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PubMed1989

Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey.

Current evidence suggests that the motor symptoms of parkinsonism are due to abnormal overactivity of the medial segment of the globus pallidus, brought about by overactivity of the subthalamic nucleus, from which it receives an excitatory amino acid-mediated projection. The possibility exits, therefore, that excitatory amino acid antagonists might have an anti-parkinson effect by normalising medial pallidal activity. The NMDA antagonist MK-801 was administered i.m. to a single cynomolgus monkey with parkinsonism induced by the neurotoxin MPTP. In fact, MK-801 exacerbated the symptoms of parkinsonism. When administered after a therapeutic dose of L-DOPA it antagonised the anti-parkinson action of L-DOPA. The results suggest that any potential anti-parkinson action of excitatory amino acid antagonists will depend upon an action at non-NMDA sites. The administration of the selective neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce a primate model of Parkinson's disease is well-documented (Burns, Markey, Phillips & Chiuch, 1984; Crossman, 1987; Langston, Forno, Rebert & Irwin, 1984). Intravenous injection of MPTP, titrated judiciously over a period of several weeks, can produce a stable manifestation of the motor disability seen in the idiopathic disease of man, with a remarkable correspondence of both symptoms and pathology. Additionally, primates rendered parkinsonian by MPTP respond well to L-DOPA treatment. As in human Parkinson's disease, long-term L-DOPA therapy of MPTP-induced parkinsonism tends to be complicated by the emergence of choreiform movements and dystonic postures (Boyce, Clarke, Luquin, Peggs, Robertson, Mitchell, Sambrook & Crossman, 1989; Clarke, Sambrook, Mitchell & Crossman, 1987).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity by tobacco smoke.

Several epidemiological studies have indicated that there may be an inverse relationship between smoking and Parkinson's disease. The purpose of this study was to determine whether chronic exposure to cigarette smoke alters the parkinsonian-like neurochemical changes caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Following 4 weeks of brief, intermittent exposure to smoke, mice were treated with MPTP, 10 mg/kg. Smoke exposure was found to reduce the decrease in striatal dopamine and metabolite levels caused by MPTP. Although smoke exposure inhibited cerebral MAO-B activity, tissues from smoke-treated mice were able to metabolize MPTP in a normal fashion. This suggests that inhibition of cerebral MAO may not be a major mechanism for the apparent protective effect of cigarette smoke.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Studies on the neuromuscular blocking action of MPTP in the mouse phrenic nerve-diaphragm.

The peripheral neurotoxicity of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in the mouse phrenic nerve-diaphragm preparation was studied. The inhibition of nerve-evoked twitches was dependent on the concentrations of MPTP, ranging from 1 to 200 microM, which only slightly increased the amplitude of the twitch evoked by direct stimulation of the muscle. Pretreatment with pargyline did not prevent this inhibitory action of MPTP. The inhibition of the twitch by MPTP was reversible and could be partially reversed by anticholinesterase agents such as neostigmine and physostigmine, as well as ecothiophate. Pretreatment with either 0.7 microM d-tubocurarine or 2.2 microM succinylcholine, did not affect the twitches individually but markedly potentiated the effects of MPTP, by shifting the concentration-inhibition curve of MPTP to the left. MPTP not only directly inhibited acetylcholine (0.1 mM)-induced contracture of the denervated mouse diaphragm but also protected the muscle from the inhibitory action of alpha-bungarotoxin. Furthermore, the specific binding of [125I]alpha-bungarotoxin to the mouse diaphragm was also inhibited by MPTP. Electrophysiological studies revealed that MPTP inhibited the frequency and amplitude of the m.e.p.p., as well as the amplitude of the e.p.p. All of these findings indicate that MPTP exerts a neuromuscular blocking action through a curare-like action, by binding to the nicotinic acetylcholine receptors of the mouse diaphragm. The inhibitory action of MPTP on the contraction of the diaphragm is considered to play a role in the respiratory failure and muscle paralysis of intoxication with MPTP.

