Search PubMed⌕ Search
Home/Archive/PubMed

PubMed · 9364513

Thalidomide reduces MPTP-induced decrease in striatal dopamine levels in mice.

A Boireau·F Bordier·P Dubédat·C Pény·A Impérato
View original source ↗Export metadata ↓

Abstract

The effects of thalidomide, a sedative, anti-inflammatory and immunosuppressive agent were studied in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) murine model of Parkinson's disease. The striatal levels of dopamine (DA) and of its main metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured both in the MPTP control group (3 x 15 mg/kg intraperitoneally) and in the thalidomide groups (repeated treatments at 25 mg/kg or 50 mg/kg postoperatively). For mice treated with thalidomide, a dose-dependent protection was observed against the MPTP-induced decrease in DA. The decrease in HVA levels was totally antagonized by thalidomide at both doses. That thalidomide has activity in this model suggests that an inflammatory process may be involved in the induction of lesions by MPTP in DAergic neurons.

Explore related subjects

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine3,4-Dihydroxyphenylacetic AcidAnimalsAnti-Inflammatory AgentsCorpus StriatumDisease Models, AnimalDopamineDose-Response Relationship, DrugHomovanillic AcidHypnotics and SedativesImmunosuppressive AgentsMaleMiceMice, Inbred C57BLParkinson DiseaseThalidomideJournal Article

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

A Boireau, F Bordier, P Dubédat, C Pény, A Impérato. 1997-10-03. Thalidomide reduces MPTP-induced decrease in striatal dopamine levels in mice.. https://doi.org/10.1016/s0304-3940(97)00685-x

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed1999

A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6.

A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been extended with a second pharmacophore in order to explain CYP2D6 catalyzed N-dealkylation reactions. A group of 14 experimentally verified N-dealkylation reactions form the basis of this second pharmacophore. The combined model can now accommodate both the usual hydroxylation and O-demethylation reactions catalyzed by CYP2D6, as well as the less common N-dealkylation reactions. The combined model now contains 72 metabolic pathways catalyzed by CYP2D6 in 51 substrates. The model was then used to predict the involvement of CYP2D6 in the metabolism of a "test set" of seven compounds. Molecular orbital calculations were used to suggest energetically favorable sites of metabolism, which were then examined using modeling techniques. The combined model correctly predicted 6 of the 8 observed metabolites. For the well-established CYP2D6 metabolic routes, the predictive value of the current combined protein and pharmacophore model is good. Except for the highly unusual metabolism of procainamide and ritonavir, the known metabolites not included in the development of the model were all predicted by the current model. Two possible metabolites have been predicted by the current model, which have not been detected experimentally. In these cases, the model may be able to guide experiments. P450 models, like the one presented here, have wide applications in the drug design process which will contribute to the prediction and elimination of polymorphic metabolism and drug-drug interactions.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Lactoferrin is synthesized by mouse brain tissue and its expression is enhanced after MPTP treatment.

The presence of iron in brain tissue in increased concentrations in Parkinson's disease cases, where it might be responsible for oxidative stress, and the parallel observation that the iron transporter lactoferrin (Lf) was present in increased amounts in surviving neurons, led us to study the synthesis of Lf in a mouse model of Parkinson's disease. In this context, the origin and expression of brain Lf in normal, aged and MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine)-treated mice were investigated. Lf immunostaining was observed mainly on microvessels in the cerebral cortex of the adult mice and to a greater extent in older mice. Lf immunoreactivity was also present in the hippocampus only in the aged mouse brains, associated with structures which seemed to be pyramidal neurons and fibers. After RT-PCR (polymerase chain reaction), Lf transcripts were found in mouse brain tissue whatever the age of the animals studied but the level of their expression was very low. No up-regulation of Lf was detectable during aging. Lf distribution and expression in the MPTP-induced Parkinsonian mouse model were also investigated. A marked depletion of dopamine (DA) occurred in the high dose MPTP-treated mice. The level of Lf expression was found to be markedly increased in the same animals and this up-regulation occurred on the first day after MPTP administration. When the brain was stressed by the neurotoxin MPTP, Lf expression increased in line with antioxidant enzymes such as catalase and gamma-glutamylcysteine synthetase, which may permit the protection of brain tissue from oxidative damage induced by the drug.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Metallothionein-I and -II knock-out mice are not more sensitive than control mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.

Oxidative stress, resulting from either excess generation or reduced scavenging of free radicals, has been proposed to play a role in damaging striatal neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Metallothionein (MT) is a scavenger of oxygen-derived free radicals and it has been suggested that MT protects against oxidative damage in the central nervous system. In the present study we compared MT-I and -II null mice (MT-null) and the parental strain with intact metallothionein genes (control mice) to determine whether the absence of MT protein alters MPTP neurotoxicity. Control and MT-null mice were treated with MPTP at different doses (30, 40 and 50 mg/kg, i.p.) for 11 days. Seven days after the last dose, brains were removed and dopamine (DA) and homovanillic acid (HVA) contents were analyzed in striatum and midbrain by high pressure liquid chromatography (HPLC). Striatal DA content in MPTP-treated control mice was reduced by 53, 74 and 84% after 30, 40 and 50 mg/kg, respectively. Similar decreases were observed in MT-null mice treated with MPTP. MT-null mice were not more sensitive than control mice to MPTP neurotoxicity. The data suggest that MT-I and -II proteins do not play a role in protecting against MPTP neurotoxicity.

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