TY - JOUR
T1 - Protective effect of a novel sigma-1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice
AU - Morihara, Ryuta
AU - Yamashita, Toru
AU - Liu, Xia
AU - Nakano, Yumiko
AU - Fukui, Yusuke
AU - Sato, Kota
AU - Ohta, Yasuyuki
AU - Hishikawa, Nozomi
AU - Shang, Jingwei
AU - Abe, Koji
N1 - Funding Information:
We thank Aki Soejima for performing preliminary studies and technical support, and Mitsubishi Tanabe Pharma Corporation for the gift of Comp-AD and NE-100. We also thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Funding Information:
This work was mainly supported by Mitsubishi Tanabe Pharma Corporation
Publisher Copyright:
© 2018 Wiley Periodicals, Inc
PY - 2018/10
Y1 - 2018/10
N2 - Sigma-1 receptor (Sig-1R) is expressed at endoplasmic reticulum (ER) membranes, where it regulates a variety of specific physiological functions. However, the profile and exact roles of ER stress-related molecules after Sig-1R agonist treatment in an in vivo stroke model are largely unknown. The aim of this study is to investigate the effect of a novel Sig-1R agonist, aniline derivative compound (Comp-AD), on the ER stress response following ischemic stroke. Male C57BL/6J mice received transient middle cerebral artery occlusion for 90 min, and were then treated with vehicle saline or Comp-AD at reperfusion. At 3 hr, 1 day, and 7 days after reperfusion, immunohis- tochemistry was performed for Sig-1R and ER stress-related proteins including phospho protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phospho inositol requiring enzyme 1α (p- IRE1α), and activating transcription factor 6 (ATF6). Neurobehavioral analysis showed improved functional recovery at 1 day and 7 days after reperfusion, and the infarct volume was significantly smaller at 7 days (p <.05), in the Comp-AD group compared with the vehicle group. Comp-AD treatment upregulated Sig-1R immunoreactivity at 3 hr and 1 day (p <.05), and reduced p-PERK and p-IRE1α expression at 1 day (p <.05, respectively), in the peri-ischemic region compared with the vehicle group. Treatment with the novel Sig-1R agonist Comp-AD was neuroprotective after transient middle cerebral artery occlusion, and was associated with upregulation of Sig-1R and a reduction of ER stress.
AB - Sigma-1 receptor (Sig-1R) is expressed at endoplasmic reticulum (ER) membranes, where it regulates a variety of specific physiological functions. However, the profile and exact roles of ER stress-related molecules after Sig-1R agonist treatment in an in vivo stroke model are largely unknown. The aim of this study is to investigate the effect of a novel Sig-1R agonist, aniline derivative compound (Comp-AD), on the ER stress response following ischemic stroke. Male C57BL/6J mice received transient middle cerebral artery occlusion for 90 min, and were then treated with vehicle saline or Comp-AD at reperfusion. At 3 hr, 1 day, and 7 days after reperfusion, immunohis- tochemistry was performed for Sig-1R and ER stress-related proteins including phospho protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phospho inositol requiring enzyme 1α (p- IRE1α), and activating transcription factor 6 (ATF6). Neurobehavioral analysis showed improved functional recovery at 1 day and 7 days after reperfusion, and the infarct volume was significantly smaller at 7 days (p <.05), in the Comp-AD group compared with the vehicle group. Comp-AD treatment upregulated Sig-1R immunoreactivity at 3 hr and 1 day (p <.05), and reduced p-PERK and p-IRE1α expression at 1 day (p <.05, respectively), in the peri-ischemic region compared with the vehicle group. Treatment with the novel Sig-1R agonist Comp-AD was neuroprotective after transient middle cerebral artery occlusion, and was associated with upregulation of Sig-1R and a reduction of ER stress.
KW - ATF6
KW - ER stress
KW - IRE1α
KW - PERK
KW - sigma-1 receptor
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U2 - 10.1002/jnr.24270
DO - 10.1002/jnr.24270
M3 - Article
C2 - 30102416
AN - SCOPUS:85052477380
VL - 96
SP - 1707
EP - 1716
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 10
ER -