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

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.

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Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph12020093 ◽

2019 ◽

Vol 12 (2) ◽

pp. 93 ◽

Cited By ~ 12

Author(s):

Shashank Masaldan ◽

Abdel Ali Belaidi ◽

Scott Ayton ◽

Ashley I. Bush

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hydroxyl Radicals ◽

Iron Accumulation ◽

Brain Iron ◽

Dependent Cell ◽

Cellular Dysfunction ◽

The Impact ◽

The Brain

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

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Dual n-back training improves functional connectivity of the right inferior frontal gyrus at rest

Scientific Reports ◽

10.1038/s41598-020-77310-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tiina Salminen ◽

Caroline Garcia Forlim ◽

Torsten Schubert ◽

Simone Kühn

Keyword(s):

Functional Connectivity ◽

Inferior Frontal Gyrus ◽

Training Group ◽

Training Intervention ◽

Superior Parietal Cortex ◽

Default State ◽

Improved Performance ◽

The Right ◽

Task Parameters ◽

The Brain

AbstractSeveral studies have shown that the benefits of working memory (WM) training can be attributed to functional and structural neural changes in the underlying neural substrate. In the current study, we investigated whether the functional connectivity of the brain at rest in the default mode network (DMN) changes with WM training. We varied the complexity of the training intervention so, that half of the participants attended dual n-back training whereas the other half attended single n-back training. This way we could assess the effects of different training task parameters on possible connectivity changes. After 16 training sessions, the dual n-back training group showed improved performance accompanied by increased functional connectivity of the ventral DMN in the right inferior frontal gyrus, which correlated with improvements in WM. We also observed decreased functional connectivity in the left superior parietal cortex in this group. The single n-back training group did not show significant training-related changes. These results show that a demanding short-term WM training intervention can alter the default state of the brain.

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Oxidative stress and genetic markers of suboptimal antioxidant defense in the aging brain: a theoretical review

Reviews in the Neurosciences ◽

10.1515/revneuro-2014-0046 ◽

2014 ◽

Vol 25 (6) ◽

Cited By ~ 47

Author(s):

Lauren E. Salminen ◽

Robert H. Paul

Keyword(s):

Oxidative Stress ◽

Antioxidant Defense ◽

Future Research ◽

Aging Brain ◽

Older Individuals ◽

Glutathione S Transferase ◽

Antioxidant Defense Enzymes ◽

Repair Mechanisms ◽

The Impact ◽

The Brain

AbstractNormal aging involves a gradual breakdown of physiological processes that leads to a decline in cognitive functions and brain integrity, yet the onset and progression of decline are variable among older individuals. While many biological changes may contribute to this degree of variability, oxidative stress is a key mechanism of the aging process that can cause direct damage to cellular architecture within the brain. Oligodendrocytes are at a high risk for oxidative damage due to their role in myelin maintenance and production and limited repair mechanisms, suggesting that white matter may be particularly vulnerable to oxidative activity. Antioxidant defense enzymes within the brain, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), are crucial for breaking down the harmful end products of oxidative phosphorylation. Previous studies have revealed that allele variations of polymorphisms that encode these antioxidants are associated with abnormalities in SOD, CAT, GPx, and GST activity in the central nervous system. This review will focus on the role of oxidative stress in the aging brain and the impact of decreased antioxidant defense on brain integrity and cognitive function. Directions for future research investigations of antioxidant defense genes will also be discussed.

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Multi-Hops Functional Connectivity Improves Individual Prediction of Fusiform Face Activation via a Graph Neural Network

Frontiers in Neuroscience ◽

10.3389/fnins.2020.596109 ◽

2021 ◽

Vol 14 ◽

Author(s):

Dongya Wu ◽

Xin Li ◽

Jun Feng

Keyword(s):

Neural Network ◽

Functional Connectivity ◽

Brain Connectivity ◽

Face Area ◽

The Face ◽

The Individual ◽

The Right ◽

And Function ◽

The Relationship ◽

The Brain

Brain connectivity plays an important role in determining the brain region’s function. Previous researchers proposed that the brain region’s function is characterized by that region’s input and output connectivity profiles. Following this proposal, numerous studies have investigated the relationship between connectivity and function. However, this proposal only utilizes direct connectivity profiles and thus is deficient in explaining individual differences in the brain region’s function. To overcome this problem, we proposed that a brain region’s function is characterized by that region’s multi-hops connectivity profile. To test this proposal, we used multi-hops functional connectivity to predict the individual face activation of the right fusiform face area (rFFA) via a multi-layer graph neural network and showed that the prediction performance is essentially improved. Results also indicated that the two-layer graph neural network is the best in characterizing rFFA’s face activation and revealed a hierarchical network for the face processing of rFFA.

