-dopa. Using this method we found that carbidopa increases the plasma input of [18F]Dopa while decreasing the rate of metabolite formation, and that previous drug treatment can significantly effect [18F]Dopa metabolism.

Animals↗
PubMed1990

Cytotoxic effect of 1-methyl-4-phenylpyridinium ion on human melanoma cell lines, HMV-II and SK-MEL-44, is dependent on the melanin contents and caused by inhibition of mitochondrial electron transport.

MPP+, an oxidative metabolite of a neurotoxin, MPTP, was found to be cytotoxic to human melanoma cell lines, HMV-II and SK-MEL-44. After 3 days of culture in the presence of MPP+, a larger amount of MPP+ was accumulated in HMV-II cells than in SK-MEL-44 cells, which correlated well with the melanin contents; HMV-II cells contain larger amounts of melanin than SK-MEL-44 cells. After 6 days of culture in the presence of MPP+, the cytotoxicity of MPP+ on these cell types was evaluated by counting cell numbers with the dye exclusion test and double-layer soft agar clonogenic assay. It was found that exposure to MPP+ reduced the survival of HMV-II cells more significantly than that of SK-MEL-44 cells. In HMV-II cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay was used to elucidate the mechanism of MPP+ lethality. The formazan formation was reduced markedly by the presence of MPP+ at concentrations much lower than those required for cell death. These results suggest that cytotoxicity of MPP+ may be ascribed to its accumulation due to high affinity for melanin, and to inhibition of the enzymes utilizing ubiquinone in the mitochondrial respiratory chain.

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

Effects of unilateral 6-hydroxydopamine lesions on neuropeptide immunoreactivity in the basal ganglia of the common marmoset, Callithrix jacchus, a quantitative immunohistochemical analysis.

Previous immunocytochemical studies in rats have indicated that striatal dopamine depletion leads to an increase in enkephalin-immunoreactivity and a decrease in substance P-immunoreactivity in the striatum. Similar studies in primates have lead to contradictory results. In the present study changes in tyrosine hydroxylase-, met-enkephalin- and substance P-immunoreactivity were determined in the basal ganglia of 6 common marmosets Callithrix jacchus following dopamine depletion by unilateral intracerebral 6-hydroxydopamine (6-OHDA) injections using three different survival times. The non-lesioned side served as an intra-individual control. Tyrosine hydroxylase immunoreactivity was strongly reduced in the entire ipsilateral striatum. Enkephalin-immunoreactivity was increased throughout the striatum. Substance P-immunoreactivity was significantly increased in only one case in the caudate nucleus and in two cases in the putamen, while in other cases either a non-significant increase or decrease was found. Therefore, the results of the present study indicate that in marmosets dopamine has a inhibiting effect on the levels of striatal enkephalin, while its effect on substance P (SP) appears to be absent.

Animals↗
PubMedDate not supplied

Effects of MPTP on locomotor activity in mice.

Thirty-two mice were randomly assigned to one of 4 groups of 8 animals each: the first received IP saline injections and the other 3 groups received 10, 20 or 30 mg/kg MPTP. Each dose or saline was administered 3 times in 3 consecutive days and locomotor activity was measured during the next 3 days. In addition, the animals were observed in 2 trials in a rotating rod (Rotarod) and a grip test. The 2 highest doses of the drug produced significant increases in locomotor activity. In the other two behavioral tests, the highest dose of MPTP significantly reduced the capability of the animals to remain on the Rotarod on the grid.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Quantification of glial fibrillary acidic protein: comparison of slot-immunobinding assays with a novel sandwich ELISA.

Detailed protocols are presented for assaying glial fibrillary acidic protein (GFAP), an astrocyte localized protein which serves as a quantitative marker of toxicant-induced injury to the central nervous system. Two different solid-phase assay procedures are described: 1) a nitrocellulose based slot-immunobinding assay and 2) a novel microtiter plate based sandwich ELISA. The performance of both assays was assessed by measuring the content of GFAP in homogenates of specific regions of the rat brain and in homogenates of brain regions damaged by the prototype neurotoxicants, trimethyltin (TMT) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both procedures gave similar results that were consistent with previously published observations. By comparing the simplicity, cost effectiveness, safety and speed of the two methods, it appears likely that the sandwich ELISA has several advantages over slot-immunobinding assays.

