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Effects of R- and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss
E Grünblatt1, S Mandel, G Maor
1Eve Topf National Parkinson's Foundation Center for Neurodegenerative Diseases, Technion, Israel.
Abstract:
In order to establish whether the antioxidant and iron-chelating activities of R-apomorphine (R-APO), a D(1)-D(2) receptor agonist, may contribute to its neuroprotective property, its S-isomer, which is not a dopamine agonist, was studied. The neuroprotective property of R- and S-APO has been studied in the MPTP model of Parkinson's disease (PD). Both S-APO (0.5-1 mg/kg, subcutaneous) and R-APO (10 mg/kg) pretreatment of C57-BL mice, protected against MPTP (24 mg/kg, intraperitoneally) induced dopamine (DA) depletion and reduction in tyrosine hydroxylase (TH) activity. However, only R-APO prevented nigro-striatal neuronal cell degeneration, as indicated by the immunohistochemistry of TH positive neurones in substantia nigra and by western analysis of striatal TH content. R-APO prevented the reduction of striatal-GSH and the increase in the ratio of GSSG over total glutathione, caused by MPTP treatment. In vitro both R-APO and S-APO inhibited monoamine oxidase A and B activity at relatively high concentrations (100 and 300 micromol/L, respectively). The elevated activity of TH induced by the two enantiomers may contribute to the maintenance of normal DA levels, suggesting that one of the targets of these molecules may involve upregulation of TH activity. It is suggested that the antioxidant and iron-chelating properties, possible monoamine oxidase inhibitory actions, together with activation of DA receptors, may participate in the mechanism of neuroprotection by APO enantiomers against MPTP.
Insights
R-apomorphine and S-apomorphine enantiomers show neuroprotective effects in Parkinson's disease models. R-apomorphine specifically prevents neuronal degeneration by maintaining dopamine levels and antioxidant status.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Parkinson's disease (PD) is a neurodegenerative disorder.
- MPTP model is used to study PD pathogenesis.
- Dopamine (DA) depletion and tyrosine hydroxylase (TH) activity reduction are key markers in PD.
Purpose of the Study:
- To investigate the neuroprotective properties of R-apomorphine (R-APO) and S-apomorphine (S-APO).
- To determine if antioxidant and iron-chelating activities contribute to R-APO's neuroprotection.
- To compare the effects of R-APO and S-APO in the MPTP model of PD.
Main Methods:
- MPTP model of Parkinson's disease in C57-BL mice.
- Pretreatment with R-APO and S-APO.
- Measurement of dopamine depletion and tyrosine hydroxylase (TH) activity.
- Immunohistochemistry for TH-positive neurons.
- Western analysis of striatal TH content.
- Measurement of glutathione (GSH) and glutathione disulfide (GSSG).
- In vitro inhibition assays for monoamine oxidase A and B (MAO-A, MAO-B).
Main Results:
- Both R-APO and S-APO pretreatment protected against MPTP-induced dopamine depletion and reduced TH activity.
- Only R-APO prevented nigro-striatal neuronal degeneration.
- R-APO maintained striatal glutathione levels and prevented GSSG increase.
- Both enantiomers inhibited MAO-A and MAO-B at high concentrations.
- Elevated TH activity was observed with both enantiomers.
Conclusions:
- R-apomorphine exhibits significant neuroprotective effects in the MPTP model, superior to S-apomorphine.
- Antioxidant properties, iron-chelation, MAO inhibition, and DA receptor activation may contribute to APO enantiomers' neuroprotection.
- Upregulation of TH activity is a potential mechanism for maintaining dopamine levels.
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