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Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression

Translational Psychiatry ◽

10.1038/s41398-021-01587-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiangchuan Chen ◽

Diana J. Beltran ◽

Valeriya D. Tsygankova ◽

Bobbi J. Woolwine ◽

Trusharth Patel ◽

...

Keyword(s):

Basal Ganglia ◽

Functional Connectivity ◽

Resting State ◽

Kynurenine Pathway ◽

Self Report ◽

Resonance Spectroscopy ◽

Neural Function ◽

Brain Chemistry ◽

The Impact ◽

The Brain

AbstractInflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

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POTENTIAL ROLE OF HAEMATOCOCCUS PLUVIALIS AGAINST DIABETES INDUCED OXIDATIVE STRESS AND INFLAMMATION IN RATS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i1.15073 ◽

2016 ◽

Vol 10 (1) ◽

pp. 245

Author(s):

Farouk Kamel Elbaz ◽

Hanan F Aly ◽

Wagdy Kb Khalil ◽

Gamila H Al ◽

Naglaa A Hafiz ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Antioxidant Enzyme ◽

Inflammatory Cytokines ◽

Dna Adducts ◽

Haematococcus Pluvialis ◽

Lipid Peroxide ◽

Ros Generation ◽

Enzymatic Antioxidants ◽

The Impact

ABSTRACTObjective: The aim of this study is to investigate the impact of Haematococcus pluvialis extract against oxidative stress and inflammatory cytokinesinduced by hyperglycemia in diabetic rats.Methods: Oxidative stress; lipid peroxide (as presented by Malondialdehyde; MDA) and nitric oxide (NO), beside total antioxidant capacity, enzymaticand non-enzymatic antioxidants including reduced glutathione, glutathione peroxidase, and glutathione reductase were evaluated. The inflammatorycytokines; tumor necrosis factor-alpha and interleukin-1 beta were also investigated in rats’ serum. Several analyses including expression ofantioxidant enzyme related genes, reactive oxygen species (ROS) formation and DNA adducts were performed.Results: The results showed that diabetes mellitus induced-rats exhibited increase in oxidative stress biomarkers and inflammatory cytokines, lowerexpression levels of the antioxidant enzyme genes; superoxide dismutase and glutathione S-transferase than those in control rats. In addition, diabeticrats exhibited significantly higher levels of ROS generation and 8-hydroxy-2’-deoxyguanosine (8-OHdG) formation. In contrary, supplementation ofdiabetic rats with H. pluvialis extract improved the negative effect of the hyperglycemia on antioxidant enzymes, the gene expression of antioxidantenzymes, and ROS generation as well as 8-OHdG formation.Conclusion: H. pluvialis extract decreased the oxidative stress, enhanced antioxidant status and inflammatory cytokines induced by hyperglycemiain diabetic rats. The effect of H. pluvialis extract involved in the increase of expression levels of antioxidant enzyme genes; decreased the levels of ROSgeneration and 8-OHdG formation which may be attributed to the presence of astaxanthin in H. pluvialis extract.Keywords: Haematococcus pluvialis, Hyperglycemia, Diabetes mellitus, Oxidative stress, Inflammatory cytokines, DNA adducts.

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Protective effect of curcumin on diazepam-induced behavioral changes and oxidative stress in rats

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.768 ◽

2016 ◽

Vol 33 (S1) ◽

pp. s286-s286

Author(s):

A. Sevastre-Berghian ◽

V. Făgărăşăn ◽

N. Decea ◽

R. Moldovan ◽

B. Sevastre ◽

...

