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PubMed1990

Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys.

Chronic low-dose MPTP exposure was previously found to impair cognitive performance in monkeys. These monkeys developed deficits in performance of delayed response and delayed alternation tasks but maintained performance on visual pattern discrimination. This, along with other subtle behavioral changes, occurred in the absence of gross parkinsonian motor symptoms. The present study reports the results of neurochemical and neuropathological examination of the brains of these animals. Chronic low-dose MPTP exposure resulted in profound decreases in caudate dopamine (DA) levels and slightly less severe depletions in the putamen. Increases in striatal HVA/DA ratios suggest an increase in DA turnover in these areas. In contrast to striatal DA depletions, we found significant increases in striatal serotonin levels without an associated increase in serotonin turnover. At the cortical level, we found inconsistent changes in frontal cortical DA levels and variable decreases in norepinephrine levels. Since the most profound and consistent deficits were in the nigrostriatal dopamine system, we suggest that most of the behavioral consequences of chronic low-dose MPTP exposure stem from the striatal dopamine depletion. We also suggest that the maintenance of motor function in the presence of massive striatal DA depletions may be due to less impairment of putamen DA vs. caudate DA, by an increase in striatal DA turnover, a compensatory increase in serotonin availability, or a combination of these and possibly other as yet undetermined compensatory mechanisms. Furthermore, we propose the present model utilizing chronic low-dose exposure to MPTP as a model for the early, compensated form of Parkinson's disease.

Animals↗

PubMed1990

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in goldfish brain.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively damages dopaminergic neurons in mammals, caused a marked depletion of tyrosine hydroxylase (TH) immunoreactivity in the goldfish brain. The concomitant ultrastructural observations showed the neurotoxic effect of MPTP on telencephalic, diencephalic and medullar neurons. The affected neurons revealed darkening of the cytoplasm and swelling of the mitochondria and the endoplasmic reticulum. Concomitant significant decreases in dopamine (DA) and noradrenaline (NA) levels were determined in the brain areas where morphological observations were performed. The loss of catecholamine levels was completely prevented by the treatment with the monoamine oxidase (MAO) inhibitor pargyline to prevent MPTP oxidation. The results indicate that in goldfish brain, acute MPTP administration causes selective catecholamine depletion, without altering the serotoninergic system.

Animals↗

PubMed1990

Contrasting tissue factors predict heterogeneous striatal dopamine neurotoxicity after MPTP or methamphetamine treatment.

Treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or (+)-methamphetamine (METH) results in regionally heterogeneous patterns of dopaminergic depletion. The magnitude of the MPTP-induced dopamine (DA) depletion corresponds directly to the density of [3H]mazindol binding to DA transport sites, but not the DA concentration, in intact mouse striatal regions. In contrast, the extent of METH-induced DA depletion corresponds to the intact dopamine concentration, not the [3H]mazindol binding, in the same striatal regions. The findings provide a rationale for testing different hypotheses regarding the neurobiological substrates of mesostriatal injury in idiopathic Parkinson's disease (PD).

Animals↗

PubMed1990

Astroglial ablation prevents MPTP-induced nigrostriatal neuronal death.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent neurotoxin which destroys nigrostriatal dopamine neurons, resulting in irreversible idiopathic parkinsonism. MPTP displays dopaminergic neurotoxicity to humans, monkeys, cats and rodents. The oxidative conversion of MPTP to 1-methyl-4-phenylpyridine (MPP+) is responsible for the generation of its neurotoxicity. This metabolism is mediated by the action of monoamine oxidase B, which in the substantia nigra pars compacta (SNc) is localized specifically in astroglia. Employing various combinations of intra-SNc injections of MPTP and the astroglia-specific toxin, L-alpha-aminoadipic acid (L-alpha-AA), we examined the effects of selective astroglial ablation on MPTP-induced nigrostriatal neuronal death in the rat. Varying nigrostriatal cell loss was assessed primarily by the aid of fluorescent retrograde axonal tracing. Treatment with MPTP alone caused tremendous nigrostriatal cell loss, while intra-SNc co-injections of MPTP and L-alpha-AA produced protection against MPTP neurotoxicity in a dose-dependent fashion. Similar effects of L-alpha-AA occurred in the SNc pretreated with the gliotoxin just prior to or 1 day before MPTP administration. However, this preventive action by L-alpha-AA was considerably reduced 3 days after its intra-SNc injection. Interestingly, 7 days following L-alpha-AA pretreatment, nigrostriatal cell loss was even enhanced rather than attenuated by MPTP administered into the SNc. Thus, our data provide clear morphological evidence for the critical importance of the presence of astroglia in the onset of MPTP neurotoxicity.

