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PubMed1998

MPTP produces differential oxidative stress and antioxidative responses in the nigrostriatal and mesolimbic dopaminergic pathways.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to produce a differential toxicity in the nigrostriatal and mesolimbic dopaminergic pathways with the nigrostriatal pathway being more vulnerable. We, therefore, investigated whether oxidative stress and the antioxidant system play a role in this phenomenon. Balb/c mice were treated with either saline or MPTP (30 mg/kg/d) for 7 d, and were sacrificed on the next day. Results revealed that MPTP increased lipid peroxidation in the striatum (ST) and decreased glutathione concentration in the substantia nigra (SN) without markedly affecting these measures in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Further, MPTP produced approximately twofold increases in both manganese superoxide dismutase (MnSOD) and copper-zinc superoxide dismutase (CuZnSOD) activities in the VTA while it only increased MnSOD activity in the SN. Both catalase and glutathione peroxidase (GPx) activities were not markedly altered by MPTP in both systems. However, the basal levels of catalase and GPx activities were higher in the VTA and NAc than in the SN and ST. These results together suggest that a lesser degree of oxidative damage and a more inducible CuZnSOD activity observed in the mesolimbic dopaminergic pathway may partially explain the differential toxicity MPTP produced in these two dopaminergic systems.

Animals↗
PubMed1999

Elevation of antioxidant potency in the brain of mice by low-dose gamma-ray irradiation and its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage.

The elevation of endogenous thiol-related antioxidants and free radical scavenging enzymes in the brain of C57BL/6 female mice after low-dose gamma-ray irradiation and its inhibitory effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced brain damage were investigated. The brain level of the reduced form of glutathione (GSH) increased soon after irradiation with 50 cGy of gamma-rays, reached a maximum at 3 h post-treatment, and remained elevated until 12 h. Thioredoxin (TRX) was also transiently increased after irradiation. The activities of free radical scavenging enzymes, including Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, were significantly induced after irradiation as well. Cerebral malondialdehyde was remarkably elevated by MPTP treatment, and this elevation was suppressed by pre-irradiation (50 cGy). The contents of GSH and TRX were significantly decreased by MPTP treatment in comparison with those of the control group. These reductions both seemed to be attenuated by pre-irradiation with gamma-rays. These results suggest that low-dose gamma-ray irradiation induces endogenous antioxidative potency in the brain of mice and might be effective for the prevention and/or therapy of various reactive oxygen species-related neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease.

Analysis of Variance↗
PubMedDate not supplied

Differential vulnerability of snake species to MPTP: a behavioral and biochemical comparison in ratsnakes (Elaphe) and watersnakes (Nerodia).

The synthetic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinsonian-like syndrome in humans and nonhuman primates, and also causes movement disorders in rodents, fish, amphibians and lizards. To date, the effects of MPTP have not been characterized in snakes. In this study, the behavioral and biochemical effects of MPTP were assessed in the black ratsnake Elaphe o. obsoleta and the banded watersnake Nerodia f. fasciata--species that display contrasting behavioral sensitivities to dopaminergic antagonists and to amphibian toxins. We report that MPTP induces depletion of norepinephrine and serotonin in fore, mid and hindbrain regions and depletion of dopamine in fore and midbrain regions in E.o. obsoleta. MPTP also induced a marked reduction in righting ability in E.o. obsoleta. In N.f. fasciata, norepinephrine and dopamine were depleted by MPTP in all three brain regions and serotonin was only significantly reduced in the forebrain. In contrast to E.o. obsoleta, N.f. fasciata demonstrated no behavioral disorders. This study demonstrates a behavioral and biochemical sensitivity to MPTP in E.o. obsoleta that differs from that in N.f. fasciata. The differential sensitivities to monoaminergic modulation may be related to the contrasting diets of these species.

Animals↗
PubMedDate not supplied

MPTP-induced Parkinsonism in minipigs: A behavioral, biochemical, and histological study.

Fourteen male Göttingen minipigs were used in this study. Nine were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dosage of 1 mg/kg/day, SC, for 6 days, the last five pigs received saline injections for 6 days. All MPTP-treated animals developed Parkinson symptoms, i.e., muscle rigidity, hypokinesia, and impaired coordination within 5 days. The brain levels of dopamine (DA), and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in caudatum and putamen 2, 14, and 93 days (n = 3/time point) after the last drug administration. In eight of the MPTP-treated animals, striatal DA, DOPAC, and HVA concentrations were reduced from 50 to 95% compared to control animals at all time intervals. Animals with the lowest striatal DA concentrations showed the most severe signs of Parkinsonism. The number of cells in substantia nigra (SN) showed a decline only 3 months after MPTP treatment. The minipigs represent a nonprimate model of MPTP-induced parkinsonism syndromes lasting at least months.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen.

