Effects of buspirone on experimental depressive syndrome induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats

It is shown that pretreatment with buspirone 45–60 min prior to MPTP administration performed daily for 12 days prevented or weakened the development of depressive symptoms in rats. Specifically, it prevented a reduction of daily water intake, weakened the preference for sugar solution over water, and, to a lesser degree, shortened the increase in the duration of immobilization and lowered the index of depression in the forced swimming test, but did not affect the drop in motor and exploratory activity. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 5, pp. 489–494, May, 1996     

Early and late effects of systemically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on tyrosine hydroxylase activity in vitro and on tyrosine hydroxylation in tissue slices of mouse striatum

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a parkinsonian-like state in humans and some animals. To compare the early biochemical abnormalities produced by this neurotoxin with late effects, we examined both in vitro tyrosine hydroxylase activity in striatal homogenates and in situ tyrosine hydroxylation in striatal tissue slices after single and repeated systemic injection of MPTP to mice. The acute administration of MPTP (30 mg/kg, s.c., 1 h prior to sacrifice) in mice resulted in a decrease of tyrosine hydroxylation in situ in tissue slices but not in vitro in homogenates. In contrast, repeated treatment of mice with MPTP (30 mg/kg, s.c. daily for 8 days) caused a decrease of tyrosine hydroxylase activity both in vitro in homogenates and in situ in tissue slices. These results suggest that MPTP inhibits tyrosine hydroxylation in dopaminergic neurons in an early stage and causes reduction of tyrosine hydroxylase itself after repeated administration.     

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on ultrastructure of nigral neuromelanin in Macaca fascicularis

In neurons of the substantia nigra (SN) of Macaca fascicularis the administration of parkinsongenic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused morphological changes of the neuromelanic granules. Under light microscopy, the granules appeared more dispersed and larger. Electron microscopy revealed coalescence of granules in large masses with loss of the electrodense component. Phagocytosis of neuromelanin by glial cells was also observed. In several neurons the neuromelanic changes were evident in the presence of morphologically intact mitochondria. These data suggest an interaction between MPTP and neuromelanin that may have relevance to the nigrotropic toxicity of MPTP and are in agreement with observations on neuromelanin in parkinsonian patients.     

The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome that resembles Parkinson's disease. To compare the biochemical abnormalities produced by this compound in human beings with those occurring in Parkinson's disease, we examined biogenic amine metabolites in cerebrospinal fluid and urine from six patients with MPTP-induced parkinsonism and eight patients with Parkinson's disease. In both forms of parkinsonism, the cerebrospinal fluid levels of homovanillic acid, the major metabolite of dopamine, were reduced, whereas the levels of the serotonin metabolite 5-hydroxyindoleacetic acid were normal. The cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine in the brain, after adjustment for plasma MHPG, were elevated (greater than 6.0 ng per milliliter) in MPTP-induced parkinsonism, whereas MHPG levels were reduced (less than 6.0) in Parkinson's disease. Neurons containing norepinephrine in the brain are involved in the degenerative process of Parkinson's disease, whereas they are spared in MPTP-induced parkinsonism. The selective destruction by MPTP of nigrostriatal dopamine neurons that is responsible for the movement disorder also appears to result in an increase in central noradrenergic activity, which is not possible in Parkinson's disease. Thus, differences in central noradrenergic activity, reflected in cerebrospinal fluid levels of MHPG, distinguish these two forms of parkinsonism.     

REM sleep disorders in rats with experimental depressive syndrome caused by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Rats receiving daily injections of the neurotoxin MPTP in a dose of 20 mg/kg for 12 days develop disorders of REM sleep, including increased frequency of REM-sleep episodes, decreased REM latency, and increased REM sleep duration, both absolute and relative. The first two of these REM sleep disorders are characteristic of endogenous depression. The results indicate that systemically administered MPTP causes a state similar to endogenous depression. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 2, pp. 138–142, February, 1997     

