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PubMed1994

Methamphetamine protects against MPTP neurotoxicity in C57BL mice.

Methamphetamine (5 mg/kg) administered 30 min prior to each injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (3 x 30 mg/kg, at 24 h intervals) prevents the reduction of striatal levels of dopamine and its metabolites in C57BL mice. Methamphetamine and amphetamine inhibit the uptake of 1-methyl-4-phenylpyridinium (MPP+) by striatal synaptosomes of rats. A 30-min post-treatment with methamphetamine or amphetamine also prevents the MPTP-induced dopamine depletion, suggesting that their protective effect is related to the blockade of MPP+ uptake into dopaminergic neurons. Since amphetamine and methamphetamine are themselves neurotoxins at higher doses, this work demonstrated the protection against the actions of one neurotoxin by the administration of another.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

Riluzole prevents MPTP-induced parkinsonism in the rhesus monkey: a pilot study.

Previous studies have shown that riluzole (2-amino-6-trifluoromethoxy-benzothiazole), a drug which interferes with glutamate neurotransmission, has a neuroprotective action in rodent models of global and focal cerebral ischemia. In this pilot study, the protective and palliative effects of riluzole have been examined using an animal model of Parkinson's disease. Two monkeys were rendered hemiparkinsonian by one intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and motor signs were evaluated using clinical examination and electromyographic recordings. When riluzole (4 mg/kg) was administered before the injection of MPTP, parkinsonian motor symptoms, in particular bradykinesia and rigidity, were absent. When injected daily in one monkey which presented stable motor symptoms, bradykinesia and rigidity were significantly reduce d. Riluzole pretreatment induced a persistent increase in dopamine turnover when compared to MPTP alone. Thus, a possible neuroprotection and a facilitation of dopamine release may explain the behavioural effects reported with riluzole treatment. These preliminary results suggest that riluzole could possess neuroprotective and palliative effects in a primate model of Parkinson's disease.

Animals↗
PubMed1990

Limited recovery of striatal dopaminergic fibers by adrenal medullary grafts in MPTP-treated aging mice.

Systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the dopaminergic (DA) nigrostriatal system in C57BL/6 mice. We have investigated the effect of MPTP neurotoxicity and subsequent adrenal medullary grafts into the striatum of young (2-3 months) and aging (12 months) mice. MPTP treatment (4 X 20 mg/kg ip given 3 or 12 h apart in young mice and 12 h apart in aging mice) resulted in 80-90% depletion of striatal DA and virtual disappearance of tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in both young and aging mice 1 week following treatment. Only partial recovery of TH-IR fibers was seen 5 weeks after MPTP treatment in young mice, while virtually no recovery was seen in aging mice. Adrenal medullary minced pieces were grafted into the striatum of young and aging mice 1 week after MPTP treatment. In young mice, dense TH-IR fibers were observed in the striatum on the grafted side 4 weeks later, far denser than those in sham-operated striatum. Although this staining was most prominent around the grafts, many TH-IR fibers also were found in the ventral striatum close to the nucleus accumbens. No such increase in TH-IR fibers was found on the nongrafted side. DA concentration on the grafted side recovered to 45% of the control level. In aging mice receiving similar grafts, TH-IR fibers also were observed in the grafted striatum, but were less dense and more restricted around the site of the graft compared with young mice. DA concentration on the grafted side was 29% of the control level. We conclude that the MPTP-depleted nigrostriatal DA system in aging mouse brain can recover partially following adrenal medullary grafts, but the degree of recovery is more limited compared with that in young brain.

Adrenal Medulla↗
PubMed1992

Effect of chronic treatment with (+)-PHNO, a D2 agonist in MPTP-treated monkeys.

