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PubMed1999

Creatine and cyclocreatine attenuate MPTP neurotoxicity.

Systemic administration of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) produces parkinsonism in experimental animals by a mechanism involving impaired energy production. MPTP is converted by monoamine oxidase B to 1-methyl-4-phenylpyridinium (MPP+), which blocks complex I of the electron transport chain. Oral supplementation with creatine or cyclocreatine, which are substrates for creatine kinase, may increase phosphocreatine (PCr) or cyclophosphocreatine (PCCr) and buffer against ATP depletion and thereby exert neuroprotective effects. In the present study we found that oral supplementation with either creatine or cyclocreatine produced significant protection against MPTP-induced dopamine depletions in mice. Creatine protected against MPTP-induced loss of Nissl and tyrosine hydroxylase immunostained neurons in the substantia nigra. Creatine and cyclocreatine had no effects on the conversion of MPTP to MPP+ in vivo. These results further implicate metabolic dysfunction in MPTP neurotoxicity and suggest a novel therapeutic approach, which may have applicability for Parkinson's disease.

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

Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP.

The loss of dopaminergic neurons in Parkinson's disease is associated with a glial reaction and the overproduction of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha). TNF-alpha acts via two different receptors, TNFR1 and TNFR2, and is believed to have both a neuroprotective and a deleterious role for neurons. In order to analyze the putative role of TNF-alpha in parkinsonism, we compared the effect of the parkinsonian drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice lacking TNFR1, TNFR2, or both receptors and in wild-type littermates. We show that MPTP does not affect spontaneous activity or anxiety in any of the groups and that it reduces motor activity on a rotarod in double knock out mice but not in mice lacking only one receptor. Postmortem analysis revealed no differences in the number of nigral dopaminergic neurons whatever the group. In contrast, striatal dopamine level was slightly decreased in double knock-out mice and more reduced by MPTP in this group than in the other groups of mice. In addition, dopamine turnover was significantly more increased in double knock out mice after MPTP injection. These data suggest that TNF-alpha does not participate in the death of dopaminergic neurons in parkinsonism but that it slightly alters dopamine metabolism or the survival of dopaminergic terminals by a mechanism involving both receptors.

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

The immunophilin ligand GPI-1046 does not have neuroregenerative effects in MPTP-treated monkeys.

Nonimmunosuppressant immunophilin ligands have been shown to have neurotrophic properties in rodent models of Parkinson's disease (PD), although little is known about the effects of these ligands in primates. The immunophilin ligand, GPI-1046, promotes the regeneration of dopamine (DA) cells in association with functional recovery in rodent models. We explored the regenerative effects of GPI-1046 in an MPTP primate model of PD. We used single photon emission computed tomography (SPECT) and the DA transporter tracer (DAT), [(123)I]beta-CIT, to evaluate DAT density and clinical recovery before and after treatment with GPI-1046 or vehicle. Subsequent histological studies were also performed. No effects of GPI-1046 were found on any of these measures. These findings show that GPI-1046 does not have regenerative effects in MPTP-treated primates and suggest that there may be species differences with respect to the trophic effects of GPI-1046 on nigrostriatal DA neurons.

Animals↗
PubMed1998

A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neurotrophic actions after oral administration in an animal model of Parkinson's disease.

Protection or regeneration of the dopaminergic (DA) system would be of significant therapeutic value for Parkinson's disease. Immunophilin ligands, such as FK506, can produce neurotrophic effects in vitro and in vivo, but their immunosuppressive effects make them unsuitable for neurological application. This study demonstrates that a novel, nonimmunosuppressive immunophilin ligand (V-10,367) increased the number of neurites extended by tyrosine hydroxylase positive (TH+) DA neurons in embryonic day 14 primary DA neuronal cultures. In contrast, the immunosuppressive immunophilin ligand FK506 increased the length of TH+ neurites. After oral administration in MPTP-treated mice, V-10,367 completely protected against MPTP-induced loss of striatal TH+ axonal density, while FK506 did not. These experiments demonstrate that nonimmunosuppressive immunophilin ligands specifically increase neurite branching in primary DA neuronal culture and possess neurotrophic actions in vivo with potential application to neurodegenerative disease.

Administration, Oral↗
PubMed1996

Striatal MPP+ levels do not necessarily correlate with striatal dopamine levels after MPTP treatment in mice.