Animals↗
PubMedDate not supplied

Neuroglial responses to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse striatum.

We have studied the reactive responses of both astrocytes and microglia to dopaminergic denervation of the striatum by MPTP. Following MPTP treatment, increased GFAP immunoreactivity reached a peak at 2 days and persisted for at least 6 weeks. Immunoreactivity to vimentin was also markedly increased in astrocytes 48 h after MPTP treatment. Striatal laminin immunoreactivity, however, appeared to be unaffected by drug treatment. GFAP protein levels increased to 196% and 321% of control 24 and 48 hours after MPTP treatment, respectively. Concomitantly, GFAP mRNA levels increased to 560% and 1620% of control, respectively. These reactive changes in striatal astrocytes in response to MPTP treatment were also accompanied by a reactive microglial response as evidenced by increased immunohistochemical visualization of striatal microglia using antibodies to Mac-1. Our results and those reported previously by O'Callaghan et al., strongly suggest that MPTP-induced reactive gliosis in mouse striatum is associated with reactive microglia, albeit without increased interleukin-1 beta.

Animals↗
PubMedDate not supplied

Differences in the reserpine-sensitive storage in vivo of 1-methyl-4-phenylpyridinium in rats and mice may explain differences in catecholamine toxicity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Administration of reserpine, an inhibitor of vesicular catecholamine storage, differentially reduced the accumulation of MPP+ formed from MPTP in rats and mice. The effects were most pronounced in the adrenal gland for either species. In rats, reserpine decreased striatal and hippocampal MPP+ levels while in mice reserpine did not affect the disposition of MPP+ in the striatum but decreased hippocampal MPP+. The data suggest that mice may be more sensitive to the toxicant because less striatal MPP+ appears to be stored in the reserpine-sensitive storage vesicle.

1-Methyl-4-phenylpyridinium↗
PubMedDate not supplied

Estrogen as a neuroprotectant against MPTP-induced neurotoxicity in C57/B1 mice.

Castrated retired breeder male and female mice were treated or not with a 17 beta-estradiol pellet. At 10 days postcastration +/- estrogen treatment all animals were treated with MPTP. Five days later, concentrations of dopamine were determined from the corpus striatum and olfactory tubercle. Both castrated male and female mice treated with estrogen had significantly greater concentrations of dopamine within the corpus striatum compared with their respective gender controls, which did not receive estrogen. By contrast, no statistically significant differences in olfactory tubercle dopamine concentrations were obtained. Overall concentrations of dopamine within the corpus striatum, but not olfactory tubercle, were substantially greater in female vs. male mice. These data demonstrate that treatment with estrogen prevents reductions in corpus striatal dopamine concentrations in castrated mice treated with MPTP. Interestingly, this effect of estrogen was observed in both male and female mice. These results suggest that estrogen may serve as a neuroprotectant against an agent that is toxic to the nigrostriatal dopaminergic system in both male and female animal models of Parkinsonism.

Animals↗
PubMed1991

MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease.

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) gives rise to motor deficits in humans and other primates which closely resemble those seen in patients with Parkinson's disease. These deficits are associated with a relatively selective loss of cells in the pars compacta of the substantia nigra and severe reductions in the concentrations of dopamine, noradrenaline and serotonin in the striatum. Similarly, in mice of various different strains the administration of MPTP also induces a marked loss of dopaminergic cells with severe depletion of biogenic amines, but higher doses of MPTP are required to produce these effects in mice than in primates. This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP. Major steps in the expression of neurotoxicity involve the conversion of MPTP to the toxic agent 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase (MAO-B) in the glia, specific uptake of MPP+ into the nigro-striatal dopaminergic neurones, the intraneuronal accumulation of MPP+, and the neurotoxic action of MPP+. This is exerted mainly through the inhibition of the enzymes of the respiratory chain (Complex I), the disturbance of Ca2+ homeostasis, and possibly by the formation of free radicals. The relevance of the MPTP model to idiopathic Parkinson's disease is discussed.

