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PubMed1995

Heavy metals and the etiology of Parkinson's disease and other movement disorders.

Heavy metals, such as iron and manganese, are involved in neurologic disease. Most often these diseases are associated with abnormal environmental exposures or abnormal accumulations of heavy metals in the body. There is increasing recognition that heavy metals normally present in the body also may play a role in disease pathogenesis through free radical formation. When a part of the brain known as the basal ganglia is affected, movements become disordered. Parkinson's disease is one of the most common movement disorders and is related to destruction of neurons in the substantia nigra pars compacta (SNpc) of the basal ganglia. The combination of high concentration of iron and the neurotransmitter, dopamine, may contribute to the selective vulnerability of the SNpc. Dopamine can auto-oxidize to produce free radicals particularly in the presence of iron and other heavy metals.

Animals↗
PubMed1990

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage of striatal dopaminergic fibers attenuates subsequent astrocyte response to MPTP.

Acute administration of the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the C57BL/6 mouse caused a rapid decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of the nigrostriatal dopaminergic pathway, followed by a large increase in the astrocyte protein, glial fibrillary acidic protein (GFAP). The astrocyte (GFAP) response declined to baseline three weeks after administration of MPTP. Administration of a second dosage of MPTP at this time evoked a second GFAP response. The magnitude of the second response, however, was decreased in comparison to the response seen after only a single exposure to MPTP. Increasing the initial dosage of MPTP resulted in greater reductions of the second GFAP response. These data indicate that MPTP-induced damage or loss of striatal dopaminergic neurons reduces the signal available for initiating astrogliosis and thereby reduces the astrocyte response to a second exposure to MPTP.

Animals↗
PubMed1990

The effects of monoamine oxidase inhibition and dopamine uptake blockade on MPTP-induced increase of 2-[3H]deoxyglucose uptake in specific mesencephalic catecholaminergic nuclei.

Intraperitoneal injection in C57 black mice of 30 or 7.5 mg/kg MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) followed 1-2 h later by 0.5 mCi/100 g 2-[3H]deoxyglucose (2-DG) produces an intense increase of 2-DG uptake in the dopaminergic zona compacta (ZC) of the substantia nigra and the adjacent ventral tegmental area (VTA) as seen in autoradiographs. Anesthetized animals also exhibit this reaction. Clorgyline (10 mg/kg), a monoamine oxidase (MAO)-A inhibitor, 30 min before MPTP does not block this reaction. Deprenyl (10 mg/kg), an MAO-B inhibitor, blocks increased 2-DG uptake in ZC and VTA if injected 30 min or 12 h before 7.5 mg/kg MPTP, but has no effect if injected 12 h before 30 mg/kg MPTP. Mazindol (10 mg/kg), a dopamine uptake blocker, is effective in blocking the action of 7.5 mg/kg MPTP, but ineffective against 30 mg/kg MPTP. Heavier doses of MPTP can, in some instances, overcome the actions of MAO inhibitors or dopamine uptake blockers in preventing the increased 2-DG uptake elicited by MPTP. But, essentially, the intensely increased glucose metabolism acutely induced in specific catecholaminergic neurons appears to be another significant pathological feature of the dopaminergic neurotoxicity caused by MPTP which can be prevented by MAO inhibition or dopamine uptake blockade.

Animals↗
PubMed1990

MPTP toxicity in the mouse brain and vitamin E.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused transient alterations in vitamin E levels in every brain region examined. However, vitamin E returned to normal levels within a few hours in all brain regions but the substantia nigra, where at 2 days vitamin E levels first rose above normal levels. Vitamin E deficient mice were much more susceptible to MPTP toxicity than controls, in terms of lethality and DOPAC depletion in the substantia nigra. However, in the same vitamin E deficient mice, the striatum was partially protected from neurotransmitter and metabolite depletion by MPTP. The mechanism of toxicity of MPTP may differ in the striatum and the midbrain.

Animals↗
PubMed1991

Neurochemical and behavioural features induced by chronic low dose treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset: implications for Parkinson's disease?

Protracted long-term treatment of common marmosets with 15 doses (0.5-4.5 mg/kg, i.p.) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; total dose 25 mg/kg, given over 29 days) caused transitory changes in motor behaviour reminiscent of human Parkinson's disease. 16 days from the start of MPTP administration, all animals showed motor impairment, consisting of profound akinesia and a rigid posture, but in no case resting tremor. Biogenic amines were measured in nigrostriatal regions one month after finishing MPTP treatment. There was a profound loss of dopamine and serotonin in the substantia nigra and in the striatum; noradrenaline was only reduced in the putamen. Continuous analyses of the concentrations of biogenic amine metabolites in the CSF during this study revealed persistent dopaminergic disturbances and temporary alterations in serotoninergic and noradrenergic function.

