7-Nitroindazole prevents dopamine depletion caused by low concentrations of MPP+ in rat striatal slices
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B Cutillas1, M Espejo, S Ambrosio
1Unitat de Bioquímica, Escola d'Infermeria, Universitat de Barcelona, Spain.
Abstract:
A significant loss of dopamine was found in rat striatal slices incubated with 1-methyl-4-phenylpyridinium ion (MPP+) at a concentration of 2 microM or higher. The addition of 7-nitroindazole, a specific inhibitor of neuronal nitric oxide synthase (nNOS), prevented this effect on dopamine when the concentration of MPP+ was between 2-5 microM, but not at higher concentrations. This protection was reproduced with other less specific NOS-inhibitors, such as nitro-arginine and nitro-arginine methylester. 7-nitroindazole did not protect against the dopamine depletion caused by the non-specific mitochondrial chain blocker rotenone. Neither MPP- nor rotenone significantly increased the nitrite concentration in striatal slices, measured as an index of nitric oxide production. The basal production of nitric oxide may be enough to trigger the dopamine depletion at very low concentrations of MPP+, probably acting synergistically with cytosolic calcium increase. Higher concentrations of MPP+ are toxic by themselves without the mediation of nitric oxide. The inhibition of nNOS may protect against dopamine loss at early stages of a neurodegenerative process, and it could then be considered in the treatment or prevention of neurodegenerative human processes such as Parkinson's disease.
Insights
Inhibiting neuronal nitric oxide synthase (nNOS) protected dopamine levels in rat brain slices treated with MPP+. This suggests nNOS inhibition may help prevent neurodegenerative diseases like Parkinson's.
Area of Science:
- Neuroscience
- Neuropharmacology
- Cellular Biology
Background:
- Dopamine neuron loss is characteristic of Parkinson's disease.
- 1-methyl-4-phenylpyridinium ion (MPP+) is a neurotoxin used to model Parkinsonism.
- Nitric oxide (NO) is implicated in various neurological processes.
Purpose of the Study:
- To investigate the role of neuronal nitric oxide synthase (nNOS) in MPP+-induced dopamine depletion.
- To explore the potential of nNOS inhibition as a neuroprotective strategy.
Main Methods:
- Rat striatal slices were incubated with varying concentrations of MPP+.
- The effect of 7-nitroindazole (a specific nNOS inhibitor) and other NOS inhibitors on dopamine levels was assessed.
- Rotenone, a mitochondrial inhibitor, was used as a control.
- Nitrite levels were measured as an indicator of nitric oxide production.
Main Results:
- MPP+ (≥2 microM) caused significant dopamine loss in striatal slices.
- 7-nitroindazole and other NOS inhibitors protected against dopamine depletion at lower MPP+ concentrations (2-5 microM) but not higher.
- nNOS inhibition did not protect against rotenone-induced dopamine depletion.
- Neither MPP+ nor rotenone significantly increased nitrite levels.
Conclusions:
- Basal nitric oxide production may synergize with low MPP+ concentrations to cause dopamine depletion.
- High MPP+ concentrations are directly toxic, independent of nitric oxide.
- Inhibiting nNOS shows potential for protecting against dopamine loss in early neurodegenerative processes, possibly aiding Parkinson's disease treatment.
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