Analysis of Variance↗
PubMed1991

MPTP-induced ATP depletion and cell death in neuroblastoma X glioma hybrid NG 108-15 cells: protection by glucose and sensitization by tetraphenylborate.

The toxic effect of the Parkinsonism-producing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was investigated using a neuronal cell culture system, namely, neuroblastoma X glioma hybrid NG 108-15. The cells were able to metabolize MPTP into its active metabolite MPP+ (1-methyl-4-phenylpyridinium ion) and to convert its derivative, 2'-methyl MPTP, to the corresponding pyridinium ion. Degenerative changes were observed in NG 108-15 cells when they were examined with a phase-contrast microscope following exposure to MPTP, MPP+, or 2'-methyl MPTP. These compounds also caused an increased leakage of LDH from the treated cells. An enhanced release of [14C]adenine nucleotides was observed from treated cells which were prelabeled with [14C]adenine. The cell death as indicated by the leakage of LDH and the release of adenine nucleotides was markedly reduced in the presence of a high concentration (25 mM) of glucose in the medium. MPTP and MPP+ induced a drastic depletion in cell ATP content prior to cell death. The ATP depletion was also reduced by the presence of a high concentration of glucose. In contrast, tetraphenylborate, a lipophilic anion, highly potentiated the ATP depletion and the subsequent cell death induced by MPTP. Thus, ATP depletion could be a major factor in MPTP-induced neuronal cell death.

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

MPTP lesions and dopaminergic drugs alter eye blink rate in African green monkeys.

Eye blink rates were studied in African green monkeys following relatively specific destruction of substantia nigra and its dopamine projections with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys treated with MPTP had a significantly lower blink rate than controls over a period from two to five and a half months after treatment. Furthermore, the degree of parkinsonism expressed in treated animals was inversely correlated with blink rate. Pharmacologic studies further supported the role of dopamine receptors in the regulation of blink rate. PHNO (4-propyl-9-hydroxynaphoxazine), a potent and highly specific D2 agonist, effective in alleviating parkinsonism, caused a significant transient increase in blink rate, while sulpiride, a D2 antagonist, caused a decrease and blocked the effect of PHNO. Apomorphine and haloperidol, although less specific, had potent and predictable effects based on their interactions with dopamine systems. Blink rate may provide a nonintrusive measure of central dopamine activity that would help to evaluate the progress of Parkinson's disease or treatments which attempt to restore dopamine function.

Animals↗
PubMed1995

Neuronal antioxidant system and MPTP-induced oxidative stress in the striatum and brain stem of the rat.

Levels of ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), noradrenaline (NA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum, striatal synaptosomes, and/or brain stem of 3- and 6-month-old male Wistar rats given MPTP 35-52 mg/kg IP. In older rats, MPTP 35 mg/kg caused a 38% death rate within 15 min-12 h. Levels of MPTP and MPP+ in the striatum, synaptosomes, and brain stem were directly correlated with the absolute MPTP dose/rat. MPTP decreased striatal DA metabolites and NA levels in the striatum and brain stem, and increased uric acid levels in all regions in all rats. All these changes were significantly correlated with MPP+ levels. GSH levels were increased in younger rats and decreased in older rats. AA oxidation was increased mainly in older rats. We conclude that acute lethality and regional brain MPTP and MPP+ levels depend upon the absolute dose of MPTP/rat rather than the relative dose/kg. In younger rats, the neuronal antioxidant GSH system is more efficient than in older rats, in which the response to MPP(+)-induced oxidative stress also involves AA oxidation. The increase in uric acid levels provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress mediated by xanthine oxidase.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Immunological changes in the MPTP-induced Parkinson's disease mouse model.

The role of the central dopaminergic system in modulating immune response is not completely established. We examined the influence of central dopamine depletion on selected parameters of immune functions in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated and untreated mice. IgM antibody production of splenocytes to sheep red blood cells was reduced in MPTP-treated mice (P < 0.001). Proliferation of splenocytes in response to a wide range of mitogen concentrations (Concanavalin A, phytohaemagglutinin, lipopolysaccharide) was also significantly diminished in MPTP-treated mice. Production of migration inhibition factor (MIF) was diminished only in low mitogen concentration. Our results obtained in the experimental model of Parkinson's disease provide evidence that the damage of the central dopaminergic pathways induces alterations of some immune functions in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Calbindin-D28K-containing neurons in animal models of neurodegeneration: possible protection from excitotoxicity.

