title: Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole.
abstract: 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 μM) as a representative, compare with the frequently used nNOS inhibitor 7-nitroindazole (7-NI; K(i): 0.09 ± 0.024 μM). 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.
authors.affiliation: Department of Pediatrics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Matthew
authors.initials: M
authors.lastname: Derrick
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whitsett
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vásquez-Vivar
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Tan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002547:Cerebral Palsy / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D011817:Rabbits
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D052248:Nitric Oxide Synthase Type I; C080122:7-nitroindazole