Elamipretide (SS-31) Improves Functional Connectivity in Hippocampus and Other Related Regions Following Prolonged Neuroinflammation Induced by Lipopolysaccharide in Aged Rats.

Yang Liu,Huiqun Fu,Wei Xiao,Binbin Nie,Long Fan,Yan Wu,Tianlong Wang,Fangyan Liu,Shuyi Yang,Minhui Kan

doi:10.3389/fnagi.2021.600484

Abstract

Neuroinflammation has been recognized as a major cause for neurocognitive diseases. Although the hippocampus has been considered an important region for cognitive dysfunction, the influence of hippocampal neuroinflammation on brain functional connectivity (FC) has been rarely studied. In this study, lipopolysaccharide (LPS) was used to induce systemic inflammation and neuroinflammation in the aged rat brain, while elamipretide (SS-31) was used for treatment. Systemic and hippocampal inflammation were determined using ELISA, while astrocyte responses during hippocampal neuroinflammation were determined by interleukin 1 beta (IL-1β)/tumor necrosis factor alpha (TNFα) double staining immunofluorescence. Oxidative stress was determined by reactive oxidative species (ROS), electron transport chain (ETC) complex, and superoxide dismutase (SOD). Short- (<7 days) and long-term (>30 days) learning and spatial working memory were tested by the Morris water maze (MWM). Resting-state functional magnetic resonance imaging (rs-fMRI) was used to analyze the brain FC by placing seed voxels on the left and right hippocampus. Compared with the vehicle group, rats with the LPS exposure showed an impaired MWM performance, higher oxidative stress, higher levels of inflammatory cytokines, and astrocyte activation in the hippocampus. The neuroimaging examination showed decreased FC on the right orbital cortex, right olfactory bulb, and left hippocampus on day 3, 7, and 31, respectively, after treatment. In contrast, rats with SS-31 treatment showed lower levels of inflammatory cytokines, less astrocyte activation in the hippocampus, and improved MWM performance. Neuroimaging examination showed increased FC on the left-parietal association cortex (L-PAC), left sensory cortex, and left motor cortex on day 7 with the right flocculonodular lobe on day 31 as compared with those without SS-31 treatment. Our study demonstrated that inhibiting neuroinflammation in the hippocampus not only reduces inflammatory responses in the hippocampus but also improves the brain FC in regions related to the hippocampus. Furthermore, early anti-inflammatory treatment with SS-31 has a long-lasting effect on reducing the impact of LPS-induced neuroinflammation.

Highlights

Neuroinflammation has been proved to be a major cause for post-operative cognitive dysfunction (POCD) and other perioperative neurocognitive disorders (Subramaniyan and Terrando, 2019)
There was no difference in the time spent in target quadrant when comparing LPS exposure rats with either SS-31- (p = 0.159) or LPS + SS-31-treated rats (p = 0.063, Figure 1D)
Our result revealed that oxidative stress induced by a single dose of LPS injection may be able to cause long-term expression of astrocyte-derived inflammatory cytokines in the hippocampus, long-term functional connectivity (FC) change in the hippocampus, and other related regions, as well as impaired learning and spatial working memory

Summary

Introduction

Neuroinflammation has been proved to be a major cause for post-operative cognitive dysfunction (POCD) and other perioperative neurocognitive disorders (Subramaniyan and Terrando, 2019). The recent studies demonstrated that various regions may participate, the hippocampus, both morphology and function, is one of the most sensitive regions that is affected by aging, neuroinflammation, and chronic stress (Fjell et al, 2014; Bartsch and Wulff, 2015). Clinical studies have reported that the disruption of the brain–blood barrier (BBB), an early event in the aging brain, begins in the hippocampus (Montagne et al, 2015). These findings suggest that the hippocampus in the aging brain is more likely to be affected by peripheral inflammatory cytokines triggered by surgery and other perioperative stress events. The hippocampus is a brain region of great importance in understanding the development and molecular mechanisms of cognitive dysfunction

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Results

Conclusion