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.     

Bladder hyperreflexia induced in marmosets by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

In marmosets, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes degeneration of the cell bodies of the substantia nigra and the animals subsequently develop parkinsonian symptoms. Cystometrograms obtained from such animals while under pentobarbitone anaesthesia, showed their bladders to be hyperreflexic when compared to those of normal animals of the same age (less than 2 years). Bladder hyperreflexia is present in many parkinsonian patients and is difficult to treat, partly because it is made worse by dopaminergic agents. This is the first demonstration of an effect of MPTP on this type of peripheral function. It suggests the suitability of MPTP-treated marmosets for studying the mechanisms by which a loss of nigrostriatal dopamine leads to bladder hyperreflexia and for devising pharmacological strategies which may be of therapeutic value in the clinic.     

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.     

Experimental parkinsonian syndrome induced in rats by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Laboratory of General Pathology of the Nervous System, Research Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR. Laboratory of Synthesis of Active Compounds and Laboratory of Psychopharmacology, Research Institute of Pharmacology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 105, No. 4, pp. 397–401, April, 1988.     

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     

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.     

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     

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.     

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.     

Effect of interferon on the development of parkinsonism induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl/6 mice

The administration of reaferon, a recombinant α-interferon preparation, hampers the development of parkinsonism caused by MPTP administration in C57Bl/6 mice. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 121, No. 5, pp. 503–505, May, 1996     

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.     

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     

Potential mechanisms of neuroprotection induced by low dose total-body γ-irradiation in C57 mice administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Low dose total-body γ-irradiation (TBI) was reported to confer neuroprotection against MPTP-induced dopaminergic neurotoxicity. After being pretreated with a single low dose (0.5 Gy, 2.0 Gy or 3.5 Gy) TBI, C57BL/6 mice were administered with MPTP (15 mg/kg, four times, 2 h apart) intraperitoneally (i.p.). In the group pretreated with 2.0 Gy TBI, with lower lymphocytes number, neuroprotection was found by High Performance Liquid Chromatography (HPLC) determination of the striatal dopamine. Contrarily, in the group pretreated with 0.5 Gy TBI, with higher lymphocytes number, dopaminergic neuron toxicity was enhanced. So it was probably the decrease of lymphocytes, not the radiation hormesis that rendered the potential neuroprotection. And it was the balance between radiation injury and lymphocytopenia neuroprotection that decided the effect of low dose γ-irradiation on MPTP-induced dopaminergic neurotoxicity.     

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     

Immunohistochemical detection of GABA in rat striatum by intraperitoneal injection of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

To study MPTP-induced muscular rigidity, we try to detect the changes of both dopamine (DA) and GABA within rat striatums by immunohistochemical means. A high dose (30 mg/kg) of MPTP i.p. injected into rats produces behavioral abnormalities (tremor and ataxia), and higher doses (greater than 60 mg/kg) develop an acutely muscular rigidity without producing a measurable histological change. GABA is induced in the striatum of 4 MPTP (30 mg/kg) i.p. treated-rats developed tremor and ataxia. But the animals recovered to an apparently normal state and are not showed GABA-immunoreactivity. Dense GABA-immunoreactivity is observed in the striatum developed muscular rigidity, when the animals are injected with 60 mg/kg MPTP i.p.. At this time, their striatums show slight decrease of DA-immunoreactivity in medium sized-spiny neurons. The results give some insight as to how DA and GABA function within the striatum with respect to the development of neuronal abnormalities. It is also suggested by our behavioral and immunohistochemical studies that effects induced by the depletion of DA within the striatum may be mediated through the inhibition of the striato-nigral GABAergic pathway, which in turn may lead to an activation of the nigrothalamic or nigro-collicular GABAergic pathway. This study indicates that the role of striatal GABAergic transmission is important in the development of muscular rigidity. The activity within the striatum can be followed with immunohistochemical technique for GABA morphologically.     

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     

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.     

Ability of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and some other pyridine derivatives to cause parkinsonism

Institute of Physiologically Active Substances, Academy of Sciences of the USSR, Chernogolovka, Moscow Region. (Presented by Academician of the Academy of Medical Sciences of the USSR, I. P. Ashmarin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 6, pp. 699–701, June, 1989.     

The dopamine D2 agonist LY 141865, but not the D1 agonist SKF 38393, reverses parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset

Marmosets treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p. daily for up to 8 days) develop profound parkinsonian akinesia. Administration of the D1 agonist SKF 38393 (1-20 mg/kg i.p.) 4-6 weeks later had no effect on the motor activity of animals pretreated with MPTP. In contrast, the administration of the D2 agonist LY 141865 (0.1 or 0.5 mg/kg i.p.) caused a marked increase in motor activity lasting for up to 2 h. We conclude that stimulation of D2 dopamine receptors is essential for motor activation of parkinsonian marmosets and that D1 stimulation alone is not sufficient to overcome the akinesia induced by MPTP treatment.