Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury.

Jingying Liu,Wenyue Cao,Weijing Liao,Jun Zheng,Yang Xu,Linyao Zhao,Jinchen Wang,Xin Zhang,Biru Wang

doi:10.3389/fnagi.2021.717644

Abstract

Enriched environment (EE) is a complex containing social, cognitive, and motor stimuli. Exposure to EE can promote functional recovery after ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remained unclear. Pyroptosis has recently been identified and demonstrated a significant role in ischemic stroke. The purpose of this study was to explore the effect of EE on neuronal pyroptosis after cerebral I/R injury. In the current study, middle cerebral artery occlusion/reperfusion (MCAO/R) was applied to establish the cerebral I/R injury model. Behavior tests including the modified Neurological Severity Scores (mNSS) and the Morris Water Maze (MWM) were performed. The infarct volume was evaluated by Nissl staining. To evaluate the levels of pyroptosis-related proteins, the levels of GSDMD-N and nod-like receptor protein 1/3 (NLRP1/3) inflammasome-related proteins were examined. The mRNA levels of IL-1β and IL-18 were detected by Quantitative Real-Time PCR (qPCR). The secretion levels of IL-1β and IL-18 were analyzed by ELISA. Also, the expression of p65 and p-p65 were detected. The results showed that EE treatment improved functional recovery, reduced infarct volume, attenuated neuronal pyroptosis after cerebral I/R injury. EE treatment also suppressed the activities of NLRP1/NLRP3 inflammasomes. These may be affected by inhabiting the NF-κB p65 signaling pathway. Our findings suggested that neuronal pyroptosis was probably the neuroprotective mechanism that EE treatment rescued neurological deficits after I/R injury.

Highlights

Stroke is a disease with the highest mortality and disability rates in the world
We firstly demonstrated that EE rescued neurological deficits after I/R injury involving the suppressing of neuronal pyroptosis
To evaluate the neurological function, modified Neurological Severity Scores (mNSS) was assessed on day 3, 7, 14, 21 after I/R injury

Summary

Introduction

Stroke is a disease with the highest mortality and disability rates in the world. Ischemic stroke is responsible for the majority of strokes (Campbell et al, 2019; Stinear et al, 2020). Despite the increasing improvement in the treatment of stroke, many survivors remain with residual functional deficits (Winstein et al, 2016). Exposure to EE enhanced the experience-dependent plasticity of the brain and promoted the recovery of cognitive and motor functions after ischemia/reperfusion (I/R) injury (Livingston-Thomas et al, 2016). EE facilitated cognitive recovery through remodeling bilateral synaptic after ischemic stroke (Wang C. et al, 2019). There has been little research on the relationship between EE-mediated ischemic stroke recovery and cell death. A recent study has demonstrated that enriched environmentinduced neuronal autophagy boosted the post-stroke recovery of neurological function (Deng et al, 2021). Our previous studies have illustrated that EE reduced neuronal apoptosis conducting to the superior recovery after I/R injury (Chen et al, 2017). The mechanisms by which EE attenuated cell death following stroke remained unclear

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