The present study offers confirmation of the fact that an MAO-B inhibitor, (-) deprenyl and a DA uptake blocker, GBR-12909, prevent MPTP-induced striatal DA decrease. This protective effect is accompanied by an almost complete prevention of MPP+ production induced by (-) deprenyl and an accelerated MPP+ clearance induced by GBR-12909 within the striatum. Similarly, the MPTP toxicity enhancers, DDC and acetaldehyde, both increase striatal MPP+ levels, as previously reported. On the contrary, the treatment with MK 801, although uneffective in preventing the long-term MPTP-induced striatal DA decrease, causes an increase in the striatal amount of MPP+. In a similar way, the administration of nicotine in combination with MPTP produces a significant increase in the levels of striatal MPP+, which does not elicit any effect on striatal DA. The effect of clonidine is consistent with these results and in sharp contrast with the current belief that a direct relationship exists between striatal MPP+ concentrations and the degree of MPTP-induced depletion of striatal DA. In this study, using different treatments, we failed to confirm the correlation between MPP+ striatal levels and dopaminergic lesions after MPTP administration in mice. We suggest that this correlation is not a rule and exceptions may depend on a different compartimentalization of the toxic metabolite.

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

Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model.

We studied the microglial reaction in mice using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model for Parkinson's disease (PD). Microglial cells were identified by means of the Griffonia simplicifolia lectin (GSA-I-B4). Dopaminergic neurons were marked by tyrosine hydroxylase antibodies. Microglial activation was demonstrated by an increase in cellular number and changes of morphology (increased lectin staining, larger cell bodies and thicker processes) were seen in the substantia nigra from the 1st to the 14th day and in the striatum from the 1st to the 4th day after intoxication. Depletion of dopaminergic neurons was most pronounced 7 and 14 days following the treatment. The results suggest that microglial activation may be involved in the sequence of pathological changes that lead to dopaminergic neuronal damage after MPTP intoxication.

Animals↗
PubMed1993

Neonatal exposure to paraquat or MPTP induces permanent changes in striatum dopamine and behavior in adult mice.

We have recently reported that environmental toxicants, such as DDT, PCBs, pyrethroids, and nicotine can induce permanent functional and neurochemical changes in adult mice when given to neonatal mice during the peak of rapid brain growth. In the present investigation the neurotoxic effects following neonatal exposure to paraquat (N,N'-dimethyl-4,4'-bipyridylium), a broad-spectrum herbicide with structural similarity to the 1-methyl-4-phenylpyridium ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which can induce Parkinson's syndrome, and MPTP were studied. Five groups of mice were given paraquat or MPTP orally: group 1, vehicle; groups 2 and 3, MPTP 0.3 and 20 mg/kg; groups 4 and 5, paraquat 0.07 and 0.36 mg/kg when 10 and 11 days old. Neonatal spontaneous motor activity was tested on Day 18 in mice given paraquat 0.36 mg/kg body wt. Adult spontaneous motor activity testing was performed at ages 60 and 120 days. On Day 125 the mice were decapitated and the contents of dopamine (DA), serotonin (5-HT), and metabolites in striatum were analyzed. The results may be summarized as follows: (1) No signs of acute toxicity or differences in weight gain were observed in any of the groups. Nor was any respiratory distress or motor performance dysfunction evident on Day 18 in mice given paraquat 0.36 mg/kg body wt. (2) The behavioral tests at 60 days of age showed a marked hypoactive condition in the mice given paraquat (at both doses) and MPTP (at both doses). (3) At the age of 120 days the hypoactive behavior persisted and appeared even more pronounced. (4) The high doses of MPTP and paraquat--and to a less extent the low doses--reduced the striatal content of DA and metabolites without affecting 5-HT. The altered behavior, together with the dose-dependent reduction of DA and metabolites in neostriata in this study, further demonstrates the susceptibility to low-dose exposure to environmental pollutants during the neonatal period.

Animals↗
PubMed1996

Biotransformation of the MPTP analog trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetra- hydropyridine to a fluorescent pyridinium metabolite by intact neuroblastoma cells.

