Abstract
Since MPTP and its metabolite MPP+ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP+ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP+ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP+ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP+ provoked large (80%) oxidations of cytochrome b and large Ko+ increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2-4% of the striatal mass, the large MPP+-induced changes suggest that while MPP+ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP+ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intercellular relationships as in intact brain.
| Original language | English |
|---|---|
| Pages (from-to) | 51-57 |
| Number of pages | 7 |
| Journal | Journal of Neuroscience Methods |
| Volume | 28 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Jan 1 1989 |
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Keywords
- Brain slice
- Cytochrome b
- Extracellular potassium
- Hippocampal slice
- MPP
- MPTP
- Striatal slice
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
MPP+-induced pathophysiology demonstrates advantages of neurotoxicology studies in brain slices. / Hollinden, Gary E.; Sanchez-Ramos, Juan R.; Sick, Thomas; Rosenthal, Myron.
In: Journal of Neuroscience Methods, Vol. 28, No. 1-2, 01.01.1989, p. 51-57.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MPP+-induced pathophysiology demonstrates advantages of neurotoxicology studies in brain slices
AU - Hollinden, Gary E.
AU - Sanchez-Ramos, Juan R.
AU - Sick, Thomas
AU - Rosenthal, Myron
PY - 1989/1/1
Y1 - 1989/1/1
N2 - Since MPTP and its metabolite MPP+ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP+ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP+ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP+ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP+ provoked large (80%) oxidations of cytochrome b and large Ko+ increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2-4% of the striatal mass, the large MPP+-induced changes suggest that while MPP+ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP+ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intercellular relationships as in intact brain.
AB - Since MPTP and its metabolite MPP+ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP+ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP+ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP+ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP+ provoked large (80%) oxidations of cytochrome b and large Ko+ increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2-4% of the striatal mass, the large MPP+-induced changes suggest that while MPP+ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP+ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intercellular relationships as in intact brain.
KW - Brain slice
KW - Cytochrome b
KW - Extracellular potassium
KW - Hippocampal slice
KW - MPP
KW - MPTP
KW - Striatal slice
UR - http://www.scopus.com/inward/record.url?scp=0024550550&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0024550550&partnerID=8YFLogxK
U2 - 10.1016/0165-0270(89)90009-5
DO - 10.1016/0165-0270(89)90009-5
M3 - Article
C2 - 2786117
AN - SCOPUS:0024550550
VL - 28
SP - 51
EP - 57
JO - Journal of Neuroscience Methods
JF - Journal of Neuroscience Methods
SN - 0165-0270
IS - 1-2
ER -