A large-scale chemical screen for regulators of the arginase 1 promoter identifies the soy isoflavone daidzeinas a clinically approved small molecule that can promote neuronal protection or regeneration via a cAMP-independent pathway
Language: 
English
Abstract: 

An ideal therapeutic for stroke or spinal cord injury should promote survival and regeneration in the CNS. Arginase 1 (Arg1) has been shown to protect motor neurons from trophic factor deprivation and allow sensory neurons to overcome neurite outgrowth inhibition by myelin proteins. To identify small molecules that capture Arg1's protective and regenerative properties, we screened a hippocampal cell line stably expressing the proximal promoter region of the arginase 1 gene fused to a reporter gene against a library of compounds containing clinically approved drugs. This screen identified daidzein as a transcriptional inducer of Arg1. Both CNS and PNS neurons primed in vitro with daidzein overcame neurite outgrowth inhibition from myelin-associated glycoprotein, which was mirrored by acutely dissociated and cultured sensory neurons primed in vivo by intrathecal or subcutaneous daidzein infusion. Further, daidzein was effective in promoting axonal regeneration in vivo in an optic nerve crush model when given intraocularly without lens damage, or most importantly, when given subcutaneously after injury. Mechanistically, daidzein requires transcription and induction of Arg1 activity for its ability to overcome myelin inhibition. In contrast to canonical Arg1 activators, daidzein increases Arg1 without increasing CREB phosphorylation, suggesting its effects are cAMP-independent. Accordingly, it may circumvent known CNS side effects of some cAMP modulators. Indeed, daidzein appears to be safe as it has been widely consumed in soy products, crosses the blood-brain barrier, and is effective without pretreatment, making it an ideal candidate for development as a therapeutic for spinal cord injury or stroke.

Author(s): 
Ma, Thong C.
Campana, Aline
Lange, Philipp S.
Lee, Hsin-Hwa
Banerjee, Kasturi
Bryson, J. Barney
Mahishi, Lata
Alam, Shabnam
Giger, Roman J.
Barnes, Stephen
Morris, Sidney M.
Willis, Dianna E.
Twiss, Jeffrey L.
Filbin, Marie T.
Ratan, Rajiv R.
Item Type: 
Journal Article
Publication Title: 
The Journal of Neuroscience: The Official Journal of the Society for Neuroscience
Journal Abbreviation: 
J. Neurosci.
Publication Date: 
Jan 13, 2010
Publication Year: 
2010
Pages: 
739-748
Volume: 
30
Issue: 
2
ISSN: 
1529-2401
DOI: 
10.1523/JNEUROSCI.5266-09.2010
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 20071539 PMCID: PMC3554247

Turabian/Chicago Citation

Thong C. Ma, Aline Campana, Philipp S. Lange, Hsin-Hwa Lee, Kasturi Banerjee, J. Barney Bryson, Lata Mahishi, Shabnam Alam, Roman J. Giger, Stephen Barnes, Sidney M. Morris, Dianna E. Willis, Jeffrey L. Twiss, Marie T. Filbin and Rajiv R. Ratan. Jan 13, 2010. "A large-scale chemical screen for regulators of the arginase 1 promoter identifies the soy isoflavone daidzeinas a clinically approved small molecule that can promote neuronal protection or regeneration via a cAMP-independent pathway." The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 30: 2: 739-748. 10.1523/JNEUROSCI.5266-09.2010.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1523/JNEUROSCI.5266-09.2010 | issn = 1529-2401 | volume = 30 | pages = 739-748 | last = Ma | first = Thong C. | coauthors = Campana, Aline, Lange, Philipp S., Lee, Hsin-Hwa, Banerjee, Kasturi, Bryson, J. Barney, Mahishi, Lata, Alam, Shabnam, Giger, Roman J., Barnes, Stephen, Morris, Sidney M., Willis, Dianna E., Twiss, Jeffrey L., Filbin, Marie T., Ratan, Rajiv R. | title = A large-scale chemical screen for regulators of the arginase 1 promoter identifies the soy isoflavone daidzeinas a clinically approved small molecule that can promote neuronal protection or regeneration via a cAMP-independent pathway | journal = The Journal of Neuroscience: The Official Journal of the Society for Neuroscience | date = Jan 13, 2010 | pmid = | pmc = }} </ref>