We have studied the effect of unilateral autografts of carotid body cell aggregates into the putamen of MPTP-treated monkeys with chronic parkinsonism. Two to four weeks after transplantation, the monkeys initiated a progressive recovery of mobility with reduction of tremor and bradykinesia and restoration of fine motor abilities on the contralateral side. Apomorphine injections induced rotations toward the side of the transplant. Functional recovery was accompanied by the survival of tyrosine hydroxylase-positive (TH-positive) grafted glomus cells. A high density of TH-immunoreactive fibers was seen reinnervating broad regions of the ipsilateral putamen and caudate nucleus. The nongrafted, contralateral striatum remained deafferented. Intrastriatal autografting of carotid body tissue is a feasible technique with beneficial effects on parkinsonian monkeys; thus, this therapeutic approach could also be applied to treat patients with Parkinson's disease.

Animals↗
PubMed2004

Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity: an immunohistological study.

We recently reported that neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole, can protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. It protected against both dopamine depletions and tyrosine hydroxylase (TH) positive neuron decreases in the mouse brain. In the present study, we further examined whether 7-nitroindazole can also protect against the alterations of TH-, microtubule-associated protein 2a,b (MAP2)-, glial fibrillary acidic protein (GFAP)-, parvalbumin (PV)-, dopamine transporter (DAT)-, nNOS- or endothelial NOS (eNOS)-positive cells, in comparison with pargyline as a relatively selective inhibitor of the monoamine oxidase-B (MAO-B). The present study showed that nNOS inhibitor as well as MAO-B inhibitor has a dose-dependent protective effect against MPTP-induced striatal dopamine and DOPAC depletion in mice. Furthermore, the present study revealed that 7-nitroindazole and pargyline can protect the alterations of immunohistochemical changes in the striatum and substantia nigra after MPTP treatment. These protective effects may be, at least in part, produced by the reduction of neuronally derived NO and peroxynitrite caused by MPTP. Our results also demonstrate that MPTP can cause functional damage of interneurons in the substantia nigra. These results suggest the possibility that nNOS inhibitors as well as MAO-B inhibitors may be therapeutically useful in neurodegenerative diseases such as Parkinson's disease. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Biochemical and immunohistological changes in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse.

We investigated neurochemically and neuropathologically the utility of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as a model of Parkinson's disease. The changes in dopamine D1 and D2 receptors and dopamine uptake sites were determined by quantitative autoradiography using [3H]SCH23390, [3H]raclopride and [3H]mazindol, respectively. Dopamine and 3,4-dihydroxyphenyl acetic acid (DOPAC) contents in the striatum were measured by high-performance liquid chromatography. The distribution of nigral neurons and reactive astrocytes was determined by immunohistochemical staining with antibody against tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 3 and 7 days after the treatments. No significant change in dopamine D1 receptors was observed in the striatum and substantia nigra after acute treatment with MPTP. Dopamine D2 receptors were reduced significantly in the substantia nigra only 7 days after the MPTP treatment, whereas striatum showed no significant change in the binding throughout the experiments. In contrast, dopamine uptake sites were reduced markedly in the striatum and substantia nigra 3 and 7 days after the MPTP treatment. Dopamine and DOPAC content were also reduced in the striatum 3 and 7 days after the MPTP treatment. An immunohistochemical study indicated a loss of the number of TH-positive neurons in the substantia nigra 7 days after the MPTP treatment. In contrast, numerous GFAP-positive astrocytes were evident in the striatum 7 days after the MPTP treatment. These results provide valuable information for the pathogenesis of acute stage of Parkinson's disease.

Animals↗
PubMed2003

TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates.

