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Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor

BACKGROUND: Our aim was to determine if pramipexole, a D(3 )preferring agonist, effectively reduced dopamine neuron and fiber loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model when given at intraperitoneal doses corresponding to clinical doses. We also determined whether su...

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Autores principales: Joyce, Jeffrey N, Woolsey, Cheryl, Ryoo, Han, Borwege, Sabine, Hagner, Diane
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC524509/
https://www.ncbi.nlm.nih.gov/pubmed/15473914
http://dx.doi.org/10.1186/1741-7007-2-22
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author Joyce, Jeffrey N
Woolsey, Cheryl
Ryoo, Han
Borwege, Sabine
Hagner, Diane
author_facet Joyce, Jeffrey N
Woolsey, Cheryl
Ryoo, Han
Borwege, Sabine
Hagner, Diane
author_sort Joyce, Jeffrey N
collection PubMed
description BACKGROUND: Our aim was to determine if pramipexole, a D(3 )preferring agonist, effectively reduced dopamine neuron and fiber loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model when given at intraperitoneal doses corresponding to clinical doses. We also determined whether subchronic treatment with pramipexole regulates dopamine transporter function, thereby reducing intracellular transport of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+). METHODS: Ten 12-month old C57BL/6 mice were treated with MPTP (or saline) twice per day at 20 mg/kg s.c. (4 injections over 48 h). Mice were pretreated for 3 days and during the 2-day MPTP regimen with pramipexole (0.1 mg/kg/day) or saline. Stereological quantification of dopamine neuron number and optical density measurement of dopamine fiber loss were carried out at 1 week after treatment, using immunostaining for dopamine transporter (DAT) and tyrosine hydroxylase (TH). Additional wild-type (WT) and D(3 )receptor knockout (KO) mice were treated for 5 days with pramipexole (0.1 mg/kg/day) or vehicle. The kinetics of [(3)H]MPP+ and [(3)H]DA uptake (V(max )and K(m)) were determined 24 h later; and at 24 h and 14 days dopamine transporter density was measured by quantitative autoradiography. RESULTS: Pramipexole treatment completely antagonized the neurotoxic effects of MPTP, as measured by substantia nigra and ventral tegmental area TH-immunoreactive cell counts. MPTP- induced loss of striatal innervation, as measured by DAT-immunoreactivity, was partially prevented by pramipexole, but not with regard to TH-IR. Pramipexole also reduced DAT- immunoreactivity in non-MPTP treated mice. Subchronic treatment with pramipexole lowered the V(max )for [(3)H]DA and [(3)H]MPP(+ )uptake into striatal synaptosomes of WT mice. Pramipexole treatment lowered V(max )in WT but not D(3 )KO mice; however, D(3 )KO mice had lower V(max )for [(3)H]DA uptake. There was no change in DAT number in WT with pramipexole treatment or D(3 )KO mice at 24 h post-treatment, but there was a reduction in WT-pramipexole treated and not in D(3 )KO mice at 14 days post-treatment. CONCLUSION: These results suggest that protection occurs at clinically suitable doses of pramipexole. Protection could be due to a reduced amount of MPP(+ )taken up into DA terminals via DAT. D(3 )receptor plays an important role in this regulation of transporter uptake and availability.
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spelling pubmed-5245092004-10-31 Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor Joyce, Jeffrey N Woolsey, Cheryl Ryoo, Han Borwege, Sabine Hagner, Diane BMC Biol Research Article BACKGROUND: Our aim was to determine if pramipexole, a D(3 )preferring agonist, effectively reduced dopamine neuron and fiber loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model when given at intraperitoneal doses corresponding to clinical doses. We also determined whether subchronic treatment with pramipexole regulates dopamine transporter function, thereby reducing intracellular transport of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+). METHODS: Ten 12-month old C57BL/6 mice were treated with MPTP (or saline) twice per day at 20 mg/kg s.c. (4 injections over 48 h). Mice were pretreated for 3 days and during the 2-day MPTP regimen with pramipexole (0.1 mg/kg/day) or saline. Stereological quantification of dopamine neuron number and optical density measurement of dopamine fiber loss were carried out at 1 week after treatment, using immunostaining for dopamine transporter (DAT) and tyrosine hydroxylase (TH). Additional wild-type (WT) and D(3 )receptor knockout (KO) mice were treated for 5 days with pramipexole (0.1 mg/kg/day) or vehicle. The kinetics of [(3)H]MPP+ and [(3)H]DA uptake (V(max )and K(m)) were determined 24 h later; and at 24 h and 14 days dopamine transporter density was measured by quantitative autoradiography. RESULTS: Pramipexole treatment completely antagonized the neurotoxic effects of MPTP, as measured by substantia nigra and ventral tegmental area TH-immunoreactive cell counts. MPTP- induced loss of striatal innervation, as measured by DAT-immunoreactivity, was partially prevented by pramipexole, but not with regard to TH-IR. Pramipexole also reduced DAT- immunoreactivity in non-MPTP treated mice. Subchronic treatment with pramipexole lowered the V(max )for [(3)H]DA and [(3)H]MPP(+ )uptake into striatal synaptosomes of WT mice. Pramipexole treatment lowered V(max )in WT but not D(3 )KO mice; however, D(3 )KO mice had lower V(max )for [(3)H]DA uptake. There was no change in DAT number in WT with pramipexole treatment or D(3 )KO mice at 24 h post-treatment, but there was a reduction in WT-pramipexole treated and not in D(3 )KO mice at 14 days post-treatment. CONCLUSION: These results suggest that protection occurs at clinically suitable doses of pramipexole. Protection could be due to a reduced amount of MPP(+ )taken up into DA terminals via DAT. D(3 )receptor plays an important role in this regulation of transporter uptake and availability. BioMed Central 2004-10-11 /pmc/articles/PMC524509/ /pubmed/15473914 http://dx.doi.org/10.1186/1741-7007-2-22 Text en Copyright © 2004 Joyce et al; licensee BioMed Central Ltd.
spellingShingle Research Article
Joyce, Jeffrey N
Woolsey, Cheryl
Ryoo, Han
Borwege, Sabine
Hagner, Diane
Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor
title Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor
title_full Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor
title_fullStr Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor
title_full_unstemmed Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor
title_short Low dose pramipexole is neuroprotective in the MPTP mouse model of Parkinson's disease, and downregulates the dopamine transporter via the D(3 )receptor
title_sort low dose pramipexole is neuroprotective in the mptp mouse model of parkinson's disease, and downregulates the dopamine transporter via the d(3 )receptor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC524509/
https://www.ncbi.nlm.nih.gov/pubmed/15473914
http://dx.doi.org/10.1186/1741-7007-2-22
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