Cytokines In Hippocampus Research Articles

The primary studies of epigallocatechin-3-gallate in improving brain injury induced by chronic high-altitude natural environment in rats by 7.0T high-field MR imaging

BackgroundEpigallocatechin-3-gallate (EGCG) is one of the most abundant and important bioactive polyphenolic compounds in green tea. However, despite its potent antioxidant effects, its neuroprotective effects on chronic high altitude (HA)-induced nerve damage have not been reported. The purpose of this study is to use quantitative susceptibility mapping (QSM) with pathology to dynamically evaluate the status of brain damage and the effect of EGCG. MethodsA model of HA environments-induced brain injury was established of Sprague-Dawley (SD) rats in a natural plateau environment for 4 weeks, 8 weeks, 12 weeks and 20 weeks. Behavioral alterations were then observed and assessed with the open field test (OFT) and Morris water maze (MWM) test. The microglial activation, nissl staining and neural degeneration by Fluoro Jade B in the hippocampus of the rats were observed by immunohistochemistry. In the rats, serum erythropoietin (EPO), hippocampal inflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]), ferritin, oxidative stress (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT] and malondialdehyde [MDA]) were detected using ELISA kits and biochemical methods. Iron accumulation was observed by QSM and colorimetry. Iron metabolisms (ceruloplasmin [Cp], transferrin [Tf], divalent metal transport1 [DMT1] and hepcidin [Hep]) were detected using qPCR. Neural ultrastructural changes were evaluated with electron microscope. Salidroside treatment was chosen as the positive control group in ELISA, biochemical detection and electron microscopy. ResultsThe susceptibility values in the left and right hippocampus, the hippocampal ferritin, serum and hippocampal iron content increased significantly after HA exposure. The expression of hippocampal Cp and Hep decreased and the expression of Tf increased. Nissl staining revealed that the neurons of hippocampal CA1 region of h-20w group were small and irregular, atrophied, and nuclear shrinkage. Tissue oxidative stress and inflammatory indicators (MDA, TNF-α, IL-1β, IL-6) increased while antioxidant enzymes (SOD, CAT, GSH-Px) decreased. EGCG attenuated HA environments-induced cognitive impairment, iron accumulation, microglial activation and neural degeneration. The effects of EGCG in reducing EPO and the metal chelating property with respect to iron were dose-dependent, with effects of EGCG (50 mg/kg) being similar to those of salidroside (50 mg/kg). ConclusionsEGCG can act as a neuroprotective agent against chronic HA environments-mediated neural injuries. QSM provides a potential complementary imaging technique to detect the effect of treating HA diseases.

Remimazolam attenuates lipopolysaccharide-induced neuroinflammation and cognitive dysfunction

ObjectiveRemimazolam, a novel benzodiazepine, is widely used as an anesthetic in endoscopic procedures; however, its effects on cognitive function remain unclear, limiting its broader application in general anaesthesia. Neuroinflammation is a well-established key factor in the etiology and progression of cognitive dysfunction, including conditions such as Alzheimer's disease, Parkinson's disease, postoperative delirium, and postoperative cognitive dysfunction. Preclinical studies have demonstrated that remimazolam exerts anti-inflammatory and neuroprotective effects, and clinical reports indicate a reduced incidence of postoperative delirium in patients treated with remimazolam. Nevertheless, whether remimazolam improves cognitive function through its anti-inflammatory properties remains uncertain. This study aimed to investigate the neuroprotective effects of remimazolam and its underlying mechanism in a lipopolysaccharide (LPS)-induced model of neuroinflammation, neuronal injury, and cognitive dysfunction MethodsC57BL/6 J male mice were administered LPS intraperitoneally to establish a model of neuroinflammation-induced cognitive impairment. A subset of mice received remimazolam via intraperitoneal injection 30 minutes prior to LPS administration. Cognitive performance was evaluated using behavioural tests, including the Morris Water Maze (MWM), Novel Object Recognition (NOR) test, and Open Field Test (OFT). Hippocampal tissues were analyzed by haematoxylin-eosin (HE) staining to assess structural changes. Inflammatory markers, including Interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, were quantified using enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR. Immunofluorescence was used to detect translocator protein (TSPO) and markers of microglia activation (IBA-1, CD16/32, and CD206). Results(1) Remimazolam reversed LPS-induced cognitive deficits, as evidenced by shorter spatial exploration latency and increased platform crossings in the MWM, and an elevated recognition index in the NOR test. (2) Remimazolam improved hippocampal morphology, reducing LPS-induced neuronal damage. (3) Remimazolam significantly decreased levels of hippocampal inflammatory cytokines, inhibited microglial activation, promoted M2-type microglia polarization, and increased TSPO expression. ConclusionRemimazolam demonstrated neuroprotective and anti-neuroinflammatory effects in a mouse model of LPS-induced cognitive impairment. These effects are likely mediated through the regulation of TSPO, which inhibits microglial activation and promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype.

