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PubMedDate not supplied

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion.

Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson's disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Lifelong feeding of a high aluminum diet to mice.

In three experiments, high aluminum diets (1000 microg Al/g diet) were fed to mice throughout their life span to determine whether neurodegenerative changes were seen with aging. Brain Al concentrations were slightly lower in Al-treated mice than controls. Generally, no increased mortality or gross evidence of neurodegeneration was seen in Al-treated mice. Eighteen and 24 month old Swiss Webster mice fed the high aluminum diet differed from controls on some neurobehavioral tests, but differences were no greater than previously seen with shorter term exposure in younger mice. Both brain Al concentration and susceptibility to oxidative damage, as measured with TBARS, were lower in the Al-treated aged mice than in controls. In addition, Al-treated aged Swiss Webster and C57BL/6J mice showed somewhat enhanced performance in the Morris water maze. Finally, Al treatment did not exacerbate the effect of MPTP treatment on a grip strength measure in either 66 or 235 day old male mice. Swiss Webster and C57BL/6J mice do not appear to provide useful models for studying Al-induced neurodegenerative changes in aging.

Aluminum↗
PubMed2000

Cell death induced by MPTP, a substrate for monoamine oxidase B.

MPTP is known to cause PD symptoms in primates and in rodents. In order to exert its neurotoxicity MPTP must be converted by monoamine oxidase B into MPP(+) which is the true toxic agent. MPP(+) is taken up by the dopaminergic neurons of the substantia nigra in which it induces cell death. The present work reviews and discusses papers in which specific methods were used to determine whether cell death induced by MPTP/MPP(+) should be considered as apoptosis or necrosis. These two cell death modes may be distinguished using morphological and biochemical criteria. The effect of MPTP/MPP(+) was studied in vitro and in vivo. The results show that no univocal answer is possible. The most widespread interpretation is that MPTP/MPP(+) causes apoptosis when its neurotoxic effect is only sligh and necrosis when it is stronger. Similar considerations may be made also concerning the type of cell death occurring in the dopaminergic neurons in the substantia nigra of PD patients.

Animals↗
PubMed1997

MPTP toxicity in rat striatal slices: dopamine uptake alteration does not appear to be related to lipid peroxidation.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is used to create experimental models of parkinsonism, induces both dopaminergic neurotoxicity and peroxidation reactions. The present work investigated the interaction between the dopamine (DA) uptake system, lipid peroxidation and MPTP in a rat striatum slice model. [3H]DA uptake was decreased and the concentration of thiobarbituric acid reactive substances (TBARS) increased after a plain preincubation in Krebs-Ringer bicarbonate buffer for 150 min. The decrease in [3H]DA uptake and the increase in TBARS were suppressed by the iron-chelating agent desferrioxamine. Inhibition of [3H]DA uptake was intensified, [3H]GBR 12 935 binding to DA uptake sites was decreased and TBARS production was inhibited in slices after preincubation with MPTP. MPTP effects were inhibited by L-deprenyl, a MAO-B inhibitor. These results suggest that the spontaneous decrease in DA uptake during simple preincubation in pure Krebs-Ringer solution was related to spontaneous TBARS generation. During MPTP preincubation, alteration of the DA uptake mechanism was not due to additional lipid peroxidation since TBARS production was decreased. MPTP effects could have resulted from other events which are discussed.

Animals↗
PubMed2001

Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta. Although the etiology of PD is unknown, major biochemical processes such as oxidative stress and mitochondrial inhibition are largely described. However, despite these findings, the actual therapeutics are essentially symptomatical and are not able to block the degenerative process. Recent histological studies performed on brains from PD patients suggest that nigral cell death could be apoptotic. However, since post-mortem studies do not allow precise determination of the sequence of events leading to this apoptotic cell death, the molecular pathways involved in this process have been essentially studied on experimental models reproducing the human disease. These latter are created by using neurotoxic compounds such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or dopamine (DA). Extensive study of these models have shown that they mimick, in vitro and in vivo, the histological and/or the biochemical characteristics of PD and thus help to define important cellular actors of cell death presumably critical for the nigral degeneration. This review reports recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD and correlates them to the phenomena occurring in human disease.

Animals↗
PubMed2001

Manganese mimics the action of 1-methyl-4-phenylpyridinium ion, a dopaminergic neurotoxin, in rat striatal tissue slices.

