Untersuchung neuroprotektiver Effekte von Radikalfängern in Tiermodellen des Morbus Parkinson
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Philipps-Universität Marburg
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Abstract
In the FG/6-OHDA rat model and the MPTP mouse
model, which are both animal models of the idiopathic Parkinson
syndrome, the radical scavengers salicylic acid (SS),
alpha-phenyl-N-tert-butyl nitron (PBN) and Troloxâ methyl ether
(Trolox) should be examined with regard to their
neuroprotective effects. The aim of this work was to record the
potential protective effects of these substances concerning
their striatal dopamine content, dopamine turnover, the number
of nigral tyrosinhydroxylase immunreactive (TH-ir) neurons. And
additionally in the FG/6-OHDA-model the number of nigral
fluorogold positive (FG-p) neurons as well as in the MPTP-model
the mice's locomotor activity was registered. FG/6-OHDA rat
model. With the help of those parameter a significant lesion of
nigral dopaminergic neurons with consecutive significant
changed neurochemical parameter could be ascertained after an
unilateral intrastriatal injection of 6-OHDA. Apart from a
partial positive effect on the reduction of FG-p neurons and
the striatal dopamine content, the SS did not show any
protective influence on the changes caused by 6-OHDA. In this
with 10mg/kg BW low dosage long-term treatment (2 weeks pre and
4 weeks post lesion; i.p.) in comparison to studies in the MPTP
mouse model with a 5-10 times higher dose of SS, which describe
a significant protective effect (Aubin et al. 1998), a
neuroprotective effect in this dosage area might also be
possible in FG/6-OHDA model. This has to be proven by further
studies. It was hinted at the gastrointestinal side effects to
be expected because of the chronic therapy with SS in high
dosage. In the FG/6-OHDA-model PBN was given low measured
(75mg/kg BW; i.p.) and high measured (150 mg/kg BW; i.p.) 2
weeks before and 4 weeks after lesion. Within both dosages no
significant neuroprotective effect could be ascertained on all
determined parameters. A significantly reduced number of nigral
TH-ir neurons caused by 150 mg, which was partly reflected by
the reduced number of FG-p neurons, but not on the
neurochemical level, could even make us presume a
dose-dependent neurotoxic effect in higher dosages. A decisive
factor seems to be the comparatively long duration of treatment
in contrast to other experimental animal studies within the
same dosage area, since those did not describe a toxic effect
on behavioral parameters. Morphologic correlates were not
scanned. This would be against a neuroprotective application on
humans/human beings, for this would rather be used in the form
of a long-term treatment. A stimulation of the dopamine
synthesis with PBN in intact nigrostriatal neurons could be
discussed in consideration of missing simultaneous reduction of
the striatal dopamine content. MPTP mouse model The single
subcutaneous application of 30 mg/kg BW MPTP also led to a
significant reduction of nigral dopaminergic TH-ir neurons,
which also had significant effects on the determined
neurochemical and behavioural parameter. In its degree this
lesion corresponds most likely to the earlier stages of the
human IPS (Schmidt and Ferger 2001). In the MPTP model the
lipophilic vitamin E derivative Trolox was tested in high (300
mg/kg BW) and low (100 mg/kg BW) dosage by means of a single
administration directly before the application of toxin. Apart
from a significant reduction of the postlesional increased
turnover of dopamine within the 300 mg/kg KG Trolox treatment
group there was no positive effect on all further determined
parameters. But remarkably all data were registered in the
order Trolox 300 > Trolox 100 > NaCl for the affected
animals, which might let you think about a dose-dependent
effect suggesting that further studies with a higher dosage of
Trolox could be successful, particularly as there were no
intolerable side effects. In summary, because of the
ascertained data and the studies that have been worked on, a
neuroprotective effect of Trolox and SS in a higher dosage than
the one applied in this case of the FG/6-OHDA model is
probable, but the combination of a water-soluble with a
fat-soluble antioxidant might even be more promising. Over and
above that PBN in the FG/6-OHDA model of rats did not prove
neuroprotection, it even showed neurotoxic effects in higher
dosages, which especially should be urgently specified in
further long-term studies, how it would be applied in human
beings in the case of a chronic degenerative
disease.
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Dates
Created: 2004Issued: 2004-04-01Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Radical scavengerThyrosinhydroxylase , Dopaminoxidative stress6-OHDAROS , MPTPSalicylsäurePBNSalicylic acidPBN , TroloxTH ,Parkinson's disease , NeuroprotectionTroloxASS6-OHDA
DFG-subjects
Oxidativer StressParkinson-KrankheitMPTP , NeuroprotektivumNervendegenerationRadikalfänger
DDC-Numbers
610
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Fritsch, Brita (128939842): Untersuchung neuroprotektiver Effekte von Radikalfängern in Tiermodellen des Morbus Parkinson. : Philipps-Universität Marburg 2004-04-01. DOI: https://doi.org/10.17192/z2004.0208.
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This item has been published with the following license: In Copyright