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PubMed1994

MPTP-induced degeneration: interference with glutamatergic toxicity.

Parkinson's disease (PD) is characterised by the progressive degeneration of nigrostriatal dopamine (DA) neurons resulting in the major symptoms of akinesia and rigidity. Although the primary cause of PD is still not known some features make this disorder a model for neurodegenerative diseases in general. It has been known for some time that symptomatic PD can be attributed to insults with symptoms occurring many years later such as post-encephalitic PD or PD following manganese poisoning. More recently, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been identified as a neurotoxin selective for melanin-containing dopaminergic neurons in humans and non-human primates. The specificity of this neurotoxin and the striking clinical similarities to idiopathic PD, seen in primates, make MPTP-induced parkinsonism the most useful animal model of a neurological disease. There are numerous theoretical possibilities to interfere with both MPTP-induced neurotoxicity and the symptomatology of PD. In recent years excitatory amino acids have gained considerable interest since they can cause excitotoxic lesion of neurons under a number of pathological conditions (Olney et al., 1989; Choi, 1988). Here we summarise the present data and provide new experimental evidence indicating that MPTP-induced degeneration of dopaminergic neurons does involve glutamate-mediated toxicity. It is concluded that glutamate-mediated excitotoxicity results in the destruction of DAergic somata in the substantia nigra. Non-competitive or competitive NMDA antagonists protect nigral neurons from MPTP-induced degeneration whereas their striatal terminals still seem to degenerate.

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

PubMed1988

[No Parkinsonian syndrome following acute paraquat poisoning].

Paraquat structurally resembles N-methyl-4-phenyltetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridine (MPP+). MPTP and MPP+ are neurotoxic chemicals, which induce in exposed humans and in animal-models a Parkinson's disease. A high correlation between the incidence of Parkinson's disease and herbicide use in Canada led to the assumption that paraquat could give rise to parkinsonism. We have therefore carried out a follow-up study with patients having had dermal contact with paraquat or having swallowed paraquat accidentally or in a suicidal attempt. 7 patients took part in the study. Three of them had dermal contact. One had ingested paraquat by accident and three were survivors from suicidal paraquat intake. It was possible to exclude parkinsonism in all patients. One patient exhibited tardive dykinesia most likely due to a long term therapy with neuroleptic drugs.

Accidents↗

PubMed2000

Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management.

Parkinson's disease (PD) is the most common movement pathology, severely afflicting dopaminergic neurons within the substantia nigra (SN) along with non-dopaminergic, extra-nigral projection bundles that control circuits for sensory, associative, premotor, and motor pathways. Clinical, experimental, microanatomic, and biochemical evidence suggests PD involves multifactorial, oxidative neurodegeneration, and that levodopa therapy adds to the oxidative burden. The SN is uniquely vulnerable to oxidative damage, having high content of oxidizable dopamine, neuromelanin, polyunsaturated fatty acids, and iron, and relatively low antioxidant complement with high metabolic rate. Oxidative phosphorylation abnormalities impair energetics in the SN mitochondria, also intensifying oxygen free radical generation. These pro-oxidative factors combine within the SN dopaminergic neurons to create extreme vulnerability to oxidative challenge. Epidemiologic studies and long-term tracking of victims of MPTP (1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine) poisoning, suggest oxidative stress compounded by exogenous toxins may trigger the neurodegenerative progression of PD. Rational, integrative management of PD requires: (1) dietary revision, especially to lower calories; (2) rebalancing of essential fatty acid intake away from pro-inflammatory and toward anti-inflammatory prostaglandins; (3) aggressive repletion of glutathione and other nutrient antioxidants and cofactors; (4) energy nutrients acetyl L-carnitine, coenzyme Q10, NADH, and the membrane phospholipid phosphatidylserine (PS), (5) chelation as necessary for heavy metals; and (6) liver P450 detoxification support.

Disease Progression↗

PubMedDate not supplied

Digoxin prevents MPTP-induced dopamine depletion in mouse striatum.

Inhibition of Na+/K+ ATPase by cardiac glycosides has been shown to potentiate toxic effects of excitatory amino acids and mitochondrial poisons in neurons in vitro. The present study tested the hypothesis that the systemic administration of the cardiac glycoside, digoxin, potentiates effects of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in vivo. Mice were injected with digoxin (1 mg/kg) or vehicle followed by MPTP (20 mg/kg) or saline 1 h later. After 1 or 8 days, mice were euthanized and dopamine levels in the striatum were measured by high-performance liquid chromatography with electrochemical detection. MPTP caused a significant 35-45% reduction in striatal dopamine levels compared to those in control mice. However, pretreatment with digoxin completely prevented the MPTP-induced dopamine depletion. This result was unexpected and suggests that cardiac glycosides may protect against MPTP neurotoxicity.

