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Open AccessArticle

SA4503, A Potent Sigma-1 Receptor Ligand, Ameliorates Synaptic Abnormalities and Cognitive Dysfunction in a Mouse Model of ATR-X Syndrome

1
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
2
Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
3
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 31005, Zhejiang, China
4
School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(9), 2811; https://doi.org/10.3390/ijms19092811
Received: 31 July 2018 / Revised: 10 September 2018 / Accepted: 12 September 2018 / Published: 18 September 2018
(This article belongs to the Section Biochemistry)
α-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX. An ATR-X model mouse lacking Atrx exon 2 displays phenotypes that resemble symptoms in the human intellectual disability: cognitive defects and abnormal dendritic spine formation. We herein target activation of sigma-1 receptor (Sig-1R) that can induce potent neuroprotective and neuroregenerative effects by promoting the activity of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). We demonstrated that treatment with SA4503, a potent activator of Sig-1R, reverses axonal development and dendritic spine abnormalities in cultured cortical neurons from ATR-X model mice. Moreover, the SA4503 treatment rescued cognitive deficits exhibited by the ATR-X model mice. We further found that significant decreases in the BDNF-protein level in the medial prefrontal cortex of ATR-X model mice were recovered with treatment of SA4503. These results indicate that the rescue of dendritic spine abnormalities through the activation of Sig-1R has a potential for post-diagnostic therapy in ATR-X syndrome. View Full-Text
Keywords: ATR-X syndrome; cognitive function; dendritic spine; sigma-1 receptor; brain-derived neurotrophic factor ATR-X syndrome; cognitive function; dendritic spine; sigma-1 receptor; brain-derived neurotrophic factor
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Yamaguchi, K.; Shioda, N.; Yabuki, Y.; Zhang, C.; Han, F.; Fukunaga, K. SA4503, A Potent Sigma-1 Receptor Ligand, Ameliorates Synaptic Abnormalities and Cognitive Dysfunction in a Mouse Model of ATR-X Syndrome. Int. J. Mol. Sci. 2018, 19, 2811.

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