Enriched environment improves post-stroke cognitive impairment and inhibits neuroinflammation and oxidative stress by activating Nrf2-ARE pathway

Abstract

Introduction

Neuroinflammation and oxidative stress are major mechanisms of post-stroke cognitive impairment (PSCI) neural injury and decreased spatial and memory capacity. Enriched environment (EE) is an effective method to improve cognitive dysfunction. However, the regulation by EE of neuroinflammation, oxidative stress and associated mechanisms in animal models remains unclear.

Materials and methods

In this study, a rat PSCI model was established by middle cerebral artery occlusion (MCAO). Rats were randomly divided into the control group, standard environment (SE) group and EE group for 28 days. A Morris water-maze test was used to measure cognitive function at 7, 14 and 28 days after MCAO. Rats were sacrificed on the 28th day. Quantitative PCR, immunohistochemistry and ELISA were respectively used to detect mRNA expression of NF-E2-related factor 2 (Nrf2) and Nrf2 response genes, the expression of IL-1β and levels of proinflammatory cytokines in the hippocampus.

Results

EE improved mNSS scores and cognitive ability in PSCI rats. EE increased mRNA expression of the Nrf2 and Nrf2 response genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1). EE significantly decreased the level of malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione (GSH), in the hippocampus of PSCI rats. EE reduced the number of IL-1β positive cells in the hippocampus, and IL-1β levels in the hippocampus and serum. EE increased GFAP-positive astrocytes in the hippocampus, and BDNF levels in the hippocampus and serum.

Conclusions

EE can improve cognitive function in PSCI rats by inhibiting neuroinflammation and oxidative stress.

Keywords:

• Post-stroke cognitive impairment (PSCI)
• middle cerebral artery occlusion (MCAO)
• enriched environment (EE)
• neuroinflammation
• oxidative stress
• astrocytes

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

XZ wrote the manuscript; XB designed the study and analyzed the data; MY, SY and XC carried out in all experiments and revised the manuscript; JW, MW and KY performed all the experiment and collected data.

Additional information

Funding

This study was supported by grants from the Leading Personnel Training Project of Shanghai Pudong New District Municipal Health Bureau (No. PWR12018-04) and the Science and Technology Development Fund of Shanghai Pudong New District (No. PKJ2018-Y38).