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

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces cytoskeletal alterations on 'Swiss 3T3' mouse fibroblasts.

The effect of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on Swiss 3T3 cells was investigated. Cell morphology alterations were observed when 3T3 cell cultures were exposed for 6 h to 1.5 mM MPTP. Using indirect immunofluorescence technique, cytoskeletal elements' organization of microfilaments and microtubules, has been analysed. MPTP modified both actin and tubulin networks, stress fibers appeared less sharp and microtubules were disorganized. The effect of MPTP was completely reversible and cell viability was unaffected. These results suggest that changes in cytoskeletal organization may be the first visible effect related to biochemical alterations induced by MPTP.

Actins↗
PubMed1991

Age-related changes in locomotor behavior induced by MPTP in rats.

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on gait was studied in young (4 weeks) and old (21 months) male rats. No significant alteration in stride length (SL) or stride width (SW) was observed 30 min after single dose MPTP treatment (3 mg/kg, i.p.) in both young and old rats. Multidose treatment with MPTP (3 mg/kg, i.p. daily for 8 days) resulted in a marked decrease in SL in old rats compared to that of old control group, while an increase in SL was found in both MPTP-treated and control young rats. In contrast, multidose MPTP administration caused no changes in SW in either young or old rats. The present result of behavioral analysis suggests that multidose MPTP neurotoxic effect on locomotor activity may be age dependent in rats and that the old rat is an appropriate model for MPTP studies.

Age Factors↗
PubMed1991

The acute convulsant effect of MPTP is dependent on intracerebral MPP+.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57 black mice causes an acute seizure syndrome the severity of which is dose dependent; there is also a good correlation between the seizure inducing potential of MPTP and the neostriatal dopamine (DA) depletion caused by MPTP. The simultaneous administration of MPTP and MAO B inhibitors attenuates both epileptiform phenomena and neostriatal DA depletion. On the contrary diethyldithiocarbamate (DDC) exacerbates both responses. All these pharmacological manipulations are known to affect the accumulation of 1-methyl-4-phenylpyridinium ion (MPP+) the main metabolite of MPTP. Thus the present data support the hypothesis of a strict dependence of the epileptiform phenomena on the presence of MPP+. Furthermore the tight correlation existing between the severity of epileptic events and DA depletion suggests that the acute excitotoxic syndrome may contribute to the long-term toxicity of MPTP. *On leave from the Department of Neurology, University of Pisa, Pisa, Italy.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced astrogliosis does not require activation of ornithine decarboxylase.

Mechanical injury to the brain results in enhanced immunostaining for glial fibrillary acidic protein (GFAP) that is markedly inhibited by difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. In the current study, systemic exposure of mice to the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), also increased GFAP but, unlike mechanical injury, this increase was not prevented by DFMO pretreatment. These results indicate that de novo polyamine biosynthesis is not obligatory for the MPTP-induced increase in GFAP. MPTP administration, unlike mechanical injury, does not disrupt the blood-brain barrier; thus, a role for polyamine biosynthesis in the astrocyte response to injury may be restricted to insults involving a compromised blood-brain barrier.

Animals↗
PubMed1993

MPTP neurotoxicity to cerebellar Purkinje cells in mice.

The pyridine derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is recognized as a crucial neurotoxin which destroys nigrostriatal dopamine cells, thereby inducing neurological signs relevant to idiopathic Parkinson's disease. In the present study, we have revealed MPTP neurotoxicity to cerebellar Purkinje cells in mice. Systemic MPTP injections to mice resulted in a substantial loss of Purkinje cells in a dose-dependent fashion. The MPTP-induced Purkinje cell loss occurred markedly in the crus I and II ansiform lobules and the paraflocculus. Such a neurotoxic effect was largely prevented by the monoamine oxidase B inhibitors pargyline and deprenyl, and the dopamine uptake inhibitors mazindol and benztropine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Correlation between 1-methyl-4-phenylpyridinium ion (MPP+) levels, ascorbic acid oxidation and glutathione levels in the striatal synaptosomes of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rat.