Animals↗
PubMed1994

Effect of lipoic acid on redox state of coenzyme Q in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and diethyldithiocarbamate.

We investigated the effects of a combined treatment of male C57Bl/6 mice with diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the absence or presence of different forms of lipoic acid (Thioctacid TR; commonly used for treatment of diabetic polyneuropathies) on levels and redox states of alpha-tocopherol and coenzyme Q in vivo and on activities of various enzymes of energy metabolism ex vivo. Treatment of mice with diethyldithiocarbamate plus MPTP resulted in a decrease in dopamine (67%) and its major metabolites dihydroxyphenylacetic acid (38%) and homovanillic acid (37%) in striatum. alpha-Tocopherol levels were unaltered in striatum; however, the reduced forms of coenzyme Q were decreased in frontal cortex and hippocampus following diethyldithiocarbamate plus MPTP. In frontal cortex activity of NADH dehydrogenase was significantly inhibited by diethyldithiocarbamate plus MPTP ex vivo, suggesting that the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium ion, is acting in brain regions other than striatum as well. Lipoic acid, administered 6 times, each at 90 min prior to MPTP, could not restore dopamine in striatum but in contrast maintained a normal ratio of the reduced form to the oxidized form of coenzyme Q, suggesting an interaction of lipoic acid with energy metabolism which seems, however, not only to be due to an activation of pyruvate dehydrogenase.

Animals↗
PubMed1994

1-Methyl-4-phenylpyridinium has greater neurotoxic effect after selenium deficiency than after vitamin E deficiency in rat striatum.

The present study was designed to assess the extent of the protective effect of antioxidative capacity of dopaminergic neurons against the possible oxidative stress produced by 1-methyl-4-phenylpyridinium. We have studied the direct effect of 1-methyl-4-phenylpyridinium on striatum slices from rats fed with selenium-deficient or vitamin E-deficient diets for 30 days. Glutathione peroxidase activity decreased significantly after selenium dietary restriction. Our results showed that the effect of 1-methyl-4-phenylpyridinium on dopamine and its metabolites 3,4-dihydroxyphenylacetic acid, homovanillic homovanillic acid and 3-methoxytyramine in animals with both restriction diets was higher than in controls. However, this effect was significantly greater in animals with low selenium diets than with vitamin E-deficient diets in terms of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, which were all significantly more depleted by 1-methyl-4-phenylpyridinium in selenium-deficient rats than in vitamin E-deficient rats. Therefore, considering changes in the levels of dopamine and its metabolites as an index of 1-methyl-4-phenylpyridinium toxicity, our results seem to indicate that the glutathione-glutathione peroxidase system has a greater protector effect than vitamin E.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Mechanisms responsible for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine (DA) neuronal death remain unknown and in mice it is even unclear whether neuronal death does occur. In vitro studies suggest that 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP, kills neurons by apoptosis. Herein, we investigated whether MPTP induces DA neuronal death in vivo in mice and whether the mechanism is that of apoptosis. C57/bl Mice received different doses of MPTP administered in four intraperitoneal injections every 2 hours and were sacrificed at different time points for analyses of tyrosine hydroxylase (TH) immunohistochemistry, silver staining, and Nissl staining within the mesencephalon. We found that MPTP induces neuronal destruction in the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA). The active phase of degeneration began at 12 h postinjection and continued up to 4 days. During this period, there was a greater decrease in TH-defined neurons than in Nissl-stained neurons suggesting that MPTP can cause a loss in TH without necessarily destroying the neuron. Thereafter, neuronal counts by both techniques equalized and there was no further loss of DA neurons. Dying neurons showed shrunken eosinophilic cytoplasm and shrunken darkly stained nuclei. Double staining revealed degenerating neurons solely among TH positive neurons of SNpc and VTA. At no time point and at no dose of MPTP was apoptosis observed. In addition, in situ labelling revealed no evidence of DNA fragmentation. This study demonstrates that the MPTP mouse model replicates several key features of neurodegeneration of DA neurons in PD and provides no in vivo evidence that, using this specific paradigm of injection, MPTP kills DA neurons by apoptosis.