2-Aminoadipic Acid↗

PubMed1990

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis).

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.

Animals↗

PubMed1990

MPTP-induced parkinsonism: relative changes in dopamine concentration in subregions of substantia nigra, ventral tegmental area and retrorubral field of symptomatic and asymptomatic vervet monkeys.

Dopamine (DA) and homovanillic acid (HVA) concentrations were measured in subregions of substantia nigra, ventral tegmental area and retrorubral field in vervet monkeys 1 to 2 months after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Identical MPTP treatment regimens produced animals with different degrees of parkinsonism. In asymptomatic monkeys, changes in DA and HVA concentrations in the midbrain DA regions were relatively small and involved central substantia nigra and dorsomedial ventral tegmental area. In contrast, changes in symptomatic monkeys were more severe and widespread, significantly affecting all examined subregions of substantia nigra (greater than 75% DA depletion), both dorsomedial and ventromedial ventral tegmental area and lateral, but not medial, retrorubral field. The data indicate that DA neurons in subregions of substantia nigra, ventral tegmental area and retrorubral field are not equally susceptible to MPTP toxicity. The pattern of MPTP-induced DA and HVA losses in the vervet monkey mesostriatal dopaminergic system may resemble postencephalitic Parkinson's disease more closely than idiopathic Parkinson's disease.

Animals↗

PubMed1990

Evaluation of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mouse model for parkinsonism.

We evaluated neurochemically, behaviorally, and neuropathologically the availability of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black (BL) mice as a model for Parkinson's disease. The dopamine and 3,4-dihydroxyphenyl acetic acid content in the striatum, measured by high-performance liquid chromatography with an electrochemical detector, decreased by 70% at 10 and 20 days after the withdrawal of MPTP (30 mg/kg, i.p. twice daily for 5 days). During these days, the mice showed a decrease in locomotor activity and exhibited akinesia in both pole and traction tests. Light microscopically, 44% of the MPTP-treated mice showed neuronal degeneration in the substantia nigra 1 month after the withdrawal (damaged group), and 56% showed no change (undamaged group). Morphometric analysis revealed that the number of neurons in the substantia nigra decreased by 33% on the average in both groups. Electron microscopically, an electron-dense degeneration of most neurons was seen in the substantia nigra of the damaged group, and even in the undamaged group, loss of rough endoplasmic reticulum and mitochondrial deformity were seen in 50-70% of the neurons. Electron-dense bodies were seen in the striatum of both groups. These results show the validity of the MPTP-treated C57 BL mice as a suitable model for parkinsonism, including Parkinson's disease.

Animals↗

PubMed1990

A novel effect of MPTP: the selective suppression of paradoxical sleep in cats.

We studied the effect of MPTP on sleep-wakefulness cycle in cats. Five mg/kg n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered i.p. for 5 consecutive days. Electrocorticographic, electrooculographic and electromyographic recordings were performed before (5 days), during (5 days) and after (14 days) the treatment. Total selective paradoxical sleep deprivation was observed from the first injection. This effect lasted 6-9 days after the last dose, while the relative amount of slow wave sleep increased. The Berg-Fourier analysis showed no significant change in the EEG power spectra of slow-wave sleep during the paradoxical sleep deprivation compared to control period. Recurrence of paradoxical sleep was parallel to the disappearance of the motor symptoms. Histopathological investigation showed neuronal loss mainly in the substantia nigra. Our present study suggests a complex behavioral effect of MPTP.