In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the crude striatal synaptosomal fraction after single injections of MPTP 35 mg/kg i.p. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a 32.5% death rate within 15 min to 10 h. Groups of surviving rats were sacrificed 1, 3, 8 and 24 h after MPTP. MPTP significantly increased levels of DHAA and uric acid and decreased levels of DOPAC and GSH. Individual synaptosomal levels of MPP+ were correlated inversely with DOPAC (r = -0.601, P < 0.002) and GSH levels (r = -0.496, P < 0.02) and directly with levels of uric acid (r = +0.627, P < 0.001); these latter, in turn, were correlated with DHAA (r = +0.418, P < 0.05) and GSH levels (r = -0.357, P = 0.07). In conclusion, the response of the endogenous antioxidant system (increase in AA oxidation, decrease in GSH levels) correlates well with the MPTP-induced increase in uric acid levels and provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress produced by xanthine oxidase.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat.

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Alteration of pallidal cholinergic activity in MPTP-treated monkeys: effect of dihydro-alpha-ergocryptine (DEK).

Monkeys, intravenously administered with MPTP at the dose of 0.3 mg/kg for 5 consecutive days, develop a severe Parkinson-like syndrome. Cholinergic enzyme activities are increased in the internal segment of the globus pallidus (GPi) and into a lesser extent in the external globus pallidus (GPe). Cholinergic activities are not significantly affected in the caudate and putamen nor in the frontal, parietotemporal, occipital cortices and in the cerebellum. The treatment of the animals twice daily for 2 weeks with dihydro-alpha-ergocryptine (DEK) starting 5 days before the first MPTP administration counteracts the neurotoxin-induced alteration in the internal pallidum and ameliorates some motor related parkinsonian symptoms.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys.

The mechanism of abnormal iron accumulation in the substantia nigra (SN) pars compacta of patients with Parkinson's disease (PD) is unknown. To explore this question, we made a hemiparkinsonism model in monkeys by injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the caudate or putamen on one side, and compared iron content in the SN and other basal ganglia structures by histochemistry. The injected side, especially the SN pars compacta, showed a marked increase in iron staining. Our study indicates that an injury to the nigrostriatal system by MPTP injection can induce iron accumulation in the SN.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Interactions among deprenyl, clorgyline and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on catecholamines in mice.

The interactive effects of clorgyline, deprenyl and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopamine (DA), serotonin (5HT) and hippocampal norepinephrine (NE) were examined in the present study. Results indicated that clorgyline did not have a preventive effect against MPTP's toxicity on DA and NE, but it had a partial therapeutic effect against subchronic MPTP-induced DA depletion when given with deprenyl together. However, this effect was not significantly different from the effect of deprenyl alone. Co-administration of clorgyline and deprenyl had a satisfactory effect in preventing MPTP-induced NE depletion. On the other hand, in all clorgyline-treated groups, there was a significant increase of 5HT in both the striatum and the hippocampus.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

MPTP-induced parkinsonism in primates: pattern of striatal dopamine loss following acute and chronic administration.

We analyzed the effect of two different schedules of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment on dopaminergic systems in the striatum of cynomolgus monkeys. Acute MPTP treatment produced a marked dopamine (DA) depletion, more severe in the caudate nucleus than in the putamen. Chronic MPTP induced a more pronounced reduction in DA levels, the putamen being slightly more affected than the caudate nucleus, in accord with immunohistochemical findings that showed a higher loss of tyrosine-hydroxylase positive neurons in ventral subpopulations of the substantia nigra pars compacta. A striking increment in the quotient DOPAC+HVA/DA was also observed in chronically but not in acutely treated monkeys, especially in the putamen. In chronically treated animals there was a nearly complete loss of DA in all subdivisions of the putamen. In the caudate nucleus, a rostrocaudal gradient of DA depletion was found, with a greater decrease in DA concentration in the rostral parts, especially in the dorsolateral portions. The pattern of striatal DA loss characteristic of Parkinson's disease can be reproduced to a certain extent in MPTP-intoxicated primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Toxicity to PC12 cells of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are inhibitors of mitochondrial function and substrates for the dopamine re-uptake system, but their neuronal toxicity is unclear. In this study, the effects of exposing PC12 cells to four isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, 6,7-methylenedioxyisoquinoline and 1,2,3,4-tetrahydroisoquinoline) and MPP+ (100-1000 microM) were examined. All compounds exhibited concentration-dependent toxicity as determined by lactate dehydrogenase release, but none of the isoquinoline derivatives were more toxic than MPP+. Cytotoxicity of these compounds appears to be directly correlated with their substrate affinity for the dopamine reuptake system, but not mitochondrial inhibition. Thus, the low toxicity of isoquinoline derivatives towards PC12 cells suggests that high concentrations of or prolonged exposure to these compounds may be necessary to cause the neurodegenerative changes related to Parkinson's disease.

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