Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice
Abstract
Abstract: Several studies suggest that nitric oxide (NO•) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7‐nitroindazole (7‐NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7‐NI dose‐dependently protected against MPTP‐induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7‐NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP‐induced depletions of both homovanillic acid and 3,4‐dihydroxyphenylacetic acid. 7‐NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO• is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO−), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3‐nitrotyrosine, which was attenuated by treatment with 7‐NI. Our results suggest that NO• plays a role in MPTP neurotoxicity, as well as novel therapeutic strategies for Parkinson's disease.
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NOS inhibition protected neurons from death in PD mouse models.
“NOS inhibition protected neuron from death in PD mouse models.464–467”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [465]
•NO's dual action makes it a contributing player in pathophysiology and makes development of effective treatments for neurodegenerative diseases particularly difficult.
“This dual action makes it a contributing player in pathophysiology, but also makes the development of effective treatments for neurodegenerative diseases particularly difficult [141,142,143,144,145].”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [144]
Several studies have linked nitric oxide as a key mediator in numerous neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and ischemic brain injury.
“In recent years, several studies have linked nitric oxide as a key mediator in numerous neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and ischemic brain injury (stroke).”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [144]
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Self-citation
- Authors
- Schulz, J. B., Matthews, R. T., Muqit, M. M. K., Browne, S. E., & Beal, M. F.
- Affiliations
- Harvard University (US)
- Corresponding author
- Beal, M. Flint
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1995-02
- Volume
- 64
- Issue
- 2
- Pages
- 936-939
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2130753694
- Cited by
- 417
- References
- 0
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 9 · 2016: 3 · 2015: 7 · 2014: 3 · 2013: 9 · 2012: 6
- FWCI
- 31.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ns031579-05)
- U.S. Public Health Service (16367)
- National Institute of Neurological Disorders and Stroke (NS10828, NS31579)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- 7-nitroindazole, neuronal nitric oxide synthase inhibition, MPTP-induced neurotoxicity, dopaminergic neurotoxicity, nitric oxide, Parkinson's disease, dopamine depletion, homovanillic acid, DOPAC, nitrotyrosine, peroxynitrite, NMDA receptor activation, neuroprotection
- MeSH terms
- Amino Acid Oxidoreductases, Animals, Dopamine, Dose-Response Relationship, Drug, Enzyme Inhibitors, Indazoles, Male, Mice, Inbred Strains, Neurons, Neurotoxins, Tyrosine, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Dopamine Antagonists, Neuroprotective Agents, Nitric Oxide Synthase, Mice
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