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

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 13 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2021.600484

DOI=10.3389/fnagi.2021.600484

ISSN=1663-4365

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 and neuroinflammation in aged rat brain while elamipretide (SS-31) was used for treatment. Systemic and hippocampal inflammation were determined using enzyme-linked immunosorbent assay (ELISA) while astrocyte responses during hippocampal neuroinflammation were determined by interleukin-1β (IL-1β)/tumor necrosis factor alpha (TNFα) double stained immunofluorescence. Oxidative stress were determined by reactive oxidative species (ROS), electron transport chain complex (ETC) and superoxide dismutase (SOD). Short- (< 7 days) and long-term (>31 days) learning and spatial working memory were tested by Morris water maze (MWM). Resting-state functional magnetic resonance imaging (rs-fMRI) was used to analyze brain FC by placing seed voxels on the left and right hippocampus. Compared with vehicle group, rats with LPS exposure showed impaired MWM performance, higher oxidative stress, higher levels of inflammatory cytokines and astrocyte activation in hippocampus. Neuroimaging examination showed decreased FC on right-orbital cortex, right- olfactory bulb and left-hippocampus on day 3, 7 and 31 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 left-parietal association cortex, left sensory cortex and left motor cortex on day 7 with right pfi 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 hippocampus but also improves brain FC in regions related to hippocampus. Furthermore, early anti-inflammatory treatment with SS-31 has a long-lasting effect on reducing the impact of LPS-induced neuroinflammation.