Effect of melipramine on the development of experimental depressive syndrome induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The effects of chronic administration of melipramine on the development of behavioral signs of depression in rats are studied using the model of a depressive syndrome induced by systemic administration of MPTP. Preadministration of melipramine prevents such MPTP-induced behavioral signs of depression in rats as decreased motor activity, reduced total daily liquid intake, reduced preference of sucrose solution over water, and increased depression index. Translated fromByulleten' Eksperimental'noi Giologii i Meditsiny, Vol. 120, N ^o . 8, pp. 160–163, August, 1995     

Acute ultrastructural and behavioral effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice

Acute actions of MPTP on behavior and on neostriatal ultrastructure were examined in young C57 Black mice. Autonomic, motor, and toxic effects of MPTP exhibited dependence on dose (20-40 mg/kg) and time during the first 4 h after subcutaneous injection. The ultrastructure of the neostriatum was altered very quickly (2-24 h) after single injections of MPTP. Darkened glial processes were found within 2-8 h, followed by dark degeneration of synaptic boutons, especially those making small symmetric synapses. More rarely, swollen axons and postsynaptic degeneration were also observed.     

A new model of the depressive syndrome induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats

Animals treated with MPTP neurotoxin displayed lowered motor and exploratory activity in the open field test, reduced daily intake of water with a preference for sugar solution over water, prolonged immobilization, and increased index of depression in the forced swimming test. The changes in rat behavior were preserved for at least a week after withdrawal of the drug. The data attest to the development of a state of lowered motivational activity combined with ahedony and “behavioral despair” in response to MPTP, making it possible to consider this state as a new experimental model of dopamine-dependent depressive syndrome in rats. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, N ^o 2, pp. 125–128, February, 1995     

The ex vivo effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on rat intra- and extraneuronal monoamine oxidase activity

After i.p. injection of 30 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) daily for 4 days and sacrificing the rats 4 h after the last injection, striatal monoamine oxidase (MAO)-A and -B activities, assayed by conventional method with 5-hydroxytryptamine (5-HT) and benzylamine, were not changed. By an uptake technique, with dopamine as the substrate for both uptake and MAO, intrasynaptosomal MAO-A and -B activities were found to be greatly reduced with a greater MAO-A reduction. Intrasynaptosomal 5-HT oxidation by MAO-A was not changed in other forebrain regions treated with these MPTP doses. Similar results were also found with two brain preparations treated with single MPTP doses (30 mg/kg). This reduction in intrasynaptosomal MAO activity was completely absent after treatment with lower MPTP doses (15 mg/kg, daily for 5 days) and 5 days of a withdrawal period. The decrease in MAO activity might have been due to the decrease in DA transport into striatal synaptosomes during the enzyme assay and/or to reversible inhibition of intrasynaptosomal MAO by MPP+.     

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.     

Destruction of norepinephrine terminals in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice reduces locomotor activity induced by L-dopa

There is little information concerning the effects of norepinephrine (NE) depletion on clinical features of patients with Parkinson's disease. By inducing two types of experimental parkinsonism, one with a dopamine (DA) deficiency alone and the other with both a DA and NE deficiency, we attempted to evaluate the differences in locomotor activity and behavioral responses between the two groups after L-DOPA administration. The results of the study revealed that increases in locomotor activity were markedly suppressed in the DA and NE deficient group. This may suggest that with striatal DA deficiency the central NE terminals play a significant role in the increase in locomotor activity after L-DOPA administration.     

Immunohistochemical evaluation of the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on dopaminergic nigrostriatal neurons of young adult mice using dopamine and tyrosine hydroxylase antibodies

The recovery of dopamine (DA) neurons in young adult mice from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damage was analyzed at various times after MPTP treatment with DA and tyrosine hydroxylase (TH) immunohistochemistry and also by chemical DA assay. A remarkable discrepancy in the recovery rate of DA and TH reactivities of the nigral neurons was observed: the TH immunoreactivities of both cell bodies in the substantia nigra and terminals in the neostriatum were markedly reduced 4 days after MPTP. However, these reactivities progressively improved and almost fully recovered after 25 days, while the DA immunoreactivities were maximally depleted 10 days after, and the depletion continued even through the 25th day. The alteration of DA levels was correlated with that of DA immunoreactivity. These findings suggest that a major effect of MPTP on the DA neurons of young adult mice is a transient neurotoxicity, and that the TH content improves more promptly than that of DA.     