Brain levels of the calcium binding protein Calbindin-D28K (CaBP28K) and CaBP28K mRNA were measured for various animal models of neurodegenerative diseases (MPTP-treated C57BL/6J mice and Sprague-Dawley rats receiving striatal/intraperitoneal kainic acid or quinolinic acid into the nucleus basalis magnocellularis). Brain areas were tested (radioimmunoassay, Western blot, slot blot, and Northern blot) for levels of CaBP28K and CaBP28K mRNA. The various models did not exhibit any changes in protein or mRNA levels from the controls, suggesting that CaBP28K-containing neurons were not lost after exposure to these neurotoxins. Immunocytochemical characterization of the substantia nigra of the MPTP-treated mice revealed that there was significant dopaminergic cell loss in this brain area after MPTP treatment. The majority of dopaminergic neurons that degenerated did not contain CaBP28K. The small percentage of surviving neurons were CaBP28K-positive. These results suggest that the presence of CaBP28K may protect neurons from calcium-mediated neurotoxicity.

Animals↗
PubMed1996

The mesolimbic dopaminergic pathway is more resistant than the nigrostriatal dopaminergic pathway to MPTP and MPP+ toxicity: role of BDNF gene expression.

In the present study we examined the role of BDNF gene expression involved in the differential vulnerability of the nigrostriatal and mesolimbic dopaminergic pathways to environmental damage. The toxins for dopamine (DA) neurons 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+) were used as pharmacological tools. Results revealed that chronic MPTP treatment produced a significant and irreversible DA depletion in the striatum (ST) as well as a marked decrease in tyrosine-hydroxylase (TH) mRNA level in the substantia nigra (SN). Under these conditions, the endogenous brain-derived neurotrophic factor (BDNF) mRNA level was increased in the SN. Only acute DA reduction was found in the nucleus accumbens (NAc) and TH mRNA level was not affected in the ventral tegmental area (VTA) by MPTP treatment. Further, when MPP+ produced a similar extent of DA depletion in the ST and NAc, the TH mRNA level was also decreased while BDNF mRNA level was increased in the SN. The same alterations were not observed in the VTA. Results from the BDNF mRNA regional distribution study revealed that structures in the mesolimbic dopaminergic pathway expressed a more than 2-fold higher basal BDNF mRNA level than structures in the nigrostriatal dopaminergic pathway. Presumably, enhanced BDNF gene expression would help the survival of DA neurons and these findings suggest a better protective mechanism in the mesolimbic pathway. Lastly, direct BDNF infusions to the SN partially protected against MPTP's toxicity on DA neurons in the ST in mice. These results together suggest that a more abundant BDNF mRNA level along the mesolimbic pathway than the nigrostriatal pathway may, at least partially, explain the differential vulnerability of different DA neurons to MPTP and MPP+ toxicity.

1-Methyl-4-phenylpyridinium↗
PubMed1992

Effects of MPTP and vitamin E treatments on immune function in mice.

The effects of treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and vitamin E, an antioxidant, on immune functions were examined. Male C57/B1 mice were fed daily with natural vitamin E for 12 weeks, subsequently injected i.p. with MPTP or its vehicle, and sacrificed 1 week later. Control mice received the stripped corn oil vehicle daily, in place of vitamin E. Oral vitamin E feeding increased cerebral vitamin E content by 60% (P = 0.05). However, MPTP attenuated this rise in cerebral vitamin E content when measured 1 week after treatment with the neurotoxin (P = 0.05). MPTP also produced an 80-90% reduction in striatal dopamine content in both the stripped corn oil control group and the vitamin E-treated group (P = 0.0000). One week after MPTP injection, the numbers of peripheral blood lymphocytes and the percent of spleen T-cells, but not B-cells, were decreased in those groups receiving MPTP alone or MPTP plus vitamin E (P less than 0.05 and 0.02, respectively). The Con A-induced IL-2 production of spleen cells was decreased in all treated groups (P less than 0.005). There was no difference in the mitogenic stimulative response to PHA, Con A or LPS. However, the response to PWM was increased in both MPTP and MPTP plus vitamin E-treated groups (P less than 0.05 and 0.001, respectively). On the other hand, the one-way mixed lymphocyte response of the splenocytes from the MPTP-treated group was increased (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Electron microscopic evidence for neurotoxicity in the basal ganglia.

