PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “MPTP Poisoning”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 595 records · Page 33Linked to original sources
PubMed2006

Partial recovery of striatal nicotinic receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys with chronic oral nicotine.

Recent studies in nonhuman primates show that chronic nicotine treatment protects against nigrostriatal degeneration, with a partial restoration of neurochemical and functional measures in the striatum. The present studies were done to determine whether long-term nicotine treatment also protected against striatal nicotinic receptor (nAChR) losses after nigrostriatal damage. Monkeys were administered nicotine in the drinking water for 6 months and subsequently lesioned with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over several months while nicotine was continued. (125)I-Epibatidine, [(125)I]5-[(125)I]iodo-3(2(S)-azetidinylmethoxy)-pyridine (A85380), and (125)I-alpha-conotoxinMII autoradiography was performed to evaluate changes in alpha4beta2* and alpha3/alpha6beta2* nAChRs, the major striatal subtypes. Nicotine treatment increased alpha4beta2* nAChRs by > or =50% in striatum of both unlesioned and lesioned animals. This increase in alpha4beta2* nAChRs was significantly greater in lesioned compared with unlesioned monkey striatum. Chronic nicotine treatment led to a small decrease in alpha3/alpha6beta2* nAChR subtypes. The decline in alpha3/alpha6beta2* subtypes, defined using alpha-conotoxinMII-sensitive (125)I-epibatidine or [(125)I]A85380 binding, was significantly smaller in striatum of nicotine-treated lesioned monkeys compared with unlesioned monkeys. This difference was not observed for alpha3/alpha6beta2* nAChRs identified using (125)I-alpha-conotoxinMII. These data suggest that there are at least two striatal alpha3/alpha6beta2* subtypes that are differentially affected by chronic nicotine treatment in lesioned animals. In addition, the results showing an improvement in striatal alpha4beta2* and select alpha3/alpha6beta2* nAChR subtypes, combined with previous work, demonstrate that chronic nicotine treatment restores and/or protects against the loss of multiple molecular markers after nigrostriatal damage. Such findings suggest that nicotine or nicotinic agonists may be of therapeutic value in Parkinson's disease.

Animals↗
PubMed2003

Differential declines in striatal nicotinic receptor subtype function after nigrostriatal damage in mice.

Nigrostriatal damage leads to a reduction in striatal nicotinic acetylcholine receptors (nAChRs) in rodents, monkeys, and patients with Parkinson's disease. The present studies were undertaken to investigate whether these nAChR declines are associated with alterations in striatal nAChR function and, if so, to identify the receptor subtypes involved. To induce nigrostriatal damage, mice were injected with the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We measured [(125)I]3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid isopropyl ester (RTI-121, dopamine transporter), (125)I-alpha-conotoxin MII (putative alpha 6-containing sites in the central nervous system), (125)I-epibatidine (multiple sites), 5-[(125)I]iodo-3-[2(S)-azetidinylmethoxy]pyridine-2HCl ([(125)I]A85380; beta2-containing sites), and (125)I-alpha-bungarotoxin (alpha 7-containing sites) binding in brains from control and MPTP-treated mice, as well as nAChR function by [(3)H]dopamine release, [(3)H]GABA release, and [(86)Rb(+)] efflux. After MPTP treatment, declines were observed in striatal dopamine transporter levels, both binding and functional measures of striatal alpha-conotoxin MII-sensitive nAChRs, and selected measures of striatal alpha-conotoxin MII-resistant nAChRs. In contrast, (125)I-alpha-bungarotoxin binding sites were not altered after nigrostriatal damage. The changes in striatal nAChRs were selective, with no declines in cortex, thalamus, or septum. Those striatal binding and functional measures of nAChRs that decreased with MPTP treatment correlated with dopamine transporter declines, an observation suggesting that the binding and functional changes in nAChRs are limited to dopaminergic terminals. The present results are the first to demonstrate differential alterations in nAChR subtype function after nigrostriatal damage, with a close correspondence between changes in receptor binding sites and function. These data suggest that the declines in nAChR sites observed in Parkinson's disease brains may be of functional significance.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

L-DOPA treatment modulates nicotinic receptors in monkey striatum.

