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Apomorphine protects against MPTP-induced neurotoxicity in mice
E Grünblatt1, S Mandel, T Berkuzki
1Technion Faculty of Medicine, Eve Topf and US National Parkinson's Foundation Centers for Neurodegenerative Diseases, Bruce Rappaport Family Research Institute, Haifa, Israel.
Abstract:
R-apomorphine is a potent radical scavenger and iron chelator. The neuroprotective property of R-apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Pretreatment with 5-10 mg/kg R-apomorphine administered subcutaneously in C57BL mice protects against MPTP (24 mg/kg administered intraperitoneally) induced loss of nigrostriatal dopamine neurons as indicated by striatal dopamine content, tyrosine hydroxylase content, and tyrosine hydroxylase activity. In vitro, R-apomorphine inhibited mice striatal MAO-A and MAO-B activities with IC50 values of 93 microM and 241 microM. It is suggested that the neuroprotective effect of R-apomorphine against MPTP neurotoxicity derives from its radical scavenging and MAO inhibitory actions and not from its agonistic activity because the mechanism of MPTP dopaminergic neurotoxicity involves the generation of oxygen radical species-induced oxidative stress.
Insights
R-apomorphine protects against Parkinson's disease by scavenging radicals and inhibiting MAO enzymes. This neuroprotective effect in the MPTP model highlights its potential therapeutic benefits.
Area of Science:
- Neuroscience
- Pharmacology
- Oxidative Stress Research
Background:
- Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons.
- MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin used to model PD, inducing oxidative stress and neuronal death.
- R-apomorphine exhibits dopamine D1-D2 receptor agonism, radical scavenging, and iron chelating properties.
Purpose of the Study:
- To investigate the neuroprotective effects of R-apomorphine in the MPTP mouse model of Parkinson's disease.
- To determine if R-apomorphine's neuroprotection is mediated by its radical scavenging and MAO inhibitory activities or its dopaminergic agonism.
Main Methods:
- C57BL mice were pretreated with R-apomorphine before MPTP administration.
- Neuroprotection was assessed by measuring striatal dopamine and tyrosine hydroxylase (TH) content and TH activity.
- In vitro studies evaluated R-apomorphine's inhibition of monoamine oxidase A (MAO-A) and MAO-B activities.
Main Results:
- R-apomorphine pretreatment significantly protected nigrostriatal dopamine neurons against MPTP-induced neurotoxicity.
- Neuroprotection was evidenced by preserved striatal dopamine levels, TH content, and TH activity.
- R-apomorphine demonstrated in vitro inhibition of MAO-A (IC50 = 93 µM) and MAO-B (IC50 = 241 µM).
Conclusions:
- R-apomorphine exhibits significant neuroprotective effects against MPTP-induced dopaminergic neurotoxicity in mice.
- The neuroprotective mechanism is attributed to R-apomorphine's radical scavenging and MAO inhibitory actions, rather than its dopaminergic agonism.
- These findings suggest R-apomorphine as a potential therapeutic agent for Parkinson's disease, targeting oxidative stress pathways.