1. Academic Validation
  2. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models

SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models

  • Neurosci Lett. 2014 Jan 24;559:174-8. doi: 10.1016/j.neulet.2013.12.005.
Yoko Ono 1 Hirotaka Tanaka 1 Masafumi Takata 1 Yuki Nagahara 1 Yasuhiro Noda 1 Kazuhiro Tsuruma 1 Masamitsu Shimazawa 1 Isao Hozumi 2 Hideaki Hara 3
Affiliations

Affiliations

  • 1 Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
  • 2 Department of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
  • 3 Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: hidehara@gifu-pu.ac.jp.
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Recently, it has been reported that a mutation in the sigma-1 receptor causes juvenile ALS. Therefore, the function of the sigma-1 receptor may be important in the pathology of ALS. In the present study, we investigated the effect of SA4503, a sigma-1 receptor agonist, against in in vitro and in vivo ALS models. We first investigated whether SA4503, a sigma-1 receptor agonist, prevented superoxide dismutase 1 (SOD1(G93A))- and serum free-induced cell death of mice motor neuron cells (NSC34) in in vitro model of an ALS. At concentrations of 1-10μM, SA4503 reduced SOD1(G93A)-induced cell death in a concentration-dependent manner, and BD1047, a sigma-1 receptor antagonist, inhibited the protective effect of SA4503. Next, we investigated whether SA4503 affected the phosphorylation levels of Akt (Ser 473) and extracellular signal-regulated kinase (ERK) 1/2 and the expression of the sigma-1 receptor. SA4503 promoted the phosphorylation of Akt (Ser 473) and ERK1/2 in a time-dependent manner, but SA4503 did not affect the expression of the sigma-1 receptor. These results suggest that the protective effect of SA4503 might be involved in promoting the phosphorylation of Akt and ERK1/2. We then investigated whether SA4503 suppressed the progression of ALS in an SOD1(G93A) ALS mouse model. SA4503 did not affect the onset time of ALS. However, it significantly extended the survival time in the SOD1(G93A) mice compared with a vehicle-treated group. These findings indicate that SA4503 is effective in suppressing motor neuron degeneration and symptom progression in ALS.

Keywords

Akt; Extracellular signal-regulated kinase (ERK) 1/2; Sigma-1 receptor.

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