Abstract
Background: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of l-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of l-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with l-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes. Results: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by l-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-l-DOPA treatment (25 μM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 μM l-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 μM), and was enhanced by concomitant treatment with entacapone (0.3 μM). The uptake of l-DOPA into and the release of glutathione from striatal astrocytes after l-DOPA treatment (100 μM) were inhibited by simultaneous exposure to 3-OMD (100 μM). Conclusions: These data suggest that l-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with l-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance l-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of l-DOPA on dopaminergic neurons.
| Original language | English |
|---|---|
| Article number | 52 |
| Journal | BMC Neuroscience |
| Volume | 17 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jul 25 2016 |
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Keywords
- 3-O-Methyldopa
- Astrocyte
- Entacapone
- Glutathione
- l-DOPA
ASJC Scopus subject areas
- Neuroscience(all)
- Cellular and Molecular Neuroscience
Cite this
3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of l-DOPA. / Asanuma, Masato; Miyazaki, Ikuko.
In: BMC Neuroscience, Vol. 17, No. 1, 52, 25.07.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 3-O-Methyldopa inhibits astrocyte-mediated dopaminergic neuroprotective effects of l-DOPA
AU - Asanuma, Masato
AU - Miyazaki, Ikuko
PY - 2016/7/25
Y1 - 2016/7/25
N2 - Background: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of l-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of l-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with l-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes. Results: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by l-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-l-DOPA treatment (25 μM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 μM l-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 μM), and was enhanced by concomitant treatment with entacapone (0.3 μM). The uptake of l-DOPA into and the release of glutathione from striatal astrocytes after l-DOPA treatment (100 μM) were inhibited by simultaneous exposure to 3-OMD (100 μM). Conclusions: These data suggest that l-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with l-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance l-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of l-DOPA on dopaminergic neurons.
AB - Background: We evaluated the effects of 3-O-methyldopa (3-OMD), a metabolite of l-DOPA which is formed by catechol-O-methyltransferase (COMT), on the uptake, metabolism, and neuroprotective effects of l-DOPA in striatal astrocytes. We examined changes in the numbers of dopaminergic neurons after treatment with l-DOPA and 3-OMD or entacapone, a peripheral COMT inhibitor, using primary cultured mesencephalic neurons and striatal astrocytes. Results: The number of tyrosine hydroxylase-positive dopaminergic neurons was not affected by l-DOPA treatment in mesencephalic neurons alone. However, the increase in viability of dopaminergic neurons in the presence of astrocytes was further enhanced after methyl-l-DOPA treatment (25 μM) in mixed cultured mesencephalic neurons and striatal astrocytes. The neuroprotective effect of 25 μM l-DOPA was almost completely inhibited by simultaneous treatment with 3-OMD (10 or 100 μM), and was enhanced by concomitant treatment with entacapone (0.3 μM). The uptake of l-DOPA into and the release of glutathione from striatal astrocytes after l-DOPA treatment (100 μM) were inhibited by simultaneous exposure to 3-OMD (100 μM). Conclusions: These data suggest that l-DOPA exerts its neuroprotective effect on dopaminergic neurons via astrocytes and that 3-OMD competes with l-DOPA by acting on target molecule(s) (possibly including glutathione) released from astrocytes. Since some amount of entacapone can cross the blood-brain barrier, this reagent may enhance l-DOPA transportation by inhibiting COMT and increase the astrocyte-mediated neuroprotective effects of l-DOPA on dopaminergic neurons.
KW - 3-O-Methyldopa
KW - Astrocyte
KW - Entacapone
KW - Glutathione
KW - l-DOPA
UR - http://www.scopus.com/inward/record.url?scp=84979210744&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979210744&partnerID=8YFLogxK
U2 - 10.1186/s12868-016-0289-0
DO - 10.1186/s12868-016-0289-0
M3 - Article
C2 - 27456338
AN - SCOPUS:84979210744
VL - 17
JO - BMC Neuroscience
JF - BMC Neuroscience
SN - 1471-2202
IS - 1
M1 - 52
ER -