Nicotinic acetylcholine receptor (nAChR) activation is well known to stimulate dopamine release in the striatum. This phenomenon may be physiologically significant in the control of motor function, as well as in pathological conditions such as Parkinson's disease. An understanding of the mechanisms that influence nAChR expression and function is therefore important. Because the dopamine precursor l-DOPA is the most commonly used therapeutic agent for Parkinson's disease, we investigated the effects of l-DOPA treatment on striatal nAChR expression in unlesioned and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In unlesioned animals, l-DOPA (15 mg/kg) administered twice daily for 2 weeks decreased both 125I-epibatidine and [125I]iodo-3-[2(S)-azetidinylmethoxy]pyridine (A-85380) binding sites in the caudate and putamen, but did not affect 125I-alpha-CtxMII sites. alpha-CtxMII inhibition of striatal 125I-epibatidine and [125I]A-85380 binding with alpha-CtxMII suggest that there are both high- (Ki < 0.2 nM) and low-affinity (Ki > 100 nM) alpha-CtxMII-sensitive sites, as well as alpha-CtxMII-resistant sites, and that l-DOPA treatment influences only the low-affinity alpha-CtxMII-sensitive subtype. The l-DOPA effect was selective for striatal nAChRs with no change in cortical sites. Monkeys with severe nigrostriatal damage did not exhibit l-DOPA-induced declines in striatal nAChRs, suggesting that l-DOPA primarily affects nAChRs associated with dopaminergic terminals. In summary, these data show that l-DOPA treatment decreases nAChR expression, in contrast with the well established up-regulation of these sites by chronic nicotine exposure. Furthermore, they demonstrate preferential l-DOPA regulation of a novel low-affinity alpha-CtxMII-sensitive site. These declines in nAChRs with l-DOPA may be relevant to both the therapeutic and side effect profiles of l-DOPA therapy in Parkinson's disease.

Animals↗
PubMed2004

Agonist-induced internalization of leukotriene B(4) receptor 1 requires G-protein-coupled receptor kinase 2 but not arrestins.

The leukotriene B(4) (LTB(4)) receptor (BLT1) becomes desensitized upon repeated agonist stimulation. Little is known, however, about BLT1 internalization, which follows desensitization in most G-protein-coupled receptors (GPCR). In the current study, transiently expressed BLT1 readily internalized, after LTB(4) stimulation, in RBL-2H3 cells that express high levels of endogenous GPCR kinase 2 (GRK2) but did not in COS-7 or human embryonic kidney (HEK) 293 cells, which do not overexpress GRK. The internalization of BLT1 could be blocked in RBL-2H3 cells by coexpressing dominant-negative (DN) GRK2 K220R and could be promoted in HEK293 cells by coexpressing wild-type (WT) GRK2. Coexpression of WT or DN nonvisual arrestins had no effect on BLT1 internalization. Moreover, upon stimulation with LTB(4), BLT1 did not induce arrestin-green fluorescence protein redistribution in either cell type, even in the presence of overexpressed GRK2. Coimmunoprecipitation experiments confirmed that BLT1 could associate with GRK2 but not with arrestins. A C-tail-truncated mutant of BLT1 lost the capacity to internalize and associate with GRK2 upon exposure to LTB(4), suggesting that the C-tail was required for receptor internalization and association with GRK2. Taken together, our results indicate that the C terminus of BLT1 plays a pivotal role in receptor internalization and GRK2 association. Moreover, ligand-induced BLT1 internalization is dependent on GRK2 but independent of arrestins. This may allow differential, cell-type-specific signaling in response to LTB(4), depending on GRK expression levels.

Animals↗
PubMed2004

S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function.

Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.

Alzheimer Disease↗
PubMed2000

Ratio of inhibited-to-activated pallidal neurons decreases dramatically during passive limb movement in the MPTP-treated monkey.

Mink advanced the hypothesis in 1996 that the role of the basal ganglia (BG) is primarily one of focused selection; the encouragement of motor mechanisms inducing a desired movement and the inhibition of competing mechanisms. This would imply, in normal subjects, a ratio of inhibited-to-activated (I/A) movement-related globus pallidus pars internalis (GPi) neurons <1 and a drastic decrease of this ratio in the parkinsonian state. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication should therefore decrease the specificity of the response of this neuronal population. To test this working hypothesis we studied the activity of GPi neurons in response to passive limb movement in the normal and the parkinsonian monkey. Extracellular unit recordings monitored any correlation between passive limb movements and eventual modifications of the neuronal activity of the GPi in two calm, awake, and drug naive monkeys (Macaca fascicularis) before and after MPTP intoxication. In the normal animal, arm- and leg-related neurons were located in clusters in the medial part of the GPi. The I/A ratio was 0.22. Most GPi cells were linked to a single joint. In the MPTP-treated monkey, the number of movement-related neurons increased, the I/A ratio dropped significantly to 0.03, and most responding cells were linked to several joints. These data, which cannot be explained by the classic "box" model, endorse Mink's hypothesis.

Animals↗
PubMedDate not supplied

6-[18F]fluoro-L-dopa and cerebral blood flow in unilaterally MPTP-treated monkeys.

