Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5–2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. these drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.     

Transplacental effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on brain dopaminergic neurons in the mouse

Summary Immunohistochemical studies of monoamme neurons werè performed to evaluate toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on young adult mice and compare them with chose of their offspring. Mice, 9–11 weeks old (C57BL/6J), injected subcutaneously with a large dose of MPTP (17 mg/kg per day) during pregnancy on Day 9 and 12 of gestation (G9 and G12) miscarried and were examined at 13 weeks of age. Conversely, mice treated during pregnancy with sequential low dose of MPTP (2.8 mg/kg per day at G9–G17 for 8 days) successfully delivered their babies and were examined at the age of 15 weeks. Baby mice were examined at 1 and 6 weeks of age. The tyrosine hydroxylase-, aromatic l-amino acid decarboxylase-and dopamine (DA)-immunoreactive density of caudoputamen was reduced in 13-week-old mice treated with high dose of MPTP but not in the 15-week-old mothers exposed to a low dose of MPTP as compared to their respective controls. The DA-immunoreactive density of the caudoputamen was the only staining that was reduced in both 1- and 6-week-old baby mice. In conclusion, these results demonstrate that MPTP injected to pregnant mice causes a DA depletion in the striatum of their offspring indicating a transplacental effect of MPTP. The findings also indicate that fetal brain is more susceptible to MPTP toxicity than the brain of young pregnant mice.Supported by Grant-in-Aid for Scientific Research on Priority Areas, Ministry of Education, Science and Culture, Japan (62623002, 62480226), and by a Fujita-Gakuen Health University Grant, Japan     

Expression of c-Jun in dopaminergic neurons of the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice

The expression of c-Jun in the brains of young (8-week-old) and older (52-week-old) mice following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was investigated immunocytochemically. Both age groups exhibited reduction in the number of dopaminergic neurons in the substantia nigra after administration of MPTP. There was a significant difference in the magnitude of decrease in the number of dopaminergic neurons between the two groups, as has previously been reported, and the older mice exhibited more extensive loss of dopaminergic neurons in the substantia nigra after MPTP administration than did the young mice. Prolonged c-Jun expression was induced in the substantia nigra following administration of MPTP, and this induction was more prominent in the older mice than in the young mice. Maximum expression of c-Jun occurred on day 7 after the administration of MPTP in both groups. Double staining for tyrosine hydroxylase (TH; a dopaminergic neuron marker) and c-Jun revealed their co-localization indicating that the cells expressing c-Jun were dopaminergic neurons. Cytoplasmic volumes of strongly c-Jun positive cells were reduced, suggesting that they may have been degenerating. In situ end labeling revealed no apoptotic neurons after MPTP administration. These results suggest the existence of some cascade mechanism of nonapoptotic death of dopaminergic neurons following administration of MPTP.     

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enhances tryptophan hydroxylase activity in mouse striatum, but not in the frontal cortex

We measured serotonin (5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA) contents and tryptophan hydroxylase (TPH) activity in mouse striatum and frontal cortex after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (7 daily injections of 30 mg/kg). In the striatum, TPH activity was increased for at least 4 weeks after injection of MPTP, along with an increase in 5-HIAA. However, no significant change was observed in 5-HT, 5-HIAA or TPH activity in the frontal cortex. These results suggest that MPTP affects 5-HT through a change in TPH activity, specifically at nerve terminals in the striatum.     

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 alectrochemical 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 fro parkinsonism, including Parkinson's disease.     

Pharmacological effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopamine receptor system

In mice, chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an increase in the maximum number of [³H]spiperone binding sites in the striatum. The sensitivity of striatal protein phosphorylation to calcium plus calmodulin is also potentiated in MPTP-treated mice. These observations are associated with an enhancement of apomorphine-induced climbing behavior in the drug-treated animals. The results of this study suggest that in an animal model for Parkinson's disease, MPTP interrupts the dopamine (DA) transmission by chemically denervating the nigrostriatal neurons and through a compensatory mechanism, it increases the number of DA receptors as well as the sensitivity of protein phosphorylation to calcium plus calmodulin in mouse striatum. The latter two events may contribute to the development of DA receptor supersensitivity.     

Reversible serotoninergic neurotoxicity ofN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse striatum studied by neurochemical and immunohistochemical approaches

Effects ofN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on serotonin (5-HT) were studied in mouse striatum. The 5-HT level was significantly reduced at 1 week after MPTP, though returned at 4 weeks. The level of 5-hydroxyindoleacetic acid (5-HIAA) increased at both 1 and 4 weeks. The ratio of increase in 5-HT induced by pargyline administration was larger in MPTP-pretreated mice than in vehicle-pretreated controls at 1 week, although it was identical in both groups at 4 weeks. The 5-HT immunohistochemical study confirmed the biochemical change of 5-HT. These results suggest that MPTP functionally affects the 5-HT metabolism in mouse striatum.     