The neuroprotective efficacy of the propargylamine TCH346 was studied in the primate model of Parkinson's disease, the bilaterally MPTP-treated monkey. Male rhesus monkeys received 2.5 mg MPTP into the left carotid artery and, 8 weeks later, 1.25 mg MPTP into the right carotid artery. Starting 2 h after the second MPTP infusion, either 0.014 mg/kg TCH346 or its solvent was subcutaneously injected twice per day for 14 days. The first MPTP treatment induced mild Parkinson symptoms, reduced right limb movements, and reduced FDOPA uptake in the left striatum. The second MPTP treatment made Parkinson symptoms worse, reduced left limb movements, and reduced FDOPA uptake in the right striatum of solvent-treated monkeys. In contrast, the second MPTP treatment did not further worsen motor symptoms and did not decrease FDOPA uptake in the right striatum of TCH346-treated monkeys. Although the effects of the second MPTP treatment were largely prevented, the effects of the first MPTP treatment were not reversed by TCH346. Immunohistochemical examination confirmed the dramatic loss of dopamine cells in vehicle-treated monkeys and the preservation of these neurons in the right brain side of the TCH346-treated animals. In conclusion, systemic administration of TCH346 prevented motor symptoms and nigrostriatal degeneration induced by MPTP in primates.

Animals↗
PubMed2001

Ultradian and circadian body temperature and activity rhythms in chronic MPTP treated monkeys.

The body temperature and locomotor activity rhythms of seven 1-Methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgous monkeys were registered over a week on two separate occasions over an interval of 2 months. Motor disability was absent in two animals and present in five: it was mild in one, moderate in two and severe in two. Both temperature and motor activity were recorded every minute using a radio telemetry system. Analysis of circadian rhythms revealed less robustness of the 24-hour circadian components of body temperature and locomotor activity with increasing motor impairment, and a fragmentation of the body temperature rhythm into 8 hour-period components. Both total activity and daytime activity correlated inversely with the degree of motor impairment. On the contrary, the monkeys did not show differences in night time activity. The proportions of variance accounted for by the body temperature and locomotor activity of 24 h + 12 h + 8 h components were correlated. Also, the average levels at which the circadian rhythm varies between body temperature and locomotor activity were correlated. The results were almost identical in the two 1-week recording sessions. The present study confirms individual differences in the vulnerability to MPTP of the nigrostriatal system of monkeys, suggesting that if a cumulative dose does not provoke stable motor alterations, this cumulative dose will not produce circadian body temperature and locomotor activity rhythm alterations either. Similarly, if a dose is able to produce motor impairment, this dose will also be able to produce circadian rhythm alterations.

Activity Cycles↗
PubMed1990

Drug-induced parkinsonism and other movement disorders.

This is a review of reserpine, haloperidol, and various phenothiazines that produce parkinsonism and other movement disorders. The by-products of illicit meperidine synthesis, MPTP and its more sinister companion, MPP, are also discussed. Movement disorders, transient or fixed, frank parkinsonism and/or dyskinesia, due to a variety of other medications and toxic agents are included. These are methanol, lithium, methyldopa, antimetabolites, antidepressants, sympathomimetic anorexiants, some types of antihistamines, and various combinations of agricultural chemicals.

Haloperidol↗
PubMed1991

MPTP-induced neurotoxicity and the quest for a preventative therapy for Parkinson's disease.

Less than 10 years have passed since the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is capable of producing parkinsonism in both humans and non-human primates. In that time, there has been considerable interest in the possibility that the pathogenesis of idiopathic Parkinson's disease (PD) might involve a process analogous to that of MPTP toxicity. One hypothesis holds that PD might arise, at least in part, from exposure to an MPTP-like environmental toxin. Rapid progress has been made towards elucidating the precise mechanism by which MPTP exerts toxicity, and clarifying the relationship of MPTP toxicity to idiopathic PD. The goal of these efforts is to develop a therapy that inhibits the underlying disease process in PD.

Environmental Pollutants↗
PubMed1993

Design and synthesis of 18F-labeled neurotoxic analogs of MPTP.

We report on the synthesis of two fluorine-18 labeled analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A piperidyl triazene was fluorinated to produce [18F]-1-methyl-4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine (2'-F-MPTP, 12) in very low yield, and 1-methyl-4-[2-(fluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (2'-FCH2-MPTP, 11) was labeled with 18F by nucleophilic displacement of the corresponding chloride in 60% yield. The biodistribution in mice of the latter radiotracer and its oxidation to 1-methyl-4-[2-(fluoromethyl)phenyl]pyridinium (2'-FCH2-MPP+, 6) is also reported. The kinetics of oxidation of 2'-FCH2-MPTP and its solvolysis products (the corresponding 2'-hydroxymethyl and 2'-chloromethyl analogs) by rat liver monoamine oxidase were investigated. 2'-FCH2-MPTP accumulated to a useful degree in the brain, was oxidized by monoamine oxidase in vitro, was converted to the oxidation product in brain in vivo, and had a neurotoxic potency similar to that of MPTP. We feel it may be useful as an 18F-labeled radiopharmaceutical for positron tomographic studies of the mechanisms of MPTP toxicity.