A group of four drug naive Macaca fascicularis were rendered parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine and then treated chronically with (+)-PHNO, a potent D2 agonist. After several days, dyskinesia appeared in all animals. At this point, the daily dose of (+)-PHNO was replaced by a dose of the D1 agonist CY 208-243. The substitution by CY 208-243 reproduced the same dyskinesia observed with (+)-PHNO. The administration of the DA synthesis inhibitor AMPT (alpha-methyl-p-tyrosine methyl ester) blocked the dyskinetic and antiparkinsonian effect of (+)-PHNO, and those effects were reestablished by the addition of a subthreshold dose of CY 208-243. Our results show that a selective D2 agonist is capable of inducing dyskinesia and suggest some kind of cooperation between D1 and D2 receptors in the antiparkinsonian and dyskinetic effect produced by (+)-PHNO.

Animals↗
PubMed1995

Neurotoxicity induced by prenatal exposure to MPTP on the monoaminergic and peptidergic systems of the marmoset brain.

The neurotoxicity induced by incidental prenatal exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in three marmosets. The baby marmosets exposed in utero to MPTP looked normal in the first few weeks of life but around 8 to 10 weeks of life they started to behave abnormally and were sacrificed when they were 20 weeks old. A marked reduction in DA levels was found in the baby marmosets prenatally exposed to MPTP as compared to the corresponding age-matched controls and this was highly significant in the caudate nucleus, putamen, and nucleus accumbens. Serotonin content was normal in the caudate and putamen and was only significantly reduced in the nucleus accumbens, hypothalamus, and cingulate cortex. Met-enkephalin levels were reduced in the caudate nucleus, putamen, and globus pallidus. Substance P content tended to be lower in all regions examined; however, the decrease was only statistically significant in the substantia nigra. These results indicate that prenatal exposure to MPTP induces a marked and long-lasting alteration in monoaminergic and peptidergic systems of the primate brain. This observation may provide a new insight into the role of toxins in the etiology of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) produces Parkinsonism in both experimental animals and in man. MPTP is metabolized to 1-methyl-4-phenylpridinium, an inhibitor of mitochondrial complex I. MPTP administration produces ATP depletions in vivo, which may lead to secondary excitotoxicity and free radical generation. If this is the case then agents which improve mitochondrial function or free radical scavengers should attenuate MPTP neurotoxicity. In the present experiments three regimens of MPTP administration produced varying degrees of striatal dopamine depletion. A combination of coenzyme Q10 and nicotinamide protected against both mild and moderate depletion of dopamine. In the MPTP regimen which produced mild dopamine depletion nicotinamide or the free radical spin trap N-tert-butyl-alpha-(2-sulfophenyl)-nitrone were also effective. There was no protection with a MPTP regimen which produced severe dopamine depletion. These results show that agents which improve mitochondrial energy production (coenzyme Q10 and nicotinamide) and free radical scavengers can attenuate mild to moderate MPTP neurotoxicity.

Animals↗
PubMed1990

Mechanism of the neurotoxicity of MPTP. An update.

This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP+ (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the 2'-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP+ and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP+ and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP+, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Transplantation of human sympathetic neurons and adrenal chromaffin cells into parkinsonian monkeys: no reversal of clinical symptoms.

Cultured human fetal sympathetic ganglion explants or adrenal chromaffin cell aggregates were implanted into the left striatum of monkeys whose left nigrostriatal pathway had been lesioned with the neurotoxin MPTP. There was no clinical reversal of parkinsonian symptoms and PET scans did not show increased striatal fluorodopa uptake from pre-implant levels. At sacrifice, left striatal contents of dopamine were not statistically different from MPTP-treated but non-implanted controls. Histological examinations revealed pockets of extrinsic cells which were found at the end of needle tracks. There was no evidence of immune rejection. The extrinsic cells did not stain for tyrosine hydroxylase or neurofilament, suggesting that they were not dopaminergic neurons. The failure to reverse clinical parkinsonian symptoms highlights the stage of infancy of neural implantation in Parkinson's disease.