Manganese and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are known to induce neurological pathologies similar to that of parkinsonism. Previous studies performed in rat striatal slices have shown that MPTP and related compounds inhibit tyrosine hydroxylation, a rate-limiting step of dopamine biosynthesis. Here, we reported that manganese inhibited tyrosine hydroxylation in rat striatal slices. In addition, manganese caused increase in the levels of lactate indicating that aerobic glycolysis was inhibited in striatal slices. This inhibition was unique to manganese since other divalent cations, such as magnesium and zinc, did not increase lactate concentrations. These results suggest that the mechanisms by which manganese produces dysfunction of the nervous system are similar to those of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra.

Cyclooxygenases (COX), key enzymes in prostanoid biosynthesis, may represent important therapeutic targets in various neurodegenerative diseases. In the present study, we explored the role of COX in Parkinson's disease (PD) by using 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine (MPTP) as a tool to create a rodent Parkinsonian model. MPTP (20 mg/kg, subcutaneously) was injected daily into COX-1- and COX-2-deficient mice and wild-type (WT) controls for five consecutive days. Immunocytochemical analysis of tissues collected 7 days after the final MPTP treatment showed that MPTP significantly decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNc) of WT (40% decrease) and COX-1(-/-) (45% decrease) mutants. However, a much smaller loss of TH-ir neurons in COX-2(-/-) mutants (20% decrease) was observed. Furthermore, electrochemical analysis revealed a more than 70% decrease in the levels of dopamine and its metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) in the striatum of the WT control COX-1(-/-) and COX-2(-/-) mutant mice. These results indicate that loss of COX-2 activity reduces MPTP-induced damage to the dopaminergic neurons of the SNc, but does not alter the levels of dopamine and its metabolites in the striatum. Interestingly, MPTP caused the same degree of loss of dopaminergic neurons in both COX-2(+/-) and COX-2(-/-) mice (20% loss). The results of this study indicate an important role of COX-2 in MPTP-induced neuronal degeneration and suggest the possibility that manipulation of the COX-2 could be an important target for therapeutic interventions in PD.

Animals↗
PubMed2002

Zinc potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced dopamine depletion in caudate nucleus of mice brain.

Present study describes the effect of zinc (Zn) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopamine depletion in mice brain. MPTP is a known neurotoxicant primarily causing marked depletion of dopamine (DA) levels in nigrostriatal dopaminergic system. Adult Male C57-mice were intraperitonially injected with 25 mg/kg MPTP in the presence or absence of zinc acetate. Twenty-four hours after treatment animals were sacrificed and DA levels were determined by high performance liquid chromatography in caudate nucleus of control and treated mice. The results showed that there was a marked depletion of DA in MPTP treated mice, whereas no change was observed in DA levels in mice treated with Zn when compare to controls. Interestingly, mice receiving MPTP in conjunction with Zn showed significantly lower DA levels in brain when compare to animals receiving MPTP alone. In summary the data suggest that Zn treatment potentiates depletion of dopamine in MPTP treated mice.

Animals↗
PubMed1998

Glial cell line-derived neurotrophic factor protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in C57BL/6 mice.

To mimic chronic exposure to neurotoxins in inducing dopaminergic cell damage, multiple doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were injected in C57BL/6 mice. Effects of pre- and post-treatment with the glial cell line-derived neurotrophic factor (GDNF) by injections into the striatum were investigated. GDNF exerts protective and reverse effects on the dopaminergic damage, supporting the potential application of GDNF in prevention and treatment of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

A stereological study on the neuroprotective actions of acute modafinil treatment on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigral lesions of the male black mouse.

The effect of an acute administration of the vigilance-promoting drug modafinil ((+/-)(diphenyl-methyl)-sulfinyl-2 acetamide; Modiodal) on the nigrostriatal dopamine system was studied after damage induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by means of immunohistochemistry for tyrosine hydroxylase (TH) and a stereological method. MPTP (40 mg/kg) reduced from 24,380 +/- 902 to 13,501 +/- 522 and from 37,868 +/- 3300 to 20,568 +/- 1270, respectively, the number of TH immunoreactive (IR) and non-TH IR nigral neurons. Co-administration of Modafinil restored to normal the number of these neuronal populations. MPTP treatment induced also a reduction in the volume of TH IR neurons, which was counteracted by Modafinil administration. The data provide morphological evidence, based on unbiased stereological analysis, for a potential neuroprotective role of Modafinil, not only in dopaminergic neurons, but also with a similar magnitude in the non-DA nerve cell population of the substantia nigra after MPTP lesion. These results suggest that Modafinil has a neuroprotective role in the substantia nigra via a still undefined mechanism in which a crucial role of DA uptake blockade should be excluded. Modafinil may therefore have a therapeutic potential in neurodegenerative processes such as those occurring in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

A 'single toxin-double lesion' rat model of striatonigral degeneration by intrastriatal 1-methyl-4-phenylpyridinium ion injection: a motor behavioural analysis.

