Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann Neurol 2009 Feb;65(2):209-17
Date
02/24/2009Pubmed ID
19235180Pubmed Central ID
PMC2658647DOI
10.1002/ana.21555Scopus ID
2-s2.0-62549102043 (requires institutional sign-in at Scopus site) 71 CitationsAbstract
OBJECTIVE: To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP.
METHODS: We used a novel computer-based drug design method called fragment hopping to identify new chemical entities, synthesized them, and conducted in vitro enzyme inhibition studies with the three isozymes of NOS and in vivo experiments to monitor cardiovascular effects on pregnant rabbit dams, NOS activity, and NO(x) (NO and NO(2)) concentration in fetal brain, and assess neurobehavioral effects on kits born to saline- and compound treated dams.
RESULTS: The computer-based design led to the development of powerful and highly selective compounds for inhibition of neuronal NOS over the other isozymes. After maternal administration in a rabbit model of CP, these compounds were found to distribute to fetal brain, to be nontoxic, without cardiovascular effects, inhibit fetal brain NOS activity in vivo, reduce NO concentration in fetal brain, and dramatically ameliorate deaths and number of newborn kits exhibiting signs of CP.
INTERPRETATION: This approach may lead to new preventive strategies for CP.
Author List
Ji H, Tan S, Igarashi J, Li H, Derrick M, Martásek P, Roman LJ, Vásquez-Vivar J, Poulos TL, Silverman RBAuthor
Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Arginine
Behavior, Animal
Blood Pressure
Brain
Cerebral Palsy
Citrulline
Crystallography, X-Ray
Disease Models, Animal
Drug Design
Enzyme Inhibitors
Female
Male
Neuroprotective Agents
Nitric Oxide
Nitric Oxide Synthase Type I
Pregnancy
Rabbits
Structure-Activity Relationship