Time-dependent inhibition of rat brain monoamine oxidase by an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine

Inhibitory effects of some MPTP and MPP+ analogues on rat brain MAO activity were studied to further clarify the structure-activity relationships of MPTP neurotoxicity. Of the analogues tested, 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (CPTP), 4-(4-chlorobenzyl)-pyridine (CBP), 4-benzylpyridine (BPY) and 4-benzylpiperidine (BPIP) dose-dependently inhibited both MAO-A and -B activities. CPTP, BPY and BPIP showed a higher MAO-A selectivity, while CBP was a selective MAO-B inhibitor. In preincubation studies, only CPTP greatly enhanced the degree of inhibition of MAO-B when the preincubation time was increased, but inhibition of MAO-A was not enhanced. Together with our previous MPTP and MPP+ analogue findings, the present results indicate that, in these chemical structures, a 4-phenyl-1,2,3,6-tetrahydropyridine ring is most essential for time-dependent inhibition of MAO. This chemical requirement is consistent with the ability to cause nigrostriatal dopaminergic neurotoxicity.     

Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice

The protective effects of 2-amino-6-trifluoromethoxy benzothiazole (riluzole), a Na(+) channel blocker with antiglutamatergic activity were investigated in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed at 3 and 7 days after the treatments. Dopamine, DOPAC and HVA levels were significantly decreased in the striatum 3 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. MPTP treatment also caused a severe decrease in the amount of nigral tyrosine hydroxylase protein (TH) and microtuble-associated protein 2 (MAP 2) and produced a marked increase in the striatal glial fibrillary acidic protein (GFAP). Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway. Our findings also may provide a rationale for the identification of astrocytes as a prominent target for the development of new therapies of Parkinson's disease.     

Central hypothermic effects of some analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+)

Effects of some MPTP or MPP+ analogues on mouse body temperature were studied. Of the analogues tested, 4-phenylpyridine (PPY) and 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) given in single i.p. doses to mice caused marked hypothermia. Intracerebroventricular (i.c.v.) injection of PPY or PTP caused similar hypothermia. Pretreatment with clorgyline or (-)-deprenyl greatly prevented hypothermia induced by i.c.v. PPY, but hypothermia by i.c.v. PTP was prevented only by (-)-deprenyl. These results indicate that, in order to cause central hypothermia, PTP does not seem to require metabolism to PPY and both analogues per se may cause hypothermia.     

Injury of nigral neurons exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a tyrosine hydroxylase immunocytochemical study in monkey

Six monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine developed a Parkinsonian syndrome (rigidity, akinesia, flexed posture and tremor). In both high and low dose groups, neurons in the substantia nigra were selectively damaged. At high dose levels, nigral neurons were severely damaged, but because the monkeys died, the evolution of the pathology could not be studied. At low dose levels, some nigral neurons survived, and a significant number of these nerve cells showed reductions in the immunoreactivity of tyrosine hydroxylase. Axonal pathology was conspicuous in the nigrostriatal pathway. Loss of the immunoreactivity of tyrosine hydroxylase in perikarya may represent a retrograde axonal reaction, a potentially reversible response. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model should prove useful for investigating abnormalities occurring as a consequence of dysfunction of the nigrostriatal system, for examining processes associated with repair of damaged neuronal systems, and for developing and testing therapeutic approaches designed to prevent or ameliorate the Parkinsonian syndrome.     

Effect of parlodel on the development of a depressive syndrome induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rats

Effects caused by the chronic administration of Parlodel on the development of behavioral signs of depression in rats are studied using the new model of depressive syndrome induced by the systemic administration of MPTP. Pretreatment with Parlodel prevents locomotor depression, weight loss, reduction of liquid intake, a decline of the preference of sucrose solution over water, and a rise of the depression index and promotes a quicker restoration of exploratory activity, i.e., it safeguards rats from manifestating the behavioral signs of MPTP-induced depression. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 7, pp. 66–70, July, 1995     

Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

BACKGROUND. Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism. METHODS. We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation. RESULTS. Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications. CONCLUSIONS. Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.