caa a22 4500 445364378 CHVBK 20180317142925.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10048-010-0268-z doi (NATIONALLICENCE)springer-10.1007/s10048-010-0268-z Hydroxyurea enhances SMN2 gene expression through nitric oxide release [Elektronische Daten] [Cheng Xu, Xin Chen, Susanna Grzeschik, Madhuri Ganta, Ching Wang] Small molecules that increase full-length survivor motor neuron (SMN) gene transcript are promising therapeutic candidates for spinal muscular atrophy (SMA). Hydroxyurea (HU) has recently been shown to increase full-length SMN transcript in cultured lymphocytes from patients with SMA. We investigate the mechanism by which HU enhances full-length SMN2 gene expression in SMA lymphocytes. Nitric oxide (NO) is a major intracellular metabolite of HU. We test whether NO donors can themselves enhance full-length SMN2 expression. Eighteen cell lines (five type I, five type II, six type III SMA, and two non-SMA controls) were treated with or without NO donors for 48h. SMA cells treated with HU and three NO donors: two long-acting donors, Deta-NONOate and S-nitrosoglutathione, and one short-acting donor, 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene, resulted in significant increase in full-length SMN2 mRNA. These effects were abolished by co-treatment with an NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide. One short-acting NO donor, S-nitroso-N-acetyl-DL-penicillamine, failed to show significant effect on full-length SMN2 expression, possibly due to high degree of cytotoxicity. These results were observed using both densitometry and quantitative PCR methods. We conclude that HU enhances SMN2 expression through the release of NO. NO donors may themselves be considered as new therapeutic candidates for SMA. Springer-Verlag, 2010 SMA nationallicence Hydroxyurea nationallicence SMN gene nationallicence Nitric oxide nationallicence Xu Cheng Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut Chen Xin Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut Grzeschik Susanna Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut Ganta Madhuri Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut Wang Ching Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut neurogenetics Springer-Verlag 12/1(2011-02-01), 19-24 1364-6745 12:1<19 2011 12 10048 https://doi.org/10.1007/s10048-010-0268-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10048-010-0268-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Xu Cheng Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut NATIONALLICENCE 700 1- Chen Xin Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut NATIONALLICENCE 700 1- Grzeschik Susanna Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut NATIONALLICENCE 700 1- Ganta Madhuri Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut NATIONALLICENCE 700 1- Wang Ching Department of Neurology and Neurological Sciences, Stanford University Medical Center, 300 Pasteur Drive, Room A343, 94305-5235, Stanford, CA, USA aut NATIONALLICENCE 773 0- neurogenetics Springer-Verlag 12/1(2011-02-01), 19-24 1364-6745 12:1<19 2011 12 10048 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer