Original Article

Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy†

  1. Haitao Ji PhD1,
  2. Sidhartha Tan MD2,
  3. Jotaro Igarashi PhD3,‡,
  4. Huiying Li PhD3,
  5. Matthew Derrick MD2,
  6. Pavel Martásek MD4,5,
  7. Linda J. Roman PhD4,
  8. Jeannette Vásquez-Vivar PhD6,
  9. Thomas L. Poulos PhD3,
  10. Richard B. Silverman PhD1,*

Article first published online: 20 FEB 2009

DOI: 10.1002/ana.21555

Issue

Annals of Neurology

Annals of Neurology

Volume 65, Issue 2, pages 209–217, February 2009

Additional Information

How to Cite

Ji, H., Tan, S., Igarashi, J., Li, H., Derrick, M., Martásek, P., Roman, L. J., Vásquez-Vivar, J., Poulos, T. L. and Silverman, R. B. (2009), Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann Neurol., 65: 209–217. doi: 10.1002/ana.21555

Author Information

  1. 1

    Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL

  2. 2

    Department of Pediatrics, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL

  3. 3

    Departments of Molecular Biology and Biochemistry, Pharmaceutical Sciences, and Chemistry, University of California, Irvine, CA

  4. 4

    Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX

  5. 5

    Department of Pediatrics and Center for Applied Genomics, 1st School of Medicine, Charles University, Prague, Czech Republic

  6. 6

    Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI

  1. ‡

    Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan

*Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113

  1. †

    Potential conflict of interest: Nothing to report.

Publication History

  1. Issue published online: 3 MAR 2009
  2. Article first published online: 20 FEB 2009
  3. Manuscript Accepted: 15 SEP 2008
  4. Manuscript Revised: 2 SEP 2008
  5. Manuscript Received: 29 APR 2008

Funded by

  • NIH. Grant Numbers: GM49725, NS43285, NS051402, GM57353, HL067244, NS54017, GM52419
  • Robert A. Welch Foundation. Grant Number: AQ1192
  • MSMT of the Czech Republic. Grant Numbers: 0021620806, 1M0520

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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 NOx (NO and NO2) 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. Ann Neurol 2008

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