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

In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species.

The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Decreased striatal levels of PEP-19 following MPTP lesion in the mouse.

PEP-19 is a neuronal calmodulin-binding protein, and as such, a putative modulator of calcium regulated processes. In the present study, we used proteomics technology approaches such as peptidomics and imaging MALDI mass spectrometry, as well as traditional techniques (immunoblotting and in situ hybridization) to identify PEP-19 and, specifically, to measure PEP-19 mRNA and protein levels in an animal model of Parkinson's disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice resulted in a significant decrease in striatal PEP-19 mRNA. Capillary nano-flow liquid chromatography electrospray mass spectrometry analysis of striatal tissue revealed a significant decrease of the PEP-19 protein level. Moreover, imaging MALDI mass spectrometry also showed that PEP-19 protein was predominantly localized to the striatum of the brain tissue cross sections. After MPTP administration, PEP-19 levels were significantly reduced by 30%. We conclude that PEP-19 mRNA and protein expression are decreased in the striatum of a common animal model of Parkinson's disease. Further studies are needed to show the specific involvement of PEP-19 in the neurodegeneration seen in MPTP lesioned animals. Finally, this study has shown that the combination of traditional molecular biology techniques with novel, highly specific and sensitive mass spectrometry methods is advantageous in characterizing molecular events of many diseases, including Parkinson's disease.

Animals↗
PubMedDate not supplied

Metabolism of [14C]MPTP in mouse and monkey implicates MPP+, and not bound metabolites, as the operative neurotoxin.

The distribution, identification, and binding of [phenyl-14C]- or [methyl-14C]MPTP metabolites have been determined in brains of mouse and monkey exposed to toxic doses of MPTP. The distribution of radiolabeled metabolites was heterogeneous, with levels of MPP+ 1-100 mumol/L in dissected and homogenized monkey brain tissues. MPP+ constituted greater than 98% of all tissue radioactivity remaining at 1-3 days in the monkey and was identified in both cortical and striatal tissue. The relevance of the 2% of unextractable ("bound") radiolabeled metabolite was assessed in mouse brain by using pargyline or mazindol pretreatments which block dopamine depletion. The amount of binding increased rather than decreased when [phenyl-14C]MPTP was used along with pargyline or mazindol but was unchanged when [methyl-14C]MPTP was employed. This demonstrates that bound metabolites are inversely correlated to neurotoxicity as well as being N-demethylated. Two extractable metabolites, demethylated MPTP (PTP) and 1-methyl-4-phenyl-2-pyridone, were found at 30-min survival times in mouse brain and probably derive from peripheral metabolism of MPTP. At 4 h, mouse brain profiles of extractable metabolites resembled those from monkey brain, containing MPP+ as the predominant (greater than 90%) constituent. The similarity of MPP+ concentrations in mouse and monkey brain homogenates with those concentrations of MPP+ known to produce biological effects in vitro, along with the inverse relationship between bound metabolites and neurotoxicity, supports the intermediacy of MPP+ as the operative neurotoxin.

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

Studies on 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Previous reports indicate that 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine (BMTP), the benzyl analogue of the Parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is not neurotoxic in the C-57 black mouse even when administered at a dose 10 times greater than the dose of MPTP required to cause an 85% depletion of neostriatal dopamine. Intrastriatal microdialysis in the rat with the corresponding 4-benzyl-1-methylpyridinium ion BMP+ for 60 min, however, causes nerve terminal destruction similar to that observed following a 15-min perfusion with the 1-methyl-4-phenylpyridinium ion MPP+, the monoamine oxidase B (MAO-B) generated metabolite derived from MPTP. With the aid of purified beef liver MAO-B and synthetic standards, we observed the efficient and quantitative conversion of BMTP to the corresponding 2,3-dihydropyridinium intermediate BMDP+, which underwent further, but incomplete, oxidation to BMP+. These MPTP-type properties point to in vivo effects, such as pharmacokinetic parameters and/or alternative metabolic pathways, to account for BMTP's lack of neurotoxicity.

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