The possibility of imaging monoamine oxidase (MAO) containing neurons through the MAO-mediated conversion of the nonfluorescent tetrahydropyridine compound trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydro pyridine (t-THP) to the corresponding fluorescent trans-1-methyl-4-[4-dimethylaminophenylethenyl]pyridinium species (t-P+) was examined with the aid of human neuroblastoma cells (SH-SY5Y). Fluorescence microscopy and fluorescence measurements established the intracellular formation of a fluorescent species with maximal excitation/emission wavelengths of 485/620 and 530/620 nm corresponding to the fluorescence characteristics of synthetic t-P+. An independent assay confirmed the presence of both MAO-A and MAO-B in these cells. As expected, the development of the fluorescence was inhibited by both clorgyline (an MAO-A inhibitor) and deprenyl (an MAO-B inhibitor). Cytotoxic effects, as determined by trypan blue dye exclusion for viability and by the MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] assay for mitochondrial integrity, were not observed in cells incubated with concentrations of t-THP as high as 10(-3) M for 4 hr. The results from these studies with a neuronal cell line of human origin suggest: (1) that SH-SY5Y cells metabolize and, therefore, can be used for study of tetrahydropyridine compounds in vitro, and (2) that t-THP may be a useful agent to monitor neurodegenerative processes in MAO-rich neurons, including the dopaminergic nigrostriatal neurons that are damaged by the parkinsonian-inducing tetrahydropyrridine MPTP. The potential advantage of using t-THP over related imaging techniques is the possibility of assessing neuronal function by an in vivo processing of the reporter molecule rather than by postmortem immunofluorescent or formaldehyde-based procedures.

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

Pyridine derivatives: structure-activity relationships causing parkinsonism-like symptoms.

In recent years, sufficient evidence has surfaced to implicate low-molecular-weight organic compounds in certain known neurological disorders. At this time, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is considered the compound capable of inducing conditions most similar to idiopathic parkinsonism in clinical, biochemical, and histopathological characteristics. Substances containing MPTP-like fragments are used as herbicides, drugs and intermediates in the synthesis of many heterocyclic compounds. The mechanistic study of toxic MPTP action has enabled development of criteria for appraising potential parkinsonogenic properties of similar chemical structures. Key features of MPTP action include the following: 1. Ability to pass through the blood-brain barrier (BBB). 2. Enzymatic biotransformation to the neuroactive form (pyridine metabolites). 3. Transfer to neurons via a neuromediator reuptake system. 4. Action on intracellular targets. This review discusses data concerning the effects of metabolite structure on the major steps in the neurotropic action mechanism of MPTP-like compounds. Special attention is focused on the key steps defining the selectivity of MPTP's neuronal action, i.e., the activation step caused by monoamine oxidase (MAO) and interaction with the dopamine (DA) reuptake system. Most structural MPTP analogs (including certain pesticide preparations) used in our experiments and described in the literature exhibit no degenerative MPTP-like properties. This is probably related to the fact that each consecutive stage in the MPTP neurotoxicity mechanism makes rather stringent demands on metabolite structure. The number of structures which concurrently meet the requirements of all the processes is finite. This, however, does not invalidate the hypotheses concerning the ecotoxic nature of idiopathic parkinsonism. Possible ecotoxins may have only a partial, presymptomatic effect which, however, promotes age-related neurodegenerative processes and accelerates development of parkinsonism. This concept necessitates designing special tests of the possible neurotoxic properties of compounds found in the environment which may be functional MPTP analogs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Potent neuroprotective and antioxidant activity of apomorphine in MPTP and 6-hydroxydopamine induced neurotoxicity.

Apomorphine is a potent radical scavenger and iron chelator. In vitro apomorphine acts as a potent iron chelator and radical scavenger with IC50 of 0.3 microM for iron (2.5 microM) induced lipid peroxidation in rat brain mitochondrial preparation, and it inhibits mice striatal MAO-A and MAO-B activities with IC50 values of 93 microM and 241 microM. Apomorphine (1-10 microM) protects rat pheochromocytoma (PC12) cells from 6-hydroxydopamine (150 microM) and H2O2 (0.6 mM) induced cytotoxicity and cell death. The neuroprotective property of (R)-apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. (R)-apomorphine (5-10 mg/kg, s.c.) pretreatment in C57BL mice, protects against MPTP (24 mg/kg, i.p.) induced loss of nigro-striatal dopamine neurons, as indicated by striatal dopamine content, tyrosine hydroxylase content and tyrosine hydroxylase activity. It is suggested that the neuroprotective effect of (R)-apomorphine against MPTP neurotoxicity derives from its radical scavenging and MAO inhibitory actions and not from its agonistic activity, since the mechanism of MPTP dopaminergic neurotoxicity involves the generation of oxygen radical species induced-oxidative stress.

Animals↗
PubMed1997

Assessment of neurotoxicity and "neuroprotection".

