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Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann Neurol 2009 Feb;65(2):209-17

Date

02/24/2009

Pubmed ID

19235180

Pubmed Central ID

PMC2658647

DOI

10.1002/ana.21555

Abstract

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 RB

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Animals, 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
jenkins-FCD Prod-398 336d56a365602aa89dcc112f077233607d6a5abc