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

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.

Management Based on Multimodal Brain Monitoring May Improve Functional Connectivity and Post-operative Neurocognition in Elderly Patients Undergoing Spinal Surgery

“…In our study, a significant correlation was observed between FC and CRP, and management based on multimodal brain monitoring may have prevented an increase in the post-operative LPS level. The results of the current study and our previous work indicate that management based on multimodal brain monitoring during surgery may improve brain FC by reducing neuroinflammation in aged patients (Fu et al, 2014;Kan et al, 2016;Liu et al, 2021).…”

“…Meanwhile, the application of NF-κB pathway blocker pyrrolidine dithiocarbamic acid reduced the levels of inflammatory cytokines in the Hip and the expression of postsynaptic density (PSD)-95, and improved long-term cognitive function in aged rats exposed to LPS (Kan et al, 2016). FC in aged rats is related to cognitive function, which may be exacerbated by neuroinflammation induced by a systemic inflammatory response (Liu et al, 2021). In our study, a significant correlation was observed between FC and CRP, and management based on multimodal brain monitoring may have prevented an increase in the post-operative LPS level.…”

Lipopolysaccharide-induced neuroinflammation disrupts functional connectivity and community structure in primary cortical microtissues

“…As such, further investigation of the role of different glial cells in these functional changes could improve our understanding of multicellular dynamics associated with neuroinflammatory mechanisms. Further, the disruption of community structure of microcircuits may have broad implications for the role of glia in cognitive impairments exhibited after LPS exposure in both rats and humans 49,50,53,64 .…”

“…While LPS-induced neuroinflammation does not model a specific disease pathology, it can add to our understanding of basic neuroinflammatory cellular dynamics. LPSinduced neuroinflammation has significant downstream effects on neural function, including connectivity changes in mesocircuits [49][50][51] , the development of epileptiform hyperactivity 52 , and cognitive deficits in rodents and humans 49,53 . Here, we examined the effect of LPS on microcircuit FC in microtissues.…”

Disentangling Mitochondria in Alzheimer’s Disease

“…SS-31 reduced Aβ production and mitochondrial dysfunction, restored mitochondrial dynamics, and enhanced mitochondrial biogenesis and synaptic activity in AD mice [ 186 , 187 ]. SS-31 was recently shown to ameliorate mitochondrial dysfunction and synaptic and memory impairment induced by neuroinflammation [ 188 , 189 ]. Despite its success in preclinical trials in aging and related health conditions, clinical trials of SS-31 have not been successful so far (tested in heart failure and primary mitochondrial myopathy).…”