Previous attempts to reproduce striatonigral degeneration, the core pathology underlying Parkinsonism in multiple system atrophy, have been impeded by interactions in the neurotoxins used to replicate striatal and nigral degeneration in rodents. To overcome these interactions, we have developed a new model of striatonigral degeneration which uses a single unilateral administration of 1-methyl-4-phenylpyridinium ion (MPP(+)) into the rat striatum. Spontaneous and drug-induced rotational behaviour, thigmotactic scanning, stepping adjusting steps and paw reaching deficits were compared in four groups of animals: group 1 (control), group 2 (20 microg quinolinic acid), group 3 (20 microg 6-hydroxydopamine), and group 4 (90 nmol MPP(+)). MPP(+) administration resulted in the absence of the amphetamine-induced ipsilateral bias observed in the 6-hydroxydopamine group and of the apomorphine-induced ipsilateral bias observed in the quinolinic acid group. There was no thigmotactic scanning asymmetry in the MPP(+)-injected rats compared to the quinolinic acid- and the 6-hydroxydopamine-injected rats. MPP(+) elicited a bilateral stepping adjustment deficit similar to that found in the quinolinic acid group when compared to controls. MPP(+) also elicited a more severe and significant contralateral deficit in paw reaching compared to controls, 6-hydroxydopamine and quinolinic acid groups. Histopathology revealed a significant reduction of the lesioned striatal surface (-47.53%) with neuronal loss and increased astrogliosis in the MPP(+) group grossly similar to that found in the quinolinic acid group. Contrary to the latter group, however, loss of intrastriatal and striatal-crossing fibre bundles was observed in the MPP(+) group as there was also some retrograde degeneration in the ipsilateral thalamic parafascicular nucleus. The mean loss of dopaminergic cells in the ipsilateral substantia nigra pars compacta in MPP(+) rats was less marked (-48.8%) than in the 6-hydroxydopamine rats (-63.6%) and was not significant in quinolinic acid rats (-5.2%). This study shows that a single unilateral intrastriatal administration of MPP(+) induces a unique motor behaviour resulting from both nigral and striatal degeneration, but also from possible extrastriatal damage. This 'single toxin-double lesion' paradigm may thus serve as a rat model of striatonigral degeneration.

1-Methyl-4-phenylpyridinium↗
PubMed2003

Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.

In humans, mutations in the alpha-synuclein gene or exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produce Parkinson's disease with loss of dopaminergic neurons and depletion of nigrostriatal dopamine. alpha-Synuclein is a vertebrate-specific component of presynaptic nerve terminals that may function in modulating synaptic transmission. To test whether MPTP toxicity involves alpha-synuclein, we generated alpha-synuclein-deficient mice by homologous recombination, and analyzed the effect of deleting alpha-synuclein on MPTP toxicity using these knockout mice. In addition, we examined commercially available mice that contain a spontaneous loss of the alpha-synuclein gene. As described previously, deletion of alpha-synuclein had no significant effects on brain structure or composition. In particular, the levels of synaptic proteins were not altered, and the concentrations of dopamine, dopamine metabolites, and dopaminergic proteins were unchanged. Upon acute MPTP challenge, alpha-synuclein knockout mice were partly protected from chronic depletion of nigrostriatal dopamine when compared with littermates of the same genetic background, whereas mice carrying the spontaneous deletion of the alpha-synuclein gene exhibited no protection. Furthermore, alpha-synuclein knockout mice but not the mice with the alpha-synuclein gene deletion were slightly more sensitive to methamphetamine than littermate control mice. These results demonstrate that alpha-synuclein is not obligatorily coupled to MPTP sensitivity, but can influence MPTP toxicity on some genetic backgrounds, and illustrate the need for extensive controls in studies aimed at describing the effects of mouse knockouts on MPTP sensitivity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Participation of manganese-superoxide dismutase in the neuroprotection exerted by copper sulfate against 1-methyl 4-phenylpyridinium neurotoxicity.

Neurodegenerative effects of 1-methyl-4-phenylpyridinium (MPP+), the main metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) include enhancement of lipid peroxidation in the striatum of mice, associated to overproduction of free radicals. Copper acts as a prosthetic group of several copper-dependent antioxidant enzymes, and we previously showed the neuroprotective effect of CuSO4 pretreatment against the MPP+-induced neurotoxicity. In those studies, acute administration of CuSO4 (2.5 mg/kg) blocked MPP+-induced striatal lipid peroxidation, suggesting the activation of Cu-dependent proteins that defend neurons from damage elicited by free radicals. In the present study, we evaluated the activity of superoxide dismutase in mice pretreated with CuSO4 16 h or 24 h prior to MPP+ administration. Copper administration produced a specific and significant increase in manganese superoxide dismutase activity in both the CuSO4/saline (fivefold increase) and the CuSO4/MPP+ groups of animals (sevenfold increase). The Na2SO4/MPP+ group showed a twofold increase in manganese superoxide dismutase activity versus control levels. The results suggest that the load of copper activating manganese-dependent superoxide dismutase could be responsible for neuroprotection against the MPP+ insult.

