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Published on: January 7, 2014
Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo
1Department of Neurology, University of Tübingen, Germany.
Abstract:
MPTP produces clinical, biochemical, and neuropathologic changes reminiscent of those that occur in idiopathic Parkinson's disease (PD). In the present study we show that MPTP treatment led to activation of microglia in the substantia nigra pars compacta (SNpc), which was associated and colocalized with an increase in inducible nitric oxide synthase (iNOS) expression. In iNOS-deficient mice the increase of iNOS expression but not the activation of microglia was blocked. Dopaminergic SNpc neurons of iNOS-deficient mice were almost completely protected from MPTP toxicity in a chronic paradigm of MPTP toxicity. Because the MPTP-induced decrease in striatal concentrations of dopamine and its metabolites did not differ between iNOS-deficient mice and their wild-type littermates, this protection was not associated with a preservation of nigrostriatal terminals. Our results suggest that iNOS-derived nitric oxide produced in microglia plays an important role in the death of dopaminergic neurons but that other mechanisms contribute to the loss of dopaminergic terminals in MPTP neurotoxicity. We conclude that inhibition of iNOS may be a promising target for the treatment of PD.
Insights
MPTP neurotoxicity activates microglia and increases iNOS expression, leading to dopaminergic neuron death in Parkinson's disease models. Inhibiting iNOS protects these neurons, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- MPTP induces Parkinson's disease (PD)-like symptoms.
- Microglial activation and iNOS expression are observed in the substantia nigra pars compacta (SNpc) after MPTP exposure.
Purpose of the Study:
- To investigate the role of inducible nitric oxide synthase (iNOS) in MPTP-induced neurotoxicity.
- To determine if iNOS deficiency protects dopaminergic neurons in the SNpc.
Main Methods:
- MPTP administration to wild-type and iNOS-deficient mice.
- Assessment of microglial activation, iNOS expression, and dopaminergic neuron survival in the SNpc.
- Measurement of dopamine and its metabolites in the striatum.
Main Results:
- MPTP treatment activated microglia and increased iNOS expression in the SNpc.
- iNOS deficiency blocked iNOS upregulation but not microglial activation.
- Dopaminergic SNpc neurons were protected in iNOS-deficient mice.
- Protection was not linked to preserved nigrostriatal terminals or striatal dopamine levels.
Conclusions:
- iNOS-derived nitric oxide from microglia is crucial for dopaminergic neuron death in MPTP neurotoxicity.
- Other mechanisms contribute to nigrostriatal terminal loss.
- Inhibiting iNOS represents a potential therapeutic strategy for Parkinson's disease.
