Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration Ying Ding a, 1 , Hiroaki Adachi a, b, **, 1 , Masahisa Katsuno a , Zhe Huang a, b , Yue-Mei Jiang a , Naohide Kondo a , Madoka Iida a , Genki Tohnai a , Hideaki Nakatsuji a , Hiroshi Funakoshi c , Toshikazu Nakamura d , Gen Sobue a, e, * a Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan b Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807- 8555, Japan c Center for Advanced Research and Education, Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510, Japan d Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034, Japan e Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan article info Article history: Received 27 October 2015 Accepted 3 November 2015 Available online xxx Keywords: Spinal and bulbar muscular atrophy Androgen receptor Hepatocyte growth factor Akt Castration Combination therapy abstract Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. © 2015 Elsevier Inc. All rights reserved. 1. Introduction Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease caused by the expansion of a CAG repeat encoding a polyglutamine (polyQ) tract within the androgen re- ceptor (AR) gene [1]. SBMA, the first identified polyQ disease, is characterized by slowly progressing muscle weakness, atrophy, contraction fasciculations, and gender-dependent manifestation of the disease phenotypes [2]. The major pathological findings of SBMA are loss of lower motor neurons and nuclear accumulation of the polyQ-expanded AR in the residual motor neurons within the spinal cord and brainstem [3,4]. Over the past two decades, basic and clinical research has provided important insights into the dis- ease phenotype and pathophysiology. Basic research using animal models has suggested that the pathogenic AR-mediated neuro- degeneration is suppressed by androgen inactivation, the efficacy of which has been tested in clinical trials [5]. Pharmacological acti- vation of cellular defense machineries, such as molecular chaper- ones, the ubiquitin-proteasome system, and autophagy, also exerts neuroprotective effects in experimental models of SBMA [6]. However, despite positive results in basic studies, no therapy has proved to be effective in clinical trials, suggesting a need to eluci- date the entire disease mechanism and to initiate therapeutic intervention early in the disease [7]. Abbreviations used: SBMA, spinal and bulbar muscular atrophy; polyQ, poly- glutamine; AR, androgen receptor; HGF, hepatocyte growth factor; ADL, activities of daily living. * Corresponding author. Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa- ku, Nagoya 466-8550, Japan. ** Corresponding author. Department of Neurology, University of Occupational and Environmental Health School of Medicine, Iseigaoka,Yahatanishi-ku, Kita- kyushu 807-8555, Japan. E-mail addresses: hadachi-ns@umin.org (H. Adachi), sobueg@med.nagoya-u.ac. jp (G. Sobue). 1 These authors contributed equally to this work. Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc http://dx.doi.org/10.1016/j.bbrc.2015.11.015 0006-291X/© 2015 Elsevier Inc. All rights reserved. Biochemical and Biophysical Research Communications xxx (2015) 1e7 Please cite this article in press as: Y. Ding, et al., Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration, Biochemical and Biophysical Research Communications (2015), http://dx.doi.org/10.1016/ j.bbrc.2015.11.015