Dopamine-releasing action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridine (MPP) in the neostriatum of the rat as demonstrated in vivo by the push-pull perfusion technique: dependence on sodium but not calcium ions

This study examined the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite, 1-methyl-4-phenylpyridine (MPP+) on the levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in push-pull perfusates of the striatum in chloral hydrate-anaesthetized rats. In control animals the levels of DA and DOPAC remained stable for at least 6 h and responded rapidly to a depolarizing stimulus of 25 mM K+. This K+-induced DA release was Ca2+-dependent since no stimulation was observed when the striatal sites were perfused with high K+ in a Ca2+-free medium containing 2 mM EGTA thus verifying that the striatal sites were functionally active. MPTP (0.025 and 0.05 microgram/microliter) stimulated DA release and inhibited DOPAC output in a dose-related manner. MPP+ (0.01, 0.025 and 0.05 microgram/microliter) produced a more robust dose-dependent increase in DA levels in the perfusates; however, the level of suppression of DOPAC was similar to that in response to MPTP. The effect of MPP+ on DA release was attenuated by 10(-6) M benztropine, the DA re-uptake blocker and completely inhibited by 10 micrograms/kg i.p. benztropine and 10(-4) M ouabain, the Na+, K+-ATPase (Na pump) inhibitor. However, although these substances prevented the MPP+-induced release of DA, the levels of DOPAC in the perfusates did not recover and remained completely suppressed suggesting that MPP+ may inhibit extraneuronal rather than intraneuronal monoamine oxidase (MAO). Perfusion of the striatal sites with a Ca2+-free medium containing 2 mM EGTA did not prevent the MPP+-induced DA release indicating that MPP+ does not release DA from the striatal DA terminals by the Ca2+-dependent process of exocytosis. The responses of DA and DOPAC to 25 mM K+ were markedly suppressed in animals treated with MPTP and MPP+, these effects being most severe with the highest dose of MPP+. Moreover, this suppression of the K+-induced responses persisted in animals perfused with MPP+ in the presence of benztropine or ouabain, thus suggesting that MPP+ may have potent deleterious membrane effects. These studies have provided the first direct in vivo demonstration of the action of MPTP and MPP+ and the neuropharmacological basis of this action on DA metabolism in the rat striatum. The results show that the elevated levels of DA in the striatal perfusates are due to a direct action of MPTP and MPP+ on the nigrostriatal DA terminals and cannot be fully accounted for solely by their inhibition of MAO activity and/or inhibition of DA re-uptake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transplacentally-transported 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects the catecholamine and indoleamine levels in the fetal mouse brain

Summary The effects of a dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the amounts of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were examined in the whole brains of fetal mice and maternal mice after its administration to pregnant mice. DA and DOPAC concentrations were decreased significantly in both the fetal and maternal brains. At 3 hr after injection, reduction of the DOPAC concentration was more marked than that of DA in both the fetal and maternal brains. Increase of 5-HT concentration was observed until 12 hr after injection in the fetal brains and 6 hr in the maternal brains. These results indicate that 1-methyl-4-phenyl-pyridinium ion (MPP⁺) and MPTP affect the levels of catechol- and indoleamines in the brain of premature stage as well as in the mature brain.     

Poly(ADP-ribose) polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57B1/6 mice

Treatment of C57B1/6 mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduced striatal dopamine and cortical noradrenaline levels by 77–83% and 43–46%, respectively, at 7 days post-treatment. Co-treatments with five different inhibitors of poly(ADP-ribose) polymerase (PARP), including benzamide, significantly prevented the MPTP-induced catecholamine depletions. Benzamide was present in the striatum, 30 min after single i.p. injection, at low millimolar concentrations known to selectively inhibit PARP in vitro. The protective activities of benzamide and its derivatives paralleled their in vitro efficacies and potencies both as neuroprotective agents and as inhibitors of PARP, while the activity of 1,5-dihydroxyisoquinoline, a structurally-unrelated compound, did not. In naive animals, the PARP inhibitors by themselves did not alter striatal dopamine levels at 7 days post-treatment. However, in acute studies, 1,5-dihydroxyisoquinoline and nicotinamide caused marked alterations in striatal dopamine metabolite levels; on the contrary, benzamide and its amino-derivatives showed little or no effect on dopamine metabolism. These results indicate that, although these compounds might act at other sites in addition to PARP, PARP inhibitors possess neuroprotective potential in vivo and suggest a role for PARP in MPTP neurotoxicity.     

