Pre-ischaemic Treatment with Enriched Environment Alleviates Acute Neuronal Injury by Inhibiting Endoplasmic Reticulum Stress-dependent Autophagy and Apoptosis

Abstract

Enriched environment (EE) is effective in preventing cerebral ischemia-reperfusion (I/R) injury. However, little is known about the mechanism underlying the neuroprotection of EE preprocessing. Endoplasmic reticulum (ER) stress has been demonstrated to be extensively involved in I/R injury. We aimed to investigate the potential regulatory mechanism of ER stress in the neuroprotection of pre-ischemic EE. Rats were subjected to middle cerebral artery occlusion (MCAO) or sham surgery after 4 weeks of exposure in standard or enriched environments. We found that EE pretreatment alleviates acute neuronal injury after MCAO, as shown by reduced infarct volume and neurological deficit score. The expression of ER stress-related proteins, markers of autophagy, and apoptosis were detected to investigate the underlying mechanism. Our results showed that pre-ischemic EE inhibited the ER stress, as evidenced by the inactivation of activating transcription factor 6 (ATF6), protein kinase RNA (PKR)-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE1) pathways. Moreover, the rats reared in EE were detected with lower autophagic activity and apoptosis levels. The decrease in activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and phospho-c-Jun N-terminal kinases (p-JNK) expression suggested EE pretreatment might inhibit autophagy and apoptosis via modulating ER stress-mediated PERK-ATF4-CHOP and IRE1-JNK signal pathways, which provides a new idea for the prevention of the deleterious cerebral and functional consequences of ischemic stroke.

Keywords: ER stress; apoptosis; autophagy; cerebral I/R injury; enriched environment.