Analysis of Variance↗
PubMed2004

Upregulation of guanylyl cyclase expression and activity in striatum of MPTP-induced parkinsonism in mice.

The aim of our study was to investigate the expression and the activity of soluble guanylyl cyclase (GC) and phosphodiesterase (PDE) activities that regulate cGMP level in the striatum, hippocampus, and brain cortex in an animal model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We observed the increase of total activity and protein level of GC in striatum after MPTP injection. It was accompanied by an enhancement of both mRNA expression and protein level of GCbeta1 subunit. MPTP induces mRNA expression and elevates protein concentration of GCbeta1 in striatum up to 14 days after its injection, which in turn causes a marked enhancement of cGMP formation. Furthermore, the activation of GC occurs through change of maximal enzyme activity (V(max)). Simultaneously, no change in PDE activity has been detected in all investigated regions of the brain after MPTP. MPTP injection caused the elevation of GCbeta1 protein level in both the membrane and cytosol fractions being significantly higher in cytosol. Western blot analysis demonstrated about 45-67% decrease of tyrosine hydroxylase protein content in striatum. These data suggest that NO/cGMP signaling pathway may at least partially contribute to dopaminergic fiber degeneration in the striatum, the damage attributed to PD.

1-Methyl-3-isobutylxanthine↗
PubMed2003

Heat shock protects PC12 cells against MPP+ toxicity.

A mild heat shock preconditioning has been shown to induce thermotolerance and protection against a number of cytotoxic agents that may induce cell death by either apoptosis or necrosis. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that selectively targets dopaminergic cells of the substantia nigra and, as such, it is often used to induce neuronal cell death in models of Parkinson's disease. PC12 cells were heat-shocked for 1 h at 41.5 degrees C. This led to a rapid induction of Hsp25 and Hsp70. Levels of these proteins remained elevated for at least 24 h post heat shock. Treatment of PC12 cells with 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of MPTP, resulted in cell death. Morphological analysis and the lack of caspase activity suggested that cell death was by necrosis. Heat shocking the cells 6 h prior to addition of MPP(+) significantly inhibited the induction of cell death by MPP(+). These results indicated that heat shock is protective against MPP(+) neurotoxicity in PC12 cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Cyclooxygenases mRNA and protein expression in striata in the experimental mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to mouse.

Cyclooxygenases (COX) are associated with complex alteration in many pathologies of the central nervous system (CNS). Increased expression of COX-2 has been shown in injured or degenerated neurons, thus suggesting that COX-2 may contribute to neuronal damage. In this study, we present the expression of COX-1 and COX-2 mRNA and protein in striatum following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration to mice. MPTP causes an acute damage of dopaminergic neurons especially in the nigrostriatal dopaminergic system, thus diminishing dopamine (DA) content in striatum and decreasing the number of dopaminergic cells in the pars compacta of the substantia nigra (SN). C57Bl mice have received 60 mg/kg of MPTP introperitoneally. A group of mice received also rofecoxib 10 mg/kg from the 1st day following MPTP administration. Dopamine content in striatum (high-performance liquid chromatography-HPLC), mRNA expression of COX-1 and -2 (reverse transcriptase-polymerase chain reaction technique-RT-PCR), COX-1 and -2 protein content (immunoblotting) have been measured on day 1st, 3rd, 7th, 14th and 21st after the injury. We have found that COX-1 mRNA expression is not changed following MPTP administration, but COX-2 gene and protein expression in striatum increases from the 3rd to the 7th and 14th days, and diminishes on the 21st day. Production of prostaglandins is augmented only briefly after MPTP treatment and did not correlate with increased COX-2 mRNA and COX-2 protein production. Thus, the increase of COX-2 expression does not follow the acute stage of cell death but rather the recovery period after the injury. We also demonstrate that COX-2 activity inhibition by rofecoxib (10 mg/kg), which has been started 1 day after the injury, has not neuroprotective effect. Our study suggests that COX-2 does not contribute to neurons death following MPTP administration and that the inhibition of COX-2 activity is not beneficial to neurons injured by MPTP. However, COX-2 mRNA and protein expressions increase after MPTP injury; the role of these findings remains obscure.

Animals↗