Coronal brain slices allow the study of neurotoxicity and "neuroprotection" under conditions where the differentiation-state and interrelationships of the neurones and glial cells are closer to those occurring in the intact tissue than is the case for co-cultured cell systems. The involvement of glial cells in the excitotoxicity of kainate and the potentiation of this toxicity by inhibition of glutamine synthase can be demonstrated. Longer-term toxicity of kainate may also be compounded by depletion of glutathione levels resulting from inhibition of gamma-glutamylcysteine synthase. The involvement of nitric oxide formation in the toxicity of N-methyl-D-aspartate can also be shown. The neurotoxicity of 1-methyl-4-phenylpyridinium can be readily demonstrated in coronal slice preparations. Taurine affords protection against this neurotoxicity. The possible mechanisms of these effects are considered in terms of the cyclic interrelationships between the different events which can lead to cell death.

Animals↗
PubMed1993

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates.

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease.

Animals↗
PubMedDate not supplied

Differential effects of acute and chronic nicotine treatment on MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced degeneration of nigrostriatal dopamine neurons in the black mouse.

Evidence exists for a negative correlation between Parkinson's disease and smoking. The present and previous studies indicate that nicotine treatment can markedly alter the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in the black mouse based on biochemical determinations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in neostriatum and substantia nigra 2 weeks after MPTP injection. Acute intermittent treatment with (-)nicotine starting 10 min before the MPTP injection partly protected against MPTP-induced neurotoxicity in the neostriatum and substantia nigra. Also, a partial protection was observed in the substantia nigra when (-)nicotine was given together with MPTP in an acute intermittent treatment schedule. Conversely, chronic infusion of (-)nicotine via minipumps produced a dose-related enhancement of MPTP-induced DA neurotoxicity in the neostriatum. It is suggested that the protective activity of nicotine in the MPTP model is related to a blockade of MPP+ uptake into the DA cells via increased DA release. Conversely, the nicotine enhancement of MPTP-induced DA toxicity is suggested to be caused by a failure of the nicotinic cholinoceptors to desensitize to the chronic (-)nicotine exposure, leading to increased chronic influx of Na+ and Ca2+ ions via the ion channels of the nicotinic cholinoceptors located on the DA neurons with associated increased Ca ion toxicity and increased energy demands.

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

Modifications of precentral cortex discharge and EMG activity in monkeys with MPTP-induced lesions of DA nigral neurons.

1. Individual neurons were recorded extracellularly in the precentral forelimb area of two monkeys trained to perform rapid, large amplitude flexion and extension movements of the contralateral forearm in response to auditory signals. Electromyographic (EMG) activity in the biceps/triceps muscles was recorded separately under the same conditions. The dopaminergic (DA) neurons of the substantia nigra (SN) were destroyed selectively by repeated series of intravenous injections of MPTP. The lesion was verified on serial slices using both tyrosine hydroxylase immunocytochemistry and classical staining methods. 2. In normal monkeys, the frequency of firing of precentral neurons shows rapid changes shortly before the onset of displacement. In our sample (n = 102), most of the neurons (49%) tested during movement in both directions (flexion, extension) showed a reciprocal pattern of activity for the two directions of movement, a small percentage (19%) exhibited a change for only one direction (unidirectional neurons), and the remaining 32% displayed a similar change for both directions of movement (bidirectional neurons). 3. In MPTP-treated monkeys, movement-related modification of neuronal activity was more gradual, beginning earlier and lasting longer relative to the onset of movement. The cellular reaction time (the time between the auditory cue and a significant change in neuronal activity) was not significantly altered. Spontaneous firing of precentral neurons (n = 124) did not increase significantly, and the dynamic discharge rate was unchanged after the nigral lesion. However, only 18% of cortical neurons still presented a reciprocal pattern of discharge for the two directions of movement, while the percentage of unidirectional neurons increased (50%), and the percentage of bidirectional neurons remained the same (32%). 4. After MPTP treatment, alterations in movement parameters and EMG activity were observed. Mean reaction time and movement duration increased by 20-25% and 25-30% respectively. The movements were slower and were associated with a generalized depression in the shape and the amplitude of EMG activity in the agonist muscle. 5. The neuronal basis for the observed central and peripheral disturbance in the MPTP-treated monkeys is discussed. We conclude that SN lesion leads to two main disturbances of cortical activity: i) the loss of the reciprocal pattern of response of movement-related cortical cells, and ii) an inability of the motor cortex to modify its activity in response to peripheral input.

Animals↗