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

PubMedDate not supplied

[Parkinsonism after methyl alcohol poisoning].

Two cases of parkinsonism due to methyl alcohol poisoning are reported. In the first patient, parkinsonism features were mild and stable, while in the second they progressively developed in the weeks following the poisoning. None of the two patients had significant visual abnormalities during the clinical evolution. Both patients had symmetrical putaminal lesions in CT, and one in NMR imaging. The response to antiparkinsonism drugs was absent in one case and it could not be evaluated in the other because of patient's death. On the basis of theses two cases the clinical and therapeutic features of this type of striatal parkinsonism are compared with those with parkinsonism due to other toxic agents. In view of the topography of the lesions of this poisoning, which is shared by other conditions such as Leber's disease or Leigh's syndrome, and the analogy with the presynaptic action of MPP+ in the parkinsonism due to MPTP, a possible implication of mitochondrial metabolism in the pathogenesis of this syndrome is discussed. The lack of knowledge of the real incidence of this complication in the survivors of methyl alcohol poisoning suggests the need to perform studies with a prolonged and systematic clinical follow up.

Adult↗

PubMedDate not supplied

Parkinsonism: a clinical marker of exposure to neurotoxins.

Parkinson must be viewed as a final common pathway resulting from a variety of neuropathological lesions which interfere with the integrity of the nigrostriatal system or its output. Exposure to a wide variety of neurotoxic compounds, namely, carbon monoxide, carbon disulfide, manganese and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), are associated with parkinsonism that has a varying neuropathology, which will be discussed.

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

PubMed2002

[Human neurotoxicity of ethylene-bis-dithiocarbamates (EBDC)].

Ethylene-bis-dithiocarbamates (EBDC) (maneb, mancozeb,...) are fungicides which rarely cause acute toxicity reactions, but may have a severe long-term toxic effect. Twelve cases reported to the Bordeaux Anti-Poison Center over a 10-year period generally exhibited short-term neurological symptoms of variable severity. Cases of acute intoxication reported in the literature have involved various neurological signs including headache, dizziness and confusion, and a few cases of seizures, all of which were rapidly reversible. Long-term exposure has been associated with parkinsonism and epidemiological studies have found an increased risk of neurocognitive impairment associated with long-term exposure to pesticides in general and to EBDC specifically. Experimentally, EBDC increases the neurotoxicity of MPTP and paraquat. Their metabolite, ethylene thiourea (ETU), is neurotoxic in utero. There are indications that EBDC and/or ETU may increase sensitivity to genetic and environmental risk factors for cell death and apoptosis. Occupational or accidental exposure to EBDC and its possible long-term consequences require adequate studies concerning their mechanism, surveillance and prevention.

Adult↗

PubMed1996

Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study.

We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximately 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinson's disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity.

Animals↗

PubMed1999

Impaired glutamate clearance as a consequence of energy failure caused by MPP(+) in astrocytic cultures.

Astrocytes are the site of bioactivation of the parkinsonism-inducing agent 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) into its toxic 1-methyl-4-phenylpyridinium (MPP(+)) metabolite. The mechanism by which MPP(+) is capable of decreasing astrocytic glutamate uptake was evaluated in this study using primary cultures of astrocytes. Addition of glutamate to these cultures was followed by its efficient clearance from the extracellular space. However, when astrocytes were preincubated with MPP(+), glutamate clearance was significantly impaired. This effect was concentration-dependent, became more pronounced by prolonging the incubation in the presence of MPP(+) and occurred at a time when cell membrane integrity was still preserved. No evidence was found that reactive oxygen species contributed to MPP(+)-induced decrease in glutamate clearance. Indeed, neither the spin trapping agent alpha-phenyl-tert-butyl nitrone, the lazaroid antioxidant U-74389G, nor the disulfide-reducing agent dithiothreitol was capable of restoring glutamate net uptake. The effect of MPP(+) on glutamate clearance: (i) was accompanied by a decrease in cellular ATP; (ii) could be enhanced by withdrawing glucose from the incubation medium or by inhibiting glycolysis with 2-deoxyglucose, and (iii) could be reproduced using the mitochondrial complex I inhibitor rotenone. Taken together, these results indicate that, by acting as a mitochondrial poison, MPP(+) impairs energy metabolism of astrocytes and significantly reduces their ability to maintain low levels of extracellular glutamate.

1-Methyl-4-phenylpyridinium↗