Intravenous administration of 15O-labeled water and 6-[18F]-L-fluorodopa were used to assess abnormal striatal activity in monkeys after long-term recovery of unilateral lesions of the dopaminergic nigro-striatal system induced by the neurotoxin MPTP. PET data were examined in relation to behavioral and biological parameters. Cerebral blood flow and 6-[18F]-L-DOPA uptake were found to be significantly reduced in the lesioned striatum, compared to the unaffected side and to normal controls. There was no correlation between cerebral blood flow and any of the behavioral parameters. The uptake rate constant of 18F-DOPA from blood to striatum and the ratios of striatum to occipital areas were highly correlated to the concentrations of homovanillic acid in the cerebrospinal fluid of the same animals but not to the rotational behavior. This MPTP-induced model of striatal dopamine deficiency in primates presents similarities with idiopathic Parkinson's disease and may be used to evaluate the effects of dopaminergic lesions and transplants on brain function.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Experimental parkinsonism in primates.

Early in the 1960s the primate model of Parkinson's disease was first introduced by placing an electrolytic lesion in the midbrain. In the 1980s, a dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was accidentally shown to induce parkinsonism in humans, and subsequently was confirmed to reproduce an almost perfect model of parkinsonism in primates. In the late 1980s chemical manipulations of the basal ganglia were shown to induce parkinson symptoms, especially dyskinesia, and more recently, chemical lesioning of the pedunculopontine tegmental nucleus has also been shown to induce parkinsonism. We still do not have a perfect animal model of parkinsonism, however, these models have offered excellent opportunities to study the basic mechanisms in parkinsonism and the function of the basal ganglia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

The role of the pedunculopontine tegmental nucleus in experimental parkinsonism in primates.

To clarify the role of the pedunculopontine tegmental nucleus (PPN) in motor behavior, we have conducted a series of experiments in primates. In the first part, PPN was damaged locally with kainic acid, which resulted in mild hemiparkinsonism in the contralateral limbs. In the second part, muscimol (a GABA agonist) was locally injected into the PPN area in monkeys who had been trained to perform a lever-pull movement with an arm, resulting in a slowness of movement and a delay of the movement onset. In the third part, a dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was systemically injected in monkeys with prior PPN lesioning. These monkeys developed no, or if any, very mild parkinsonism. PPN lesioning was supposed to have protected the nigral neurons from the MPTP- toxicity. The PPN facilitates the motor system through its nigral projection. The decreased activity of the PPN may underlie the pathophysiology of parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Circadian determinations of cortisol, prolactin and melatonin in chronic methyl-phenyl-tetrahydropyridine-treated monkeys.

The aim of this study was to investigate whether prolactin, melatonin and cortisol are altered in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and if so, whether MPTP may alter the availability of these hormones in chronic experimental parkinsonism. Furthermore, vegetative and sleep disorders have been described in both parkinsonian patients and in MPTP chronic monkeys; these may result indirectly from concomitant hormonal variations. Seven adult male cynomolgus monkeys were used for this experiment. Five were treated with systemic doses of intravenous MPTP but not with L-DOPA or dopaminergic agonists. In their 3rd year of parkinsonism, plasma samples were obtained day and night at 3-hour intervals. Sample collection was repeated three times for each animal. Prolactin, melatonin and cortisol concentrations were determined by enzyme immunoassay and compared with samples taken from the control group. Both MPTP-treated monkeys and the control group displayed a similar secretion pattern for the three hormones, except at several specific times when prolactin and melatonin showed significant differences. No changes were found for cortisol. The results suggest a possible alteration of hormonal metabolism in chronic MPTP parkinsonian monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Time-course evaluation of whole blood phagocytosis in mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Immunological abnormalities have been described in idiopathic Parkinson's disease and in the mouse model of this disorder induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This investigation was aimed to study the effect of MPTP on inflammatory response of whole blood phagocytes at different time intervals. C57BL male mice were injected intraperitoneally with either MPTP (30 mg/kg) or saline (control group) and the blood samples were collected at 4, 24 and 48 h. 50 microl of a 500-fold diluted blood sample was mixed with 150 microl of reaction mixture (0.4 mM luminol + 50 microg opsonized zymosan + 0.1% gelatin, in Hanks' balanced salt solution) and the chemiluminescence (CL) signal was measured in a luminometer at 37 degrees C. Although the CL response of the whole blood from control and MPTP groups was similar at 4 h, a significant increase in the CL signal was observed in MPTP-treated mice at 24 h post-treatment, which got subsided at 48 h. The findings of this study suggest that in an early stage a pro-inflammatory response following MPTP might trigger a chain of potentially toxic pathways mediated by reactive oxygen species, leading to progressive neuronal damage.

Animals↗
PubMed1991

The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice.

To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand.

