Neuronal Nitric Oxide Synthase Inhibition Prevents Cerebral Palsy following Hypoxia-Ischemia in Fetal Rabbits: Comparison between JI-8 and 7-Nitroindazole
Open accessAbstract
Cerebral palsy and death are serious consequences of perinatal hypoxia-ischemia (HI). Important concepts can now be tested using an animal model of cerebral palsy. We have previously shown that reactive oxygen and nitrogen species are produced in antenatal HI. A novel class of neuronal nitric oxide synthase (nNOS) inhibitors have been designed, and they ameliorate postnatal motor deficits when administered prior to the hypoxic-ischemic insult. This study asks how the new class of inhibitors, using JI-8 (K i for nNOS: 0.014 µ M) as a representative, compare with the frequently used nNOS inhibitor 7-nitroindazole (7-NI; K i: 0.09 ± 0.024 µ M). A theoretical dose equivalent to 75 K i of JI-8 or equimolar 7-NI was administered to pregnant rabbit dams 30 min prior to and immediately after 40 min of uterine ischemia at 22 days gestation (70% term). JI-8 treatment resulted in a significant decrease in NOS activity (39%) in fetal brain homogenates acutely after HI, without affecting maternal blood pressure and heart rate. JI-8 treatment resulted in 33 normal kits, 2 moderately and 13 severely affected kits and 5 stillbirths, compared with 8 normal, 3 moderately affected and 5 severely affected kits and 10 stillbirths in the 7-NI group. In terms of neurobehavioral outcome, 7-NI was not different from saline treatment, while JI-8 was superior to saline and 7-NI in its protective effect (p < 0.05). In the surviving kits, JI-8 significantly improved the locomotion score over both saline and 7-NI scores. JI-8 was also significantly superior to saline in preserving smell, muscle tone and righting reflex function, but 7-NI did not show significant improvement. Furthermore, a 100-fold increase in the dose (15.75 µmol/kg) of 7-NI significantly decreased systolic blood pressure in the dam, while JI-8 did not. The new class of inhibitors such as JI-8 shows promise in the prevention of cerebral palsy and is superior to the previously more commonly used nNOS inhibitor.
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Other regulators of NOX4 include TNF-α, hypoxia, and PDGF.
“Other regulators include TNF-α (70, 681, 884, 1048), hypoxia (455), and PDGF (487).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1048]
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- Authors
- Yu, L., Derrick, M., Ji, H., Silverman, R. B., Whitsett, J., Vásquez-Vivar, J., & Tan, S.
- Affiliations
- Endeavor Health (US)
- Medical College of Wisconsin (US)
- Venue
- Developmental Neuroscience
- Publisher
- S. Karger AG
- Published
- 2011
- Volume
- 33
- Issue
- 3-4
- Pages
- 312-319
- ISSN
- 0378-5866 (ISSN-L)
- 1421-9859
- PMC
- PMC3225251
- OpenAlex
- W2091163223
- Cited by
- 38
- References
- 39
- Citations by year
- 2024: 2 · 2023: 6 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 6 · 2012: 2
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Developmental Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM049725, R01GM049725)
- National Institute of Neurological Disorders and Stroke (NS 043285, R01NS043285, NS063141, R01NS051402, R56NS043285, NS051402, R21NS063141)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Cerebral Palsy and Movement Disorders
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- neuronal nitric oxide synthase inhibition, cerebral palsy prevention, hypoxia-ischemia, 7-nitroindazole, perinatal hypoxia-ischemia, fetal brain, neuroprotection, reactive oxygen and nitrogen species, neurobehavioral outcomes, locomotion, maternal blood pressure, rabbit fetus, uterine ischemia
- MeSH terms
- Animals, Animals, Newborn, Cerebral Palsy, Enzyme Inhibitors, Female, Fetus, Humans, Indazoles, Neuropsychological Tests, Pregnancy, Rabbits, Hypoxia-Ischemia, Brain, Nitric Oxide Synthase Type I
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