Adrenal Medulla↗
PubMed1990

Alterations of somatostatin and its modulation by levodopa in MPTP-treated mouse brain.

We examined the changes in the concentrations of neuropeptides in various regions of the mouse brain 1, 2 or 6 weeks after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment (30 mg/kg i.p. twice/day for 5 days) and further examined the effects of levodopa injections (200 mg/kg i.p.) for 14 days starting 4 weeks after MPTP treatment on regional somatostatin (SRIF) concentrations. Substance P, cholecystokinin-octapeptide and thyrotropin-releasing hormone did not show any significant changes up to 6 weeks after MPTP treatment, whereas the SRIF concentration increased 1 week after MPTP treatment but decreased thereafter, showing a marked decrease in the striatum and hippocampus after 6 weeks. In the striatum, the decreased concentration of SRIF recovered to the normal level with levodopa injections. This SRIF depletion could be a change secondary to dopamine depletion. On the other hand, in the cerebral cortex, while showing no change in the SRIF concentration after MPTP treatment, the concentration decreased significantly with levodopa injections. In the hippocampus, the decreased SRIF levels were still low after levodopa treatment. Since it has been reported that SRIF concentrations are significantly reduced in the frontal cortex and hippocampus of demented parkinsonians and patients with senile dementia of the Alzheimer type and that levodopa treatment induced various psychiatric side effects, the results of the present study suggest some relationship among levodopa treatment, SRIF depletion and the demented state.

Animals↗
PubMed1993

Behavioral tolerance to repeated apomorphine administration in parkinsonian monkeys.

Four consecutive injections (s.c.) of apomorphine (Apo) were given to 5 parkinsonian monkeys after i.v. MPTP administration. The minimal effective dose (MED) of Apo was defined as that capable of reducing motor disability by 50% or more for a minimum period of 30 min. Repeated apomorphine injections were given with an interval of 30 min after the motor effect of the previous injection had worn off or with a separation of 3 h between injections. The doses used in different experiments were the MED (2.4 micrograms/kg), 4 MED and 8 MED. In every experiment the duration of motor benefit was longest with the first Apo injection. There was a decay in the duration of the response elicited by consecutive Apo injections when given 30 min after the previous effect had waned. This was significant for the MED and 4 MED (ANOVA, P < 0.01). When Apo boluses were given with an interval of 3 h there was a significant reduction in the duration of the response elicited by the MED, 4 MED and 8 MED of apomorphine. For the MED the reduction in the duration of the motor response was significantly greater for injections given with a 30-min interval than 3-h interval. These findings indicate that behavioral hyposensitivity to repeated Apo administration in parkinsonian monkeys occurs preferentially when near threshold doses are given with short intervals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Medium latency stretch reflexes in young-onset Parkinson's disease and MPTP-induced parkinsonism.

It is still unclear why components of the phasic stretch reflex are increased in Parkinson's disease (PD). To study the role of aging, we assessed medium latency (ML) stretch reflexes in 19 Parkinson patients (8 with young-onset PD, 11 with late-onset PD) and 23 normal subjects (10 young, 13 old). To assess the contribution of supraspinal dopaminergic influences, we also studied 5 young parkinsonian patients with a selective central dopamine deficiency induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). ML responses were recorded from the medial gastrocnemius muscle which was stretched by 4 degrees toe-up rotations of a platform upon which subjects were standing. ML responses were significantly enhanced in late-onset patients compared with older controls. In contrast, ML responses did not differ between young-onset patients and young controls. This observation could be attributed to the significantly different influence of age on ML-amplitudes in patients and controls. Thus, ML-amplitudes declined with age in controls, whereas they increased with age in PD possibly because older patients were more severely affected than younger patients. Thus, the difference between young-onset and late-onset PD seems to be related to the opposite effects of increasing age and disease severity in patients and controls. ML-amplitudes did not differ between patients with MPTP-induced parkinsonism, patients with young-onset PD and controls, suggesting that supraspinal dopaminergic systems are not critically involved in control of ML responses. This result also indicates that the severity effect in PD may be related to disruption of non-dopaminergic pathways which occurs in late-onset, but not young-onset patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Continued administration of GM1 ganglioside is required to maintain recovery from neuroleptic-induced sensorimotor deficits in MPTP-treated mice.

