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 of Neuroscience - Tập 30 Số 2 - Trang 739-748 - 2010
C. Thong1, Aline Campana2, Philipp S. Lange3,4, Hsinhwa Lee3, Kasturi Banerjee3, J. Barney Bryson2, Lata Mahishi3, S. Munir Alam5, Roman J. Giger6, Stephen Barnes7, Sidney M. Morris8, Dianna E. Willis9, Jeffrey L. Twiss9, Marie T. Filbin2, Rajiv R. Ratan3
1Burke/Cornell Medical Research Institute, White Plains, New York 10605, USA.
2City University of New York
3Burke-Cornell Medical Research Institute
4University of Bonn
5University of Rochester
6Cell and Developmental Biology
7University of Alabama at Birmingham
8University of Pittsburgh
9Alfred I duPont Hospital for Children

Tóm tắt

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 thearginase 1gene 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 primedin vitrowith daidzein overcame neurite outgrowth inhibition from myelin-associated glycoprotein, which was mirrored by acutely dissociated and cultured sensory neurons primedin vivoby intrathecal or subcutaneous daidzein infusion. Further, daidzein was effective in promoting axonal regenerationin vivoin 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.

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Journal of Neuroscience

Tập 30 Số 2

739-748

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