1-Methyl-4-phenylpyridinium↗
PubMed2001

Mechanisms of MPP(+) incorporation into cerebellar granule cells.

Exposure of cerebellar granule cells to 1-methyl-4-phenylpiridinium (MPP(+)) results in cell death. We have studied the implication of various membrane transporter systems on MPP(+) neurotoxicity, including the dopamine transporter system (DAT) and cationic amino acid transporters (CAT). We have showed a partial protection against MPP(+) toxicity when the dopamine transporter is inhibited by 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]4-(3-phenylpropyl)piperazinedihydrochloride (GBR-12909). However, almost full protection is only achieved by the simultaneous addition of GBR-12909 and cationic amino acids. These results suggest two ways system of MPP(+) entrance into cerebellar granule cells: the DAT with high activity and the CAT with low activity. We also demonstrated that 5,7-dichlorokynurenic acid (MK-801) failed to protect against MPP(+) exposure, evidencing that N-methyl-D-aspartate (NMDA) receptor is not involved in the MPP(+)-induced cell death.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Cognitive changes in mice following moderate MPTP exposure.

We evaluated the cognitive effects of two moderate doses (30 mg/kg x 3 every 12 h and 20 mg/kg x 6 every 8 h, i.p.) of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in mice. The dose of 30 mg/kg x 3 caused about 60% depletion of striatal dopamine but did not reduce the levels of its metabolites. Mice treated with MPTP did not differ from controls in their motor behavior in the open field. Mice treated with MPTP were comparable to controls in T-maze delayed alternation with fixed delays but were impaired when trials with mixed 20 s and 120 s delays were presented, indicative of a spatial working memory impairment. Dexmedetomidine at 10 microg/kg (s.c.) slightly improved delayed alternation performance in all groups but also slowed initiation of the motor response. Mice treated with MPTP at the dose of 30 mg/kg x 3 were less sensitive to this adverse effect of dexmedetomidine. The impairment in spatial working memory after MPTP exposure in mice parallels the findings in monkeys, but the deficit is much less severe.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Use of positron emission tomography in analysing receptor function in vivo.

The non-invasive radiotracer technique positron emission tomography (PET) may provide valuable information in the toxicokinetic-toxicodynamic evaluation of endogenous or toxic environmental compounds. Assessment of mechanism of action of toxins is often difficult to validate. In this respect, PET may offer advantages since it can quantify not only the distribution and kinetics of the radiolabelled toxin in the body, but also the altered rates of physiological or biochemical processes induced by the toxin. It is even possible to validate the body distribution and tissue accumulation of the toxic compound in primates, since linear kinetics can be assumed after administration of the radiolabelled compound in minute amounts without any toxic or physiological effects. Quantitative estimates can be derived with accuracy and high precision. Using a multi-tracer protocol, it is often possible to illuminate both the kinetics and the dynamics of a toxic compound. Long-term effects of different toxins on dopamine receptor function have been evaluated with PET as well as the influence of Parkinson disease medication on pre- and postsynaptic dopaminergic receptor function over the course of the disease. In conclusion, PET may provide very informative insight into complex receptor interactions of both toxic compounds and drugs under development.

Animals↗
PubMed2002

Role of hydroxyl radical formation in neurotoxicity as revealed by in vivo free radical trapping.

Reactive oxygen species have been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP(+)) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP(+) is a highly potent dopaminbergic-releasing agents and dopamine (DA) autoxidation catalyzed by iron and oxidative stress may be involved in the pathogenesis of Parkinson's disease. Neuromelanine synthesis from DA produce highly reactive free radicals. Although the controversy possible neurotoxin and/or neuroprotective roles of nitric oxide (NO) was discussed, NO contributes to oxidative injury to brain neurons in vivo. An environmental estrogen-like chemical also related to MPP(+)-induced *OH generation. This review describes actual mechanism of the free radicals formation by dialysis studies of in vivo free radical trapping in the pathogenesis of neurodegenerative disorders, including in the Parkinson's disease, Alzheimer disease and traumatic brain injuries.

1-Methyl-4-phenylpyridinium↗