Injection of a dose of haloperidol that has no obvious behavioral effects in normal mice, produces akinesia, catalepsy, and sensory neglect in MPTP-treated mice. Chronic GM1 ganglioside administration improves the behavioral impairments, partially restores striatal dopamine (DA) content and prevents DA D-2 receptor up-regulation. Discontinuation of GM1 ganglioside treatment results in a time-dependent decline of striatal DA content to pretreatment pathological levels, return of haloperidol-induced sensorimotor deficits and a rise of DA D-2 receptor density in the striatum. Apparently, continuous administration of GM1 ganglioside is necessary to maintain the biochemical and behavioral recovery in the MPTP-treated mouse. These observations may provide useful cues for understanding the mechanism of action of GM1 ganglioside.

Animals↗
PubMed1991

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in prenatal stage on the dopamine system in the postnatal mouse brain.

A dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP), administered to a pregnant female was found to affect postnatally the catecholamine metabolism of the pups. MPTP (5 mg/kg body weight/day) was administered to pregnant C57 Black BYA mice daily for 7 days between the 12th and 18th day of gestation. Dopamine levels and tyrosine hydroxylase (TH) activity were measured in the whole brain from the pups sacrificed after birth. In MPTP-treated pups at 7 days of age, TH total activity (TH activity/brain) did not change (92% of the control value), while TH specific activity (TH activity/mg protein) was increased to 163% of that in control mice. Thus, TH homospecific activity (TH activity/mg TH protein) doubled compared to the control mice. At 28 days of age, both the total activity and the specific activity of TH in the brains of postnatal mice were reduced to 50% and 78% of the control, respectively. Dopamine concentration in the striatum was also reduced significantly. Reduction in the TH activity and dopamine concentration were also observed at the age of 12 weeks. These data suggest that the prenatal exposure to MPTP induced a prolonged reduction of TH activity in the brains of mice with a transient increase of TH homospecific activity during the postnatal period.

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

Effects of tobacco smoke constituents on MPTP-induced toxicity and monoamine oxidase activity in the mouse brain.

Exposure to cigarette smoke has been found to attenuate the reduction in striatal dopamine levels caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and to inhibit monoamine oxidase (MAO) activity in brain tissue. To confirm whether specific smoke constituents which have been reported to protect against MPTP toxicity were responsible for these effects, mice were treated chronically with nicotine, 4-phenylpyridine and hydrazine. Although all three compounds prevented the decrease in dopamine metabolite levels induced by MPTP, there was no significant effect on dopamine levels. None of the three compounds inhibited MAO activity in cerebral tissue following treatment in vivo. However, an extract of tobacco smoke particulate matter caused a marked inhibition of MAO A and MAO B activity when added in vitro. The results suggest that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.

Animals↗
PubMed1994

Development of a model for Parkinson's disease in sheep using unilateral intracarotid injection of MPTP via slow continuous infusion.

