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Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

Scriptaid Protects Against TBI via AKT

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Neurotherapeutics

Abstract

Traumatic brain injury (TBI) is a leading cause of motor and cognitive deficits in young adults for which there is no effective therapy. The present study characterizes the protective effect of a new histone deacetylase inhibitor, Scriptaid (Sigma-Aldrich Corporation, St. Louis, MO), against injury from controlled cortical impact (CCI). Scriptaid elicited a dose-dependent decrease in lesion size at 1.5 to 5.5 mg/kg and a concomitant attenuation in motor and cognitive deficits when delivered 30 minutes postinjury in a model of moderate TBI. Comparable protection was achieved even when treatment was delayed to 12 h postinjury. Furthermore, the protection of motor and cognitive functions was long lasting, as similar improvements were detected 35 days postinjury. The efficacy of Scriptaid (Sigma-Aldrich Corporation) was manifested as an increase in surviving neurons, as well as the number/length of their processes within the CA3 region of the hippocampus and the pericontusional cortex. Consistent with other histone deacetylase inhibitors, Scriptaid treatment prevented the decrease in phospho-AKT (p-AKT) and phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN) induced by TBI in cortical and CA3 hippocampal neurons. Notably, the p-AKT inhibitor LY294002 attenuated the impact of Scriptaid, providing mechanistic evidence that Scriptaid functions partly by modulating the prosurvival AKT signaling pathway. As Scriptaid offers long-lasting neuronal and behavioral protection, even when delivered 12 h after controlled cortical impact, it is an excellent new candidate for the effective clinical treatment of TBI.

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Acknowledgments

This research is supported in part by the Special Research Funds from the Chinese Ministry of Science and Technology to State Key Laboratories (to G.H.W, Y.G, and J.C); the National Institutes of Health/National Institute of Neurological Disorders and Stroke (grants NS36736, NS43802 and NS45048 to J.C.); the Veterans Administration Merit Review (grant to J.C.); and the Chinese Natural Science Foundation (grants No. 30870794, No. 81020108021, No. 81171149, No. 81150110494 to Y.G., and No. 81000497 to G.W.) The authors declare no conflict of interest. Full conflict of interest disclosures is available in the electronic supplementary material for this article.

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Correspondence to Yanqin Gao or Jun Chen.

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Wang, G., Jiang, X., Pu, H. et al. Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway. Neurotherapeutics 10, 124–142 (2013). https://doi.org/10.1007/s13311-012-0157-2

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