Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If You Use a Screen Reader

This content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.

Potent Blockade of Sodium Channels and Protection of Brain Tissue from Ischemia by BIII 890 CL

Adrian J. Carter, Matthias Grauert, Uwe Pschorn, Wolf Dietrich Bechtel, Christina Bartmann-Lindholm, Yusheng Qu, Todd Scheuer, William A. Catterall and Thomas Weiser
Proceedings of the National Academy of Sciences of the United States of America
Vol. 97, No. 9 (Apr. 25, 2000), pp. 4944-4949
Stable URL: http://www.jstor.org/stable/122496
Page Count: 6
  • Read Online (Free)
  • Subscribe ($19.50)
  • Cite this Item
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Potent Blockade of Sodium Channels and Protection of Brain Tissue from Ischemia by BIII 890 CL
Preview not available

Abstract

We have synthesized a new benzomorphan derivative, 2R-[2α ,3(S*),6α ]-1,2,3,4,5,6,-hexahydro-6,11,11-trimethyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced [3H]batrachotoxinin A-20α -benzoate from neurotoxin receptor site 2 of the Na+ channel in rat brain synaptosomes (IC50 = 49 nM), but exhibited only low affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na+ channels in cells transfected with type IIA Na+ channel α subunits and shifted steady-state inactivation curves to more negative potentials. The IC50 value for the inactivated Na+ channel was much lower (77 nM) than for Na+ channels in the resting state (18 μ M). Point mutations F1764A and Y1771A in transmembrane segment S6 in domain IV of the α subunit reduced the voltage- and frequency-dependent block, findings which suggest that BIII 890 CL binds to the local anesthetic receptor site in the pore. BIII 890 CL inhibited veratridine-induced glutamate release in brain slices, as well as glutamate release and neurotoxicity in cultured cortical neurons. BIII 890 CL (3-30 mg/kg s.c.) reduced lesion size in mice and rats when administered 5 min after permanent focal cerebral ischemia at doses that did not impair motor coordination. In contrast to many other agents, BIII 890 CL was neuroprotective in both cortical and subcortical regions of the rat brain. Our results demonstrate that BIII 890 CL is a potent, selective, and highly use-dependent Na+ channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents.

Page Thumbnails

  • Thumbnail: Page 
4944
    4944
  • Thumbnail: Page 
4945
    4945
  • Thumbnail: Page 
4946
    4946
  • Thumbnail: Page 
4947
    4947
  • Thumbnail: Page 
4948
    4948
  • Thumbnail: Page 
4949
    4949