The effects of unilateral intracarotid administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in sheep were studied with the goal of producing a non-primate, large animal model of Parkinson's Disease. Adult female sheep were given an acute (over 30 min) or chronic (over 1 week) injection of MPTP (0.4-5.0 mg/kg) via the common carotid artery. Both methods produced parkinsonian-like behavior. Turning contralateral to the side of injection was induced by apomorphine (APO) in both groups. However, amphetamine (AMP) induced ipsilateral turning only in the chronic treatment group. Acute and chronic MPTP treatment resulted in a loss of substantia nigra tyrosine hydroxylase immunoreactive (THIR) neurons with a significantly greater loss ipsilateral to the injection in each treatment group (acute p < 0.05; chronic p < 0.01). Caudate dopamine (DA) was depleted in both treatment groups, although the difference between ipsilateral and contralateral DA content was significant only in the chronic treatment group (p < 0.05). The best results were seen in those animals with chronic infusion with the occipital artery occluded to prevent entry of drug into the posterior circulation with subsequent bilateral distribution. Use of slow and continuous intracarotid administration of MPTP with the ipsilateral occipital artery occluded can prevent some of the bilateral effects of acute treatment, and results in statistically significant ipsilateral reduction of THIR neurons in the substantia nigra and reduction of tissue levels of DA in the caudate nucleus. Such treatment produces appropriate turning responses to both AMP and APO challenge not seen in the acute treatment group, and appears to be an effective method of producing parkinsonian-like behavior in a large animal.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

The novel anticonvulsant lamotrigine prevents dopamine depletion in C57 black mice in the MPTP animal model of Parkinson's disease.

The effect of the novel anticonvulsant Lamotrigine (LTG) was studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopamine depletion in C57BL/6 mouse brain. Whole brain dopamine levels were measured by HPLC-ED 2 days after treatment with MPTP (15 mg/kg s.c.). While LTG alone had no direct effect on dopamine levels at two hours or two days after treatment, MPTP induced dopamine depletion was significantly less in mice pretreated with LTG (approximate ED50: 6 mg/kg). LTG (38 mg/kg) was shown to completely protect against dopamine depletion when given 1 or 2 hours prior to MPTP administration. The effect of LTG (38, 100 mg/kg) on MPTP toxicity was compared to the effects of the anticonvulsants phenytoin (67 mg/kg), carbamazepine (156 mg/kg), and riluzole (33 mg/kg) and the Ca++ channel blocker nicardipine (0.1 mg/kg). Only phenytoin and LTG showed significant protection against MPTP. Results suggest LTG prevents MPTP induced dopamine depletion via a novel mechanism.

Animals↗
PubMed1989

The acute effect on levels of catecholamines and metabolites in brain, of a single dose of MPTP in 8 strains of mice.

The neurotoxic agent MPTP produces profound and sustained changes in the biochemistry of the brain in mice after a single dose of 20 mg/kg. Acute neurochemical changes have been examined in detail in 8 strains of mice. Coloured mice were more intoxicated than white mice when treated with MPTP: white mice were little affected behaviourally by a dose that could kill a sensitive coloured strain. Although changes in levels of dopamine were a good indication of the effect of treatment--particularly in the dopaminergic areas, the best discriminator between strains was changes in the levels of adrenaline and noradrenaline. Changes in levels of dopamine, which generally decreased in coloured mice, were not good indicators of toxicity. The changes in levels of adrenaline and noradrenaline discriminated better between strains: they were usually decreased in coloured mice but could substantially increase in white strains, particularly in certain areas of the brain. This study showed that there is a very considerable genetic component to the acute toxicity of MPTP within a single species. Even very closely related mice reacted quite differently to the effect. Also, it showed that white mice, in particular those from the commonly used BALB/c strain, are a poor model for any study of the toxicity of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Evidence for an epileptogenic action of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine.

Based on behavioral observation alone, poorly characterized paroxysmal motor abnormalities have been reported in mice after acute MPTP administration. This study investigated electroencephalographic (EEG) and behavioral effects of acute MPTP in young and older mice. Single MPTP injections (30 mg/kg i.p.) produced limbic and/or generalized seizures in older (6 mo) and frank epileptiform interictal hippocampal spikes in younger (6-8 wks) mice. These latter showed behavioral seizures only after the 3rd drug administration. Studies of the acute effects of MPTP must take in consideration that seizures "per se" modify brain biochemical and metabolic activity and alter the permeability of the blood brain barrier, adding several confounding variables.

Aging↗