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Protective effect of a novel sigma‐1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice
Author(s) -
Morihara Ryuta,
Yamashita Toru,
Liu Xia,
Nakano Yumiko,
Fukui Yusuke,
Sato Kota,
Ohta Yasuyuki,
Hishikawa Nozomi,
Shang Jingwei,
Abe Koji
Publication year - 2018
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24270
Subject(s) - endoplasmic reticulum , agonist , unfolded protein response , neuroprotection , sigma 1 receptor , downregulation and upregulation , atf6 , endocrinology , chemistry , medicine , receptor , pharmacology , biochemistry , gene
Abstract 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.