Animals↗
PubMedDate not supplied

Bridging the gap between in vitro and in vivo toxicology testing.

In vitro systems for neurotoxicological studies can be useful for the investigation of events associated with pertubations of cellular and molecular targets that are similar to those in the intact animal. The toxicities of organophosphorus compounds, which inhibit esterases, and 1,2,3,6-tetrahydropyridine (MPTP), which depletes dopamine, can be studied in human neuroblastoma cells.

Acetylcholinesterase↗
PubMed1995

Effect of intraventricular injection of 1-methyl-4-phenylpyridinium: protection by acetyl-L-carnitine.

1-methyl-4-phenylpyridinium (MPP+) is the bioactivated product of 1-methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyridine (MPTP). The neurotoxic action of MPP+ injected intracerebroventricularly (ICV) in the rat has been studied, using dopaminergic systems in the substantia nigra, striatum, olfactory bulb, median eminence and hypophysis. The following results were obtained: (1) Rats with ICV administration of 1 microliter MPP+ solution (62.5 micrograms of MPP+ rat) showed 50% mortality; (2) The ICV administration of MPP+ produced a decrease in dopamine (DA) concentration in different areas of rat CNS studied: striatum (83%), hypophysis (95%) and median eminence (70%). However, olfactory bulb and substantia nigra were not affected; (3) MPP+ by ICV administration produced neurotoxic effect on the dopaminergic system. We also studied the possible protective action of acetyl-L-carnitine (ALC) against the neurotoxic action of MPP+. Rats were intraperitoneally injected daily for 8 days with 100 mg kg-1 of ALC and 3 days from the beginning of the MPP+ treatment; (4) We found that the ALC treatment significantly protected against mortality produced by the ICV injection of MPP+. Rats treated with ALC showed no mortality; (5) We did not find a protective effect on the dopaminergic system studying either catecholamine concentration or measuring tyrosine hydroxylase, neurofilament or glial fibrillary acid protein; (6) The results suggest that the ALC protective action could be related to energy metabolism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Neurotoxicity risk assessment of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as a synthetic impurity of drugs.

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induces symptoms indistinguishable from those of Parkinson's disease. It selectively destroys dopaminergic neurons in the substantia nigra and the globus pallidus. Death of these same neurons is apparently the cause of idiopathic Parkinson's disease. As phenyl-1,2,3,6 tetrahydropyridine is a commonly encountered subunit in heterocyclic drugs and because MPTP was found as a minor impurity in early batches of a candidate drug at Merck KGaA, it may be assumed that MPTP will also be present as an as yet undiscovered minor impurity in various existing drugs. A neurotoxicity risk assessment on MPTP has been conducted to define the risk of MPTP as an impurity in drugs that are used orally. This risk assessment has shown that compounds containing less than 5.0 p.p.m. MPTP administered orally will not cause a neurotoxicological health risk to patients treated with such a drug.

Animals↗
PubMed2003

Protective action of recombinant neurturin on dopaminergic neurons in substantia nigra in a rhesus monkey model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by muscular trembling palsy due to lack of dopamine (DA) in the substantia nigra-striatum (nigrostriatal) system resulting from the degeneration and necrosis of dopaminergic neurons. No effective cure has been found. Neurturin (NTN) has been demonstrated to act specifically on midbrain (mesencephalic) dopaminergic neurons with protective actions specifically. In the present study, we induced rhesus monkey model of Parkinson's disease by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Rhesus monkeys were randomly divided into a PD model group, NTN treatment group and normal control groups. In the NTN treatment group, 1 mg of E. coli-derived recombinant human NTN was injected into the cerebral ventricles 48 h before the injection of MPTP. Results indicated that Rhesus monkeys in the PD model group acquired PD symptoms that increasingly aggravated over time, while monkeys treated with NTN had less apparent or no symptoms. Using fluorospectrophotometry, the dopamine (DA), 5, 5-hydroxytrytamine (5-HT) and the 5-hydroxyindoleacetic acid (5-HIAA) contents of DA, 5-HT and 5-HIAA in substantia nigra, putamen and caudate nucleus in monkeys from the model group was found to be significantly lower than in the normal control group. While no significant differences were found between monkeys treated with NTN and normal control groups, the contents of DA, 5-HT and 5-HIAA in the NTN treatment group were higher than those observed in the PD model group. A dramatic loss of neurons in the substantia nigra in monkeys in the PD model group was observed by light microscopy, while no obvious loss was observed in the NTN treatment group in which the numbers of neurons were similar to those in normal controls. These results indicate that recombinant human NTN can prevent PD symptoms as well as protect dopaminergic neurons and preserve DA content in midbrain substantia nigra in rhesus monkeys exposed to MPTP.

Animals↗