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

PubMed1990

Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP.

In order to determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuronal death or the loss of tyrosine hydroxylase (TH) immunoreactivity, 4 catecholaminergic nuclei in the mouse: substantia nigra compacta (SNc), locus coeruleus (LC), ventral tegmental area (VTA) and the A13 nucleus in the hypothalamus were quantitatively examined. Serial sections were taken through the rostrocaudal extent of each nucleus: alternate sections were incubated with TH antiserum and reacted with an immunoperoxidase technique while the alternate set was Nissl stained. Counts and 3 dimensional reconstructions of TH reactive somata were made for each nucleus for saline-treated controls and mice treated with different doses of MPTP (37.5, 75, 150 and 300 mg/kg). TH-positive neurons were counted along with their counterparts on the Nissl-stained alternative sections to both identify the catecholaminergic neurons and to measure their destruction. Concentrations of striatal dopamine and cortical norepinephrine were measured for all dosages of MPTP in order to determine the relationship between dosage, target tissue neurotransmitter concentration and neuronal destruction. By 20 days after MPTP injection there was a dose-dependent random loss of TH-immunoreactive neurons that was almost identical in all 4 nuclei examined. Analysis of the Nissl versus TH cell counts revealed that MPTP resulted in neuronal destruction in the SNc and the LC rather than just a loss of TH immunoreactivity. There was no difference in sensitivity to MPTP between the SNc and the LC. Decreases in cortical norepinephrine concentrations were about one third of the decreases of LC neuronal counts for all MPTP doses; while decreases in striatal dopamine and SNc cell loss was similar to the LC for the two lower doses of MPTP but for the higher doses, the relationship approached or exceeded a one to one ratio. Hence estimates of neuronal death based upon target tissue transmitter concentrations could not be made using the same relationship for SNc and the LC catecholaminergic neurons and use of the same relationship for higher MPTP dosages results in an underestimate of LC neuronal destruction relative to that in the SNc.

Animals↗

PubMed1990

MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells.

To determine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alters the tyrosine hydroxylase (TH) immunoreactivity of murine dopaminergic retinal amacrine cells, 8-10-week-old C57BL/6J mice were treated with i.p. with saline or cumulative doses of MPTP ranging from 10 to 300 mg/kg. Paraformaldehyde-fixed retinal whole mounts and cross sections were examined using immunochemistry with a tyrosine hydroxylase (TH) or a choline acetyltransferase (ChAT) polyclonal antibody and an avidin-biotin peroxidase reaction. Both TH+ amacrines and ChAT+ retinal neurons showed somal and process morphology and distributions that were commensurate with previous studies of the same or several related species. At 20 days following the MPTP treatment, there was a loss of TH+ amacrines according to a logarithmic relationship relative to MPTP dosage. The loss ranged from 18 to 87% for the dosage range without any decrease in the numbers of ChAT+ neurons. The TH+ amacrines were deleted randomly from the retinas without any peripheral-central predilection. By 273 days after MPTP treatment, the number of TH+ amacrines had returned to values found for age-matched controls demonstrating that the loss of TH immunoreactivity was reversible and occurred without destruction of TH+ amacrines. Computer densitometry revealed that the MPTP-treated TH+ amacrines were divided into two distinct populations: one with normal TH immunodensity levels and a second with TH immunodensity levels below our detection capability. Increasing the MPTP dosage increased the proportion of TH amacrines in the second population. The transient and completely reversible disappearance in the number of TH+ amacrines: (1) appears to form the basis for the decreased concentrations of dopamine and the loss of catecholamine fluorescent neurons previously described for MPTP-treated mouse retinae; (2) may underlie the defects in the electroretinograms of MPTP-treated monkeys, and (3) may result as a response to neurite damage similarly to the alterations in protein synthesis in other central neurons following axonal damage.

