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Published on: January 7, 2014
Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice
Hironori Yokoyama1, Sho Takagi, Yu Watanabe
1Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan.
Abstract:
There is growing evidence indicating that reactive nitrogen species (RNS) and reactive oxygen species (ROS) are a major contributor to the pathogenesis and progression of Parkinson's disease. Here we investigated whether edaravone (free radical scavenger), minocycline (inducible nitric oxide synthase, iNOS inhibitor), 7-nitroindazole (neuronal NOS, nNOS inhibitor), fluvastatin (endothelial NOS, eNOS activator) and pitavastatin (eNOS activator) can protect against MPTP neurotoxicity in mice under the same condition. The present study showed that 7-nitroindazole could protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletion. Our immunohistochemical study showed that TH (tyrosine hydroxylase) and DAT (dopamine transporter) immunoreactivity was decreased significantly in the striatum and substantia nigra 5 days after MPTP treatment. The administration of 7-nitroindazole showed a protective effect against the severe reductions in levels of TH and DAT immunoreactivity in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the remarkable loss of TH protein levels in the striatum 5 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant loss in TH protein levels in the striatum 5 days after MPTP treatment. On the other hand, GFAP (glial fibrillary acidic protein) immunoreactivity increased significantly in the striatum and substantia nigra, 5 days after MPTP treatment. 7-Nitroindazole ameliorated severe increases in number of GFAP immunoreactive astrocytes in the striatum and substantia nigra 5 days after MPTP treatment. Furthermore, our Western blot analyses study showed the increase of GFAP protein levels in the striatum 5 days after MPTP treatment. 7-Nitroindazole prevented a significant increase in the GFAP protein levels in the striatum 5 days after MPTP treatment. The present results indicate that 7-nitroindazole can protect dose-dependently against the striatal dopamine depletions in mice 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin and pitavastatin did not show the neuroprotective effect on MPTP-induced striatal dopamine depletions. These findings demonstrate that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared to the production of ROS, the overexpression of iNOS and the modulation of eNOS. Thus, our findings provide strong evidence for neuroprotective properties of nNOS inhibitor in this animal model of Parkinson's disease.
Insights
7-Nitroindazole, a neuronal nitric oxide synthase (nNOS) inhibitor, demonstrated dose-dependent neuroprotection against MPTP-induced Parkinson
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Reactive nitrogen species (RNS) and reactive oxygen species (ROS) are implicated in Parkinson's disease pathogenesis.
- MPTP neurotoxicity in mice is a common model for studying Parkinson's disease.
Purpose of the Study:
- To investigate the neuroprotective effects of various compounds against MPTP-induced neurotoxicity in mice.
- To determine the role of different nitric oxide synthase (NOS) isoforms and free radical scavenging in Parkinson's disease progression.
Main Methods:
- MPTP neurotoxicity was induced in mice.
- Mice were treated with edaravone, minocycline, 7-nitroindazole, fluvastatin, and pitavastatin.
- Neuroprotection was assessed by measuring striatal dopamine depletion, tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity, and glial fibrillary acidic protein (GFAP) levels using immunohistochemistry and Western blot.
Main Results:
- 7-Nitroindazole significantly protected against MPTP-induced striatal dopamine depletions in a dose-dependent manner.
- 7-Nitroindazole administration preserved TH and DAT immunoreactivity and protein levels, and reduced GFAP upregulation.
- Edaravone, minocycline, fluvastatin, and pitavastatin did not exhibit neuroprotective effects against MPTP neurotoxicity.
Conclusions:
- Neuronal nitric oxide synthase (nNOS) inhibition confers significant neuroprotection in an MPTP-induced Parkinson's disease mouse model.
- Overexpression of nNOS, rather than ROS, iNOS, or eNOS modulation, appears to play a critical role in MPTP neurotoxicity.
- 7-Nitroindazole shows potential as a therapeutic agent for Parkinson's disease.
