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Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy.
- Source :
-
Annals of neurology [Ann Neurol] 2009 Feb; Vol. 65 (2), pp. 209-17. - Publication Year :
- 2009
-
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.<br />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.<br />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.<br />Interpretation: This approach may lead to new preventive strategies for CP.
- Subjects :
- Animals
Animals, Newborn
Arginine metabolism
Behavior, Animal drug effects
Blood Pressure drug effects
Brain drug effects
Brain metabolism
Cerebral Palsy metabolism
Cerebral Palsy pathology
Cerebral Palsy physiopathology
Citrulline metabolism
Crystallography, X-Ray methods
Disease Models, Animal
Drug Design
Enzyme Inhibitors chemistry
Female
Male
Nitric Oxide metabolism
Nitric Oxide Synthase Type I metabolism
Pregnancy
Rabbits
Structure-Activity Relationship
Cerebral Palsy prevention & control
Enzyme Inhibitors therapeutic use
Neuroprotective Agents therapeutic use
Nitric Oxide Synthase Type I antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1531-8249
- Volume :
- 65
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Annals of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 19235180
- Full Text :
- https://doi.org/10.1002/ana.21555