Animals↗

PubMed1990

3-Acetylpyridine results in degeneration of the extrapyramidal and cerebellar motor systems: loss of the dorsolateral striatal dopamine innervation.

3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), potently inhibited in vitro MAOB activity and in contrast weakly inhibited MAOA activity. However, in vitro inhibition of MAOB by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.

Animals↗

PubMed1990

Gangliosides prevent MPTP toxicity in mice--an immunocytochemical study.

The role of gangliosides in preventing neuronal degeneration was examined in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse parkinsonian model. Intraventricular injections of a ganglioside mixture prior to MPTP treatment reduced MPTP's toxicity on tyrosine hydroxylase-positive neurons in the substantia nigra. This raises the interesting possibility that early ganglioside administration may be beneficial in the treatment of neurodegenerative disorders.

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

PubMed1990

Effects of MPTP on the fine structure of neurons in substantia nigra of dogs.

This study evaluates fine structural changes in neurons from pars compacta of substantia nigra in dogs 1 and 4 days after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The toxin induced a disruption and high amplitude swelling of mitochondria, and dispersion of rough endoplasmic reticulum at 4 days. Mitochondria in dendrites were less damaged than those in the soma. Swelling of myelinated axons in the nigrostriatal pathway was evident at 1 and 4 days after injection. Similar morphologic changes are produced by axotomy and inhibitors of mitochondrial function.

Animals↗

PubMed1990

Characterization of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We used the dopaminergic neurotoxicant, 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), as a tool to characterize the origins of astroglial response to injury. Radioimmunoassay of the astrocyte protein, glial fibrillary acidic protein (GFAP), was used to quantify the astrocyte reaction to MPTP. Assays of neuron-localized proteins and of dopamine were used to assess neuronal damage caused by MPTP. A single administration of MPTP (12.5 mg/kg, s.c.) to the C57BL/6J mouse resulted in more than a 3-fold increase in striatal GFAP within 48 h, followed by a decline to baseline at 3 weeks. A decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of dopaminergic neurons, preceded the rise in GFAP. The concentration of striatal DARPP-32, a phosphoprotein enriched in neurons receiving dopaminergic input, was not affected by MPTP. Protecting the dopaminergic neurons from the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), either by blocking its formation or by preventing its uptake into dopaminergic neurons, completely blocked the increase in GFAP. MPTP did not appear to disrupt the blood-brain barrier, therefore, blood-borne elements probably did not mediate the increase in GFAP. In addition, immunoblot data indicated that brain-derived interleukin 1, an astrocyte growth factor, also did not play a role in MPTP-induced gliosis. Together, these findings suggest that diffusible factors derived from damaged dopaminergic neurons initiate the astrocyte response to MPTP and that large increases in GFAP can be induced without the participation of serum-derived growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effects of internal carotid administration of MPTP on rat brain and blood-brain barrier.

Unlike primates, rats are resistant to systemic 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) neurotoxicity, but direct infusion of MPTP into rat substantia nigra causes specific destruction of dopaminergic neurons. We now demonstrate that rats are resistant to MPTP neurotoxicity even when MPTP is injected directly into the brain circulation. Injection of 1-3.5 mg of MPTP into the internal carotid artery of Wistar rats causes no behavioral or motor abnormalities and small, but significant, dopamine loss in the ipsilateral striatum. MPTP caused no changes in the levels of norepinephrine or serotonin in the cerebral cortex. Higher doses of intracarotid MPTP were lethal. Pretreatment with pargyline, a monoamine oxidase inhibitor, did not alter the mortality but prevented dopamine depletion. The high uptake and retention of MPTP by rat brain, yet its failure to cause major dopaminergic toxicity suggest that MPTP is rapidly metabolized in brain capillaries to 1-methyl-4-phenylpyridinium (MPP+) and other polar metabolites that have difficulty in traversing the blood-brain barrier. Sequestration of MPTP metabolites in brain capillary endothelial cells could result in their dysfunction. However, we found no defects in the ability of the blood-brain barrier to prevent the entry of vascular aminoisobutyric acid or horseradish peroxidase into brain in spite of morphologic evidence of endothelial changes and astrocytic swelling after intracarotid MPTP injections. Our results provide further evidence that the rat's resistance to systemic MPTP neurotoxicity is probably due to its unique blood-brain barrier properties.