The dopaminergic projection from the substantia nigra to the neostriatum is vulnerable to several neurotoxins including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), amphetamine, and 5-hydroxydopamine. We have treated rats or mice with these agents and examined various regions of their brains with a combination of Fink-Heimer, immunohistochemical, serial-section electron microscopic, and three-dimensional reconstruction methods. In addition to degenerating or swollen axons, we found darkened glial processes and some damage to postsynaptic cells and dendrites. The particular effects observed critically depend on experimental variables such as dose, time, species and strain and raise questions about the correlation of light and electron microscopic results. These studies provide the basis for a discussion of the advantages and disadvantages of an ultrastructural examination of the effects of neurotoxins.

Amphetamine↗
PubMed1994

Quinolinic acid but not MK-801 protects the dopaminergic system from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced toxicity in goldfish retina.

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, intravitreally injected in goldfish eye, involves interplexiform retinal neurons and depletes tyrosine hydroxylase immunoreactivity and dopamine levels. This induced neurotoxicity was prevented by the concomitant administration in non-toxic doses (10 micrograms) of quinolinic acid, an endogenous structural analogue of N-methyl D-aspartate with excitotoxic properties. Quinolinic acid is ineffective on the retinal degeneration induced by 1-methyl-4-phenylpyridinium ion. This fact suggests that quinolinic acid inhibits the MAO-B oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. MK-801, a noncompetitive antagonist of glutamate NMDA-receptors, exerts partial protective effects on MPTP-induced delayed toxicity in mammals. In the goldfish eye, MK-801, injected in low concentration, and in conjunction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium ion, did not prevent retinal neurodegeneration. Ten micrograms of MK-801 alone did not affect retinal neurons, while a higher concentration (20 micrograms) causes the chromatolysis of some photoreceptor nuclei.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Blockade of 1-methyl-4-phenylpyridinium ion (MPP+) nigral toxicity in the rat by prior decortication or MK-801 treatment: a stereological estimate of neuronal loss.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, (MPTP), produces a parkinsonian syndrome both in man and in experimental animals. Its toxicity is mediated by a metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). When injected into the striatum, MPP+ is accumulated by dopaminergic nerve terminals and retrogradely transported to the substantia nigra pars compacta (SNc) where it causes neuronal degeneration. MPP+ accumulates in mitochondria and blocks complex I of the electron transport chain. A proposed mechanism of neurotoxicity is excitotoxic neuronal degeneration induced by this energy depletion. We examined whether either prior decortication or administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) could prevent or diminish the selective nigral neuronal degeneration that follows unilateral intrastriatal injection of MPP+. We quantified the extent of neuronal death in the SNc ipsilateral and contralateral to the injections on Nissl-stained sections with unbiased stereological techniques. One week after injection of MPP+, approximately 75% of the SNc neurons were lost on the side of the injection. The loss was a consequence of the reduction in both SNc volume and neuronal density. Both prior decortication or the administration of MK-801 for 2 days nearly completely prevented MPP(+)-induced neuronal loss in the ipsilateral SNc. These results are consistent with an NMDA receptor mediated excitotoxic mechanism for MPP(+)-induced nigral toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Increased susceptibility to MPTP toxicity in middle-aged rhesus monkeys.

