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Role of nitric oxide synthase against MPTP neurotoxicity in mice
R Kurosaki1, Y Muramatsu, M Michimata
1Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Sendai, Japan.
Abstract:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway injury similar to that observed in Parkinson's disease. Many hypotheses have been proposed to explain the mechanisms underlying MPTP neurotoxicity. Previous work showed that the inhibitor of neuronal nitric oxide synthase (nNOS) might produce protection against MPTP-induced dopaminergic toxicity. To exactly test the role of NO in MPTP neurotoxicity, we examined the effect of nNOS inhibitor 7-nitroindazole, in comparison with that of nonselective NOS inhibitor (L-NAME), immunosuppressant (FK-506), monoamine oxidase (MAO) inhibitors (clorgyline and pargyline), N-methyl-D-aspartate receptor antagonist (MK-801) and Ca2+ antagonist (amlodipine). Among seven compounds, 7-nitroindazole produced dose-dependent protection against MPTP-induced depletion of striatal dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid (DOPAC) in mice. Clorgyline and pargyline also showed a significant effect on MPTP-induced dopamine depletion in the mouse striatum. However, both compounds did not protect against MPTP-induced depletion of striatal DOPAC Our immunohistological study with tyrosine hydroxylase (TH) and microtuble-associated protein 2 (MAP 2) showed that 7-nitroindazole or pargyline can protect against MPTP-induced depletion of TH and MAP 2 immunostained neurons in the substantia nigra. Furthermore, these compounds reduced a marked increase in GFAP-positive astrocytes of the mouse striatum after MPTP treatments. The present study demonstrates that nNOS inhibitor 7-nitroindazole as well as MAO inhibitors clorgyline and pargyline can produce dose-dependent neuroprotection against the dopaminergic neurotoxicity of MPTP. However, nonselective NOS inhibitor L-NAME, immunosuppressant FK-506, NMDA receptor antagonist MK-801 and Ca2+ antagonist amlodipine did not show a beneficial effect on MPTP neurotoxicity.
Insights
The nNOS inhibitor 7-nitroindazole and MAO inhibitors clorgyline and pargyline protect against MPTP-induced neurotoxicity. These compounds offer dose-dependent neuroprotection, unlike other tested agents, highlighting their potential therapeutic role in Parkinson's disease models.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure induces nigrostriatal dopaminergic pathway injury, mimicking Parkinson's disease pathology.
- Nitric oxide synthase (NOS) activity, particularly neuronal NOS (nNOS), has been implicated in the mechanisms of MPTP neurotoxicity.
Purpose of the Study:
- To investigate the precise role of nitric oxide (NO) in MPTP-induced neurotoxicity.
- To evaluate the neuroprotective potential of an nNOS inhibitor (7-nitroindazole) and other pharmacological agents against MPTP toxicity.
Main Methods:
- Mice were treated with MPTP and various compounds, including nNOS inhibitor 7-nitroindazole, nonselective NOS inhibitor L-NAME, MAO inhibitors (clorgyline, pargyline), an NMDA receptor antagonist (MK-801), and a Ca2+ antagonist (amlodipine).
- Striatal dopamine and DOPAC levels were measured.
- Immunohistochemistry was used to assess tyrosine hydroxylase (TH) and MAP 2 positive neurons in the substantia nigra and GFAP-positive astrocytes in the striatum.
Main Results:
- 7-Nitroindazole demonstrated dose-dependent protection against MPTP-induced depletion of striatal dopamine and DOPAC.
- Clorgyline and pargyline significantly reduced dopamine depletion but not DOPAC levels; however, they protected TH and MAP 2 positive neurons.
- L-NAME, FK-506, MK-801, and amlodipine did not show significant neuroprotective effects against MPTP toxicity.
Conclusions:
- Inhibition of nNOS by 7-nitroindazole provides significant neuroprotection against MPTP-induced dopaminergic neurotoxicity.
- MAO inhibitors clorgyline and pargyline also exhibit neuroprotective properties against MPTP, suggesting multiple pathways are involved.
- These findings underscore the potential of targeting nNOS and MAO for therapeutic strategies in Parkinson's disease.