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

PubMed1991

Protection and potentiation of MPTP-induced toxicity by cytochrome P-450 inhibitors and inducer: in vitro studies with brain slices.

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes loss of dopaminergic neurons in humans, primates and mice. Exposure of sagittal slices of mouse brain to MPTP (100 pM) caused inhibition of mitochondrial NADH-dehydrogenase activity. Leakage of lactate dehydrogenase from the slice into the medium was observed following incubation of slices with 1 nM MPTP. Neurotoxicity induced by MPTP was prevented by prior exposure of the slices to the dopamine uptake inhibitor GBR 12935. Deprenyl and pargyline (inhibitors of monoamine oxidase), also protected the slices from MPTP-induced toxicity. However, both pargyline and deprenyl also inhibited cytochrome P-450 mediated aminopyrine N-demethylase activity in brain slices. Pargyline, when administered in vivo to mice, decreased brain cytochrome P-450 levels significantly. Other cytochrome P-450 inhibitors, namely, piperonyl butoxide and SKF 525A were found to offer protection against MPTP induced neurotoxicity in slices without affecting monoamine oxidase activity. MPTP toxicity was potentiated significantly in brain slices prepared from mice pretreated with phenobarbital, an inducer of cytochrome P-450. The present study suggests the possible involvement of cytochrome P-450 in MPTP-induced neurotoxicity, in vitro, in brain slices.

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

PubMed1991

Correlation of MPTP neurotoxicity in vivo with oxidation of MPTP by the brain and blood-brain barrier in vitro in five rat strains.

We studied 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in 5 strains of rats by assessing mortality and brain monoamine changes after MPTP injections into the internal carotid artery. We then attempted to correlate the differences among rat strains in their susceptibility to MPTP neurotoxicity in vivo with MPTP oxidation by monoamine oxidase (MAO) of the cerebral cortex, striatum, and brain microvessels in vitro. Despite the fact that the carotid route delivers much higher amounts of MPTP to the ipsilateral cerebrum than can be achieved by systemic injections, no significant dopamine depletion occurred in ipsilateral striata of Sprague-Dawley rats (the most resistant strain), but significant reductions of about 40% in striatal dopamine were evident in the more sensitive strains. Decreased striatal dopamine levels in these latter rat strains were associated with increased dopamine turnover. Higher doses of MPTP resulted in acute death. MPTP-induced mortality was not affected, but striatal dopamine depletion was prevented, by MAO inhibition. Differences among rat strains in their susceptibility to MPTP neurotoxicity correlated best with MAO activity in their isolated brain microvessels, but not with MAO activity in their striata or cerebral cortices. These results are consistent with the hypothesis that the rats' resistance to MPTP neurotoxicity is to some extent a property of their unique brain endothelium which has high MAO activity.

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

PubMed1991

Extensive loss of brain dopamine and serotonin induced by chronic administration of MPTP in the marmoset.

Common marmosets were given a subcutaneous injection of MPTP (1.25-2.5 mg/kg twice a week) for 5 or 10 consecutive months and were sacrificed after a survival time of 6 months or 15 days, respectively. The parkinsonian symptoms were not very marked at the time of sacrifice but there was a strong decrease of dopamine and, to a lesser extent, of its metabolites in the striatum and in some extrastriatal regions. There was also a profound loss of serotonin in the striatum and in all of the extrastriatal regions analyzed, which was still highly significant 6 months after discontinuation of MPTP treatment. The results suggest that the selected dosage schedule produces a widespread and lasting neuronal degeneration closely resembling the neurochemical pathology of Parkinson's disease.

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