Keyword(s):

Oxidative Stress ◽

Working Memory ◽

Cognitive Performance ◽

Spatial Working Memory ◽

Vehicle Group ◽

Behavioral Tests ◽

Ambulatory Activity ◽

Group I ◽

Y Maze ◽

And Oxidative Stress

IntroductionCurcumin (CUR), a polyphenolic compound, extracted from Curcuma longa, is known for its neuroprotective, antioxidant and anti-inflammatory effects.ObjectivesTo evaluate the effect of CUR on ambulatory activity, spatial working memory and on oxidative stress in rats induced by Diazepam (DZP) administration.AimsTo analyze whether CUR may improve the cognitive performance and offer systemic protection from oxidative stress.MethodsThe effect of CUR on DZP-induced memory impairment and oxidative stress was studied on Wistar rats. Group I received a vehicle, group II – vehicle and CUR, group III – vehicle and DZP, group IV – vehicle, CUR and DZP. CUR (150 mg/kg bw) and vehicle were orally administered for five weeks long. DZP (2 mg/kg bw) was administered i.p. 20 minutes before the behavioral tests. Behavioral tests, i.e. Open Field and Y Maze Test, were performed. Malondialdehyde and reduced glutathione/oxidized glutathione ratio were determined in the serum and brain tissue homogenate. Hippocampal sections were histologically assessed. The data were statistically analyzed by one-way ANOVA, followed by Dunns post-test.ResultsDZP decreased (P < 0.01) the number of spontaneous alternations, as compared to control group, thus suggesting an impairment of spatial working memory. Behavioral tests revealed no enhancing effect of CUR on spontaneous alternation behaviors in Y Maze. CUR reversed (P < 0.01) the inhibitory effect of diazepam (P < 0.05) on the ambulatory activity in OFT and decreased the lipid peroxidation in the serum (P < 0.05).ConclusionsThe results show that CUR may offer systemic protection from oxidative stress, thus improving the cognitive performance.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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HIV-Associated Structural and Functional Brain Alterations in Homosexual Males

Frontiers in Neurology ◽

10.3389/fneur.2021.757374 ◽

2022 ◽

Vol 12 ◽

Author(s):

Qiong Ma ◽

Xiudong Shi ◽

Guochao Chen ◽

Fengxiang Song ◽

Fengjun Liu ◽

...

Keyword(s):

Sexual Orientation ◽

Hiv Infection ◽

Brain Regions ◽

Regional Homogeneity ◽

Anterior Cingulate ◽

Parahippocampal Gyrus ◽

Functional Brain ◽

The Right ◽

The Impact ◽

The Brain

Purpose:Neuroimaging elucidations have shown structural and functional brain alterations in HIV-infected (HIV+) individuals when compared to HIV-negative (HIV–) controls. However, HIV− groups used in previous studies were not specifically considered for sexual orientation, which also affects the brain structures and functions. The current study aimed to characterize the brain alterations associated with HIV infection while controlling for sexual orientation.Methods:Forty-three HIV+ and 40 HIV– homosexual men (HoM) were recruited and underwent resting-state MRI scanning. Group differences in gray matter volume (GMV) were assessed using a voxel-based morphometry analysis. Brain regions with the altered GMV in the HIV+ HoM group were then taken as regions of interest in a seed-based analysis to identify altered functional connectivity. Furthermore, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity values were compared between the two groups to evaluate the HIV-associated functional abnormalities in local brain regions.Results:HIV+ HoM showed significantly increased GMV in the bilateral parahippocampal gyrus and amygdala, and decreased GMV in the right inferior cerebellum, compared with the HIV– HoM. The brain regions with increased GMV were hyper-connected with the left superior cerebellum, right lingual gyrus, and left precuneus in the HIV+ HoM. Moreover, the ALFF values of the right fusiform gyrus, and left parahippocampal gyrus were increased in the HIV+ HoM. The regional homogeneity values of the right anterior cingulate and paracingulate gyri, and left superior cerebellum were decreased in the HIV+ HoM.Conclusion:When the study population was restricted to HoM, HIV+ individuals exhibited structural alterations in the limbic system and cerebellum, and functional abnormalities in the limbic, cerebellum, and visual network. These findings complement the existing knowledge on the HIV-associated neurocognitive impairment from the previous neuroimaging studies by controlling for the potential confounding factor, sexual orientation. Future studies on brain alternations with the exclusion of related factors like sexual orientation are needed to understand the impact of HIV infection on neurocognitive function more accurately.

