Technical Report abstract
Nature Neuroscience 10, 523 - 530 (2007)
Published online: 25 February 2007 | doi:10.1038/nn1862
Anticonvulsant and anesthetic effects of a fluorescent neurosteroid analog activated by visible light
Lawrence N Eisenman1, Hong-Jin Shu2, Gustav Akk3, Cunde Wang4, Brad D Manion3, Geraldine J Kress2, Alex S Evers3,4, Joe Henry Steinbach3,5, Douglas F Covey4, Charles F Zorumski2,5 & Steven Mennerick2,5
Abstract
Most photoactivatable compounds suffer from the limitations of the ultraviolet wavelengths that are required for activation. We synthesized a neuroactive steroid analog with a fluorescent (7-nitro-2,1,3-benzoxadiazol-4-yl) amino (NBD) group in the 
configuration at the C2 position of (3
,5)-3-hydroxypregnan-20-one (allopregnanolone, 35P). Light wavelengths (480 nm) that excite compound fluorescence strongly potentiate GABAA receptor function. Potentiation is limited by photodepletion of the receptor-active species. Photopotentiation is long-lived and stereoselective and shows single-channel hallmarks similar to steroid potentiation. Other NBD-conjugated compounds also generate photopotentiation, albeit with lower potency. Thus, photopotentiation does not require a known ligand for neurosteroid potentiating sites on the GABAA receptor. Photoactivation of a membrane-impermeant, fluorescent steroid analog demonstrates that membrane localization is critical for activity. The photoactivatable steroid silences pathological spiking in cultured rat hippocampal neurons and anesthetizes tadpoles. Fluorescent steroids photoactivated by visible light may be useful for modulating GABAA receptor function in a spatiotemporally defined manner.
- Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA.
- Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA.
- Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA.
- Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA.
- Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, Missouri 63110, USA.
Correspondence to: Steven Mennerick2,5 e-mail: menneris@psychiatry.wustl.edu
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