Changes in the local cerebral metabolic rate for glucose in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson''s disease

Nine adult monkeys (Macaca fascicularis) were used in this study. Five animals were used as controls. Three animals were injected intravenously daily with 0.5 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over a 4-day period; one animal was injected weekly over a 4-week period. Neurological examination of the MPTP-treated animals revealed a flexed posture of trunk and extremities, bradykinesia, increased tone without cogwheel rigidity, loss of vestibular righting reflexes, decreased vocalization and swallowing, failure of upgaze and abnormal pursuit eye movements. Reflexes were hyperactive. The compound 2-deoxy-D-[14C]glucose (2-DG) was utilized for the determination of the local cerebral metabolic rate for glucose (lCMRg). A generalized decrease in lCMRg was noted in all cerebral cortical areas as compared to control values. The cerebellar cortex demonstrated no change in lCMRg. Areas that demonstrated a significant increase in lCMRg were: the internal and external segments of the globus pallidus (P less than 0.01), the pars compacta and the pars reticulata of the substantia nigra (P less than 0.05). Areas that demonstrated a significant decrease in lCMRg were: the head of the caudate nucleus (P less than 0.05), the anterior dorsomedial putamen (P less than 0.05) and the anterior segment of the subthalamic nucleus (P less than 0.05). The 2-DG analysis of the MPTP primate model of Parkinson's disease is particularly suited to demonstrate areas in the central nervous system that are affected by this neurotoxin. Further studies of these areas may lead to a better understanding of the mechanisms that underlie the clinical symptomatology of Parkinson's disease.     

Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson's disease

We have recently demonstrated that rodents treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) display time-dependent impairments in olfactory, emotional, cognitive and motor functions associated with disruption of dopaminergic neurotransmission in different brain structures conceivably analogous to those observed during different stages of Parkinson's disease (PD). On the other hand, lithium (Li) and valproate (VPA) are two primary drugs used to treat bipolar mood disorder that have recently emerged as promising neuroprotective agents. The present data indicates that the pretreatment with Li (47.5 mg/kg) or VPA (200 mg/kg) by intraperitoneal route during 7 consecutive days was able to prevent olfactory discrimination and short-term memory impairments evaluated in the social recognition and step-down inhibitory avoidance tasks in rats infused with a single intranasal (i.n.) administration of MPTP (0.1 mg/nostril). Despite the absence of clear depressive-like responses following the current MPTP dose, Li and VPA treatment presented an antidepressant profile reducing the immobility time in the forced swimming test. Importantly, at this time no significant alterations on the locomotor activity of the animals were observed in the open field test. Moreover, Li and VPA prevented dopamine depletion in the olfactory bulb and striatum of MPTP-infused rats. These results provide new insights in experimental models of PD, indicating that Li and VPA may represent new therapeutic tools for the management of olfactory and cognitive symptoms associated to early preclinical phases of PD, together with their neuroprotective potential demonstrated in previous research.     

Benzamide, an inhibitor of poly(ADP-ribose) polymerase, attenuates methamphetamine-induced dopamine neurotoxicity in the C57B1/6N mouse

Previous studies have indicated that the activation of poly(ADP-ribose) polymerase (PARP), an enzyme involved in DNA plasticity-related phenomena, is an early event occurring in glutamate-induced neurotoxicity in vitro, and that inhibitors of PARP, including benzamide, are protective against both glutamate- and methamphetamine (METH)-induced neurotoxicity in vitro. To evaluate a central neuroprotective potential of benzamide in vivo, the present study examined the effect of benzamide on the nigrostriatal dopamine toxicity (i.e. long-lasting striatal dopamine depletion) induced by METH in the C57B1/6N mouse. Intraperitoneal injection of METH at 2-h intervals (4 injections of 5 mg/kg, 4 injections of 10 mg/kg, or 2 injections of 20 mg/kg) dose-dependently reduced the levels of striatal dopamine in male C57B1/6N mice by up to 53% at 7 days post-treatment. Administration of benzamide (2 injections of 160 mg/kg spaced by a 4 h interval) during the different METH treatment protocols partially and significantly attenuated the METH-induced dopamine depletions. Benzamide (160 mg/kg i.p.) by itself had no acute effect on striatal dopamine metabolism and did not reduce body temperature. The concentrations of benzamide measured in the striatum at different times following this same dose of drug were in a range (0.09–0.64 mM) reported in in vitro studies to be both neuroprotective and effective in inhibiting PARP activity. These results indicate a neuroprotective potential of benzamide in vivo and suggest a role of PARP in METH neurotoxicity.     

Acute administration of 1-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a compound producing parkinsonism in humans, stimulates [2-C]deoxyglucose uptake in the regions of the catecholaminergic cell bodies in the rat and guinea pig brains

A modification of the [2-¹⁴C]deoxyglucose (2-DG) autoradiographic technique of Sokoloff et al.¹² was used to study the effects of acute administration of 1-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (10 mg/kg, s.c.) in the rat and guinea pig brains. MPTP administration resulted in both species in a dramatic increase in the 2-DG uptake in the substantia nigra pars compacta, ventral tegmental area and locus ceruleus, brain areas containing the cell bodies of dopaminergic and noradrenergic neurons. Many other brain areas were not affected. In the rat the effects were time dependent, being maximal between 1 and 2 h after drug administration. The effects of MPTP on 2-DG uptake differ from those of other dopaminergic or catecholaminergic drugs and suggest a specificity of the action of this drug on catecholaminergic neurons.