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Brain Activity after Intermittent Hypoxic Brain Condition in Rats

Brain Sciences ◽

10.3390/brainsci12010052 ◽

2021 ◽

Vol 12 (1) ◽

pp. 52

Author(s):

Bora Mun ◽

Yun-Chol Jang ◽

Eun-Jong Kim ◽

Ja-Hae Kim ◽

Min-Keun Song

Keyword(s):

Hypoxic Exposure ◽

Association Cortex ◽

Control Group ◽

Exposure Group ◽

Hypoxia Exposure ◽

Hypoxic Brain Injury ◽

Hypoxic Brain ◽

Pet Ct ◽

The Right ◽

The Brain

Hypoxic brain injury is accompanied by a decrease in various functions. It is also known that obstructive sleep apnea (OSA) can cause hypoxic brain injury. This study aimed to produce a model of an intermittent hypoxic brain condition in rats and determine the activity of the brain according to the duration of hypoxic exposure. Forty male Sprague–Dawley rats were divided into four groups: the control group (n = 10), the 2 h per day hypoxia exposure group (n = 10), the 4 h per day hypoxia exposure group (n = 10), and the 8 h per day hypoxia exposure group (n = 10). All rats were exposed to a hypoxic chamber containing 10% oxygen for five days. Positron emission tomography–computed tomography (PET-CT) brain images were acquired using a preclinical PET-CT scanner to evaluate the activity of brain metabolism. All the rats were subjected to normal conditions. After five days, PET-CT was performed to evaluate the recovery of brain metabolism. Western blot analysis and immunohistochemistry were performed with vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). The mean SUV was elevated in the 2 h per day and 4 h per day groups, and all brain regions showed increased metabolism except the amygdala on the left side, the auditory cortex on the right side, the frontal association cortex on the right side, the parietal association cortex on the right side, and the somatosensory cortex on the right side immediately after hypoxic exposure. However, there was no difference between 5 days rest after hypoxic exposure and control group. Western blot analysis revealed the most significant immunoreactivity for VEGF in the 2, 4, and 8 h per day groups compared with the control group and quantification of VEGF immunohistochemistry showed more expression in 2 and 4 h per day groups compared with the control group. However, there was no significant difference in immunoreactivity for BDNF among the groups. The duration of exposure to hypoxia may affect the activity of the brain due to angiogenesis after intermittent hypoxic brain conditions in rats.

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Juglone Suppresses Inflammation and Oxidative Stress in Colitis Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.674341 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shuai Chen ◽

Xin Wu ◽

Zengli Yu

Keyword(s):

Oxidative Stress ◽

Inflammatory Cytokines ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Activity Index ◽

Uncoupling Protein ◽

Vehicle Group ◽

Related Factor ◽

Mitochondrial Uncoupling ◽

And Oxidative Stress

Juglone (JUG), a natural product found in walnut trees and other plants, shows potent antioxidant, antimicrobial, and immunoregulatory activities. However, it remains unknown whether JUG can alleviate ulcerative colitis. This study aims to explore the effect of JUG on dextran sulfate sodium (DSS)-induced colitis in mice. The mice were randomly assigned into three groups: the vehicle group, the DSS group, and the JUG group. The experiments lasted for 17 days; during the experiment, all mice received dimethyl sulfoxide (DMSO, 0.03% v/v)-containing water, while the mice in the JUG group received DMSO-containing water supplemented with JUG (0.04 w/v). Colitis was induced by administering DSS (3% w/v) orally for 10 consecutive days. The results showed that the JUG treatment significantly ameliorated body weight loss and disease activity index and improved the survival probability, colon length, and tissue damage. JUG reversed the DSS-induced up-regulation of proinflammatory cytokines, including interleukin (IL)-6, 12, 21, and 23, and tumor necrosis factor-alpha, and anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta, in the serum of the colitis mice. Additionally, the activation of mitochondrial uncoupling protein 2 and phospho-Nuclear Factor-kappa B p65 and the inhibition of the kelch-like ECH-associated protein 1 and NF-E2-related factor 2 induced by DSS were also reversed under JUG administration. Although the JUG group possessed a similar microbial community structure as the DSS group, JUG enriched potential beneficial microbes such as Lachnospiraceae_NK4A136_group but not pathogens such as Escherichia Shigella, which was dominative in DSS group, at the genus level. In conclusion, our results demonstrated that JUG could be a promising agent for UC prevention to regulate inflammatory cytokines and oxidative stress.

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