In the present study, age-associated effects of the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) administered via the right carotid artery were evaluated pre- and post-MPTP treatment in 26 female rhesus monkeys ranging in age from young adulthood to middle age (5 to 23 years old). A significant inverse correlation was seen between age and MPTP dose needed to produce stable, moderate parkinsonian features. Rhesus in the 5- to 9-year-old group required approximately three times the amount of MPTP as 20- to 23-year-old animals. Even though they received less MPTP, the older animals consistently displayed more severe bradykinesia, upper limb rigidity, and balance and gait abnormalities. Prior to MPTP treatment, home cage activity levels were strongly age dependent, with animals in the 10- to 19-year and 20- to 23-year groups displaying significantly less daytime activity than 5- to 9-year-old rhesus. Home cage activity levels tended to decrease in all age groups following MPTP treatment, but significant decreases were only measured in daytime activity in the 10- to 19- and 20- to 23-year age groups.

Age Distribution↗
PubMed1995

Effect of adding the D-1 agonist CY 208-243 to chronic bromocriptine treatment of MPTP-monkeys: regional changes of brain dopamine receptors.

1. Eleven monkeys were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): eight were treated with bromocriptine for one week and then CY 208-243 (four monkeys) or saline (four monkeys) was added to the bromocriptine treatment. 2. Addition of CY 208-243 increased the therapeutic response observed with the ergot alone without inducing dyskinesia. 3. Following MPTP, [3H]-SCH 23390 specific binding to D-1 receptors as well as [3H]-spiperone and [3H]-N-n-propylnorapomorphine specific binding to D-2 receptors increased in posterior striatum compared to control animals, whereas [3H]-SKF 38393 binding to D-1 receptors tended to decrease. 4. Dopamine receptor density was unchanged in anterior striatum of untreated MPTP-monkeys. 5. In the posterior striatum, both dopaminergic treatments decreased towards control values [3H]-SCH 23390, [3H]-spiperone and [3H]-N-n-propylnorapomorphine binding whereas they did not significantly change [3H]-SKF 38393 specific binding. [3H]-SKF 38393 specific binding increased in anterior striatum of bromocriptine-treated MPTP-monkeys, compared to untreated MPTP-animals, and this increase was abolished in animals treated with bromocriptine+CY 208-243. 6. The present study shows that in MPTP-monkeys, treated or not with DA agonists, the D1 and D2 receptor changes are concentrated in the posterior striatum and that denervation appears to cause a shift from the high to the low affinity agonist state of D1 receptors but not for the D2 subtype.

Animals↗
PubMed1991

Placental toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a well-known model substance for inducing in humans and monkeys a severe extrapyramidal syndrome similar to Parkinson's disease. The neurotoxic action of MPTP can be exerted not only in adult animals but also during fetal development by diaplacental passage. Here we show that, during the gestation period of mice, the placenta is another important target organ of MPTP cytotoxicity. Pregnant NMRI mice on gestation day 15 received a single intraperitoneal dose of 20, 40, or 60 mg/kg MPTP. Developmental parameters of the fetuses and the placentas were determined on gestation day 18. Placental weight was consistently reduced in all experimental groups. Histology showed conspicuous alterations of the labyrinth layer; at 20 mg/kg MPTP there was already a significant reduction of the trabecular diameters and from 40 mg/kg onwards, severe necrosis of the syncytial trophoblast cells. In addition, there were necrotic alterations of the cells of the visceral yolk sac. The toxic effects are confined to the placenta at the doses used in the present experiments, leading at just 60 mg/kg to a marked placental insufficiency syndrome.

Abnormalities, Drug-Induced↗
PubMed1994

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) affects the actin cytoskeleton and calcium level of Swiss 3T3 mouse fibroblasts.

Organization of the actin cytoskeleton, the cytosolic free-calcium concentrations and ATP levels were analyzed in 3T3 mouse fibroblasts treated with 0.75 or 1.5 mM MPTP. In the presence of the drug actin filaments were time- and dose-dependently disorganized, ATP level was unaffected and intracellular calcium increased within 5 s. The correlation between MPTP cytotoxicity and [Ca2+]i level emerging from these results, suggests that the primary effect of the molecule itself is on the plasma membrane's integrity for calcium ion regulation.

Actins↗