Interleukin‐6 induces cognitive impairment via toll‐like receptor 4 (TLR4)‐mediated neuroinflammation and neurodegeneration in mice with chronic kidney disease

AbstractBackgroundsPast epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease (CKD) leads to cognitive impairment. However, the underlying mechanism requires further investigation. Herein, a mouse model of CKD was established using conventional 5/6 nephrectomy. We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.MethodsCognitive behavior was assessed using the Morris water maze, novel object recognition test, and fear conditioning test. Further experiments were also conducted to investigate the underlying molecular mechanisms.ResultsOur clinical data revealed a decrease in cognitive function among patients with CKD, accompanied by elevated plasma levels of pro‐inflammatory cytokines. A positive correlation between cytokine concentrations and serum creatinine levels, as well as a significant positive correlation with cognitive dysfunction, were observed. Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice. Furthermore, 20 mg/mL interleukin‐6 (IL‐6) significantly decreased HT22 cell activity in vitro. Further, HT22 cells treated with IL‐6 showed increased expression levels of toll‐like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), thereby inducing the nuclear factor kappa‐B p65 inflammatory pathway and mitochondria‐dependent apoptosis. The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus. TLR4 knockdown antagonized the IL‐6‐mediated pro‐inflammatory and pro‐apoptotic effects in HT22 cells. TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites, thus ameliorated cognitive impairment.ConclusionThese results suggest that IL‐6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD, ultimately culminate in cognitive impairment.

Foxq1 activates CB2R with oleamide to alleviate POCD.

Postoperative cognitive dysfunction (POCD) is a major concern, particularly among older adults. This study used social isolation (ISO) and multiomics analyses in aged mice to investigate potential mechanisms underlying POCD development. Aged mice were divided into two groups: ISO and paired housing (PH). Oleamide and the cannabinoid receptor type 2 (CB2R) antagonist AM630 were administered intraperitoneally, while Foxq1 adeno-associated viral (AAV) vector was injected directly into the hippocampus. Intramedullary tibial surgeries were subsequently performed to establish the POCD models. Behavioral tests comprising the Y-maze, open field test, and novel object recognition were conducted 2 days after surgery. Hippocampal and serum inflammatory cytokines were assessed. Following surgery, ISO mice demonstrated intensified cognitive impairments and escalated inflammatory markers. Integrative transcriptomic and metabolomic analysis revealed elevated oleamide concentrations in the hippocampus and serum of PH mice, with associative investigations indicating a close relationship between the Foxq1 gene and oleamide levels. While oleamide administration and Foxq1 gene overexpression substantially ameliorated postoperative cognitive performance and systemic inflammation in mice, CB2R antagonist AM630 impeded these enhancements. The Foxq1 gene and oleamide may be crucial in alleviating POCD. While potentially acting through CB2R-mediated pathways, these factors may modulate neuroinflammation and attenuate proinflammatory cytokine levels within the hippocampus, substantially improving cognitive performance postsurgery. This study lays the groundwork for future research into therapeutic approaches targeting the Foxq1-oleamide-CB2R axis, with the ultimate goal of preventing or mitigating POCD.

Reduction in Hippocampal Amyloid-β Peptide (Aβ) Content during Glycine-Proline-Glutamate (Gly-Pro-Glu) Co-Administration Is Associated with Changes in Inflammation and Insulin-like Growth Factor (IGF)-I Signaling.

Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-β peptides (Aβs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1, and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme, was also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.

4R-cembranoid suppresses glial cells inflammatory phenotypes and prevents hippocampal neuronal loss in LPS-treated mice.

Chronic neuroinflammation has been implicated in neurodegenerative disease pathogenesis. A key feature of neuroinflammation is neuronal loss and glial activation, including microglia and astrocytes. 4R-cembranoid (4R) is a natural compound that inhibits hippocampal pro-inflammatory cytokines and increases memory function in mice. We used the lipopolysaccharide (LPS) injection model to study the effect of 4R on neuronal density and microglia and astrocyte activation. C57BL/6J wild-type mice were injected with LPS (5 mg/kg) and 2 h later received either 4R (6 mg/kg) or vehicle. Mice were sacrificed after 72 h for analysis of brain pathology. Confocal images of brain sections immunostained for microglial, astrocyte, and neuronal markers were used to quantify cellular hippocampal phenotypes and neurons. Hippocampal lysates were used to measure the expression levels of neuronal nuclear protein (NeuN), inducible nitrous oxide synthase (iNOS), arginase-1, thrombospondin-1 (THBS1), glial cell-derived neurotrophic factor (GDNF), and orosomucoid-2 (ORM2) by western blot. iNOS and arginase-1 are widely used protein markers of pro- and anti-inflammatory microglia, respectively. GDNF promotes neuronal survival, and ORM2 and THBS1 are astrocytic proteins that regulate synaptic plasticity and inhibit microglial activation. 4R administration significantly reduced neuronal loss and the number of pro-inflammatory microglia 72 h after LPS injection. It also decreased the expression of the pro-inflammatory protein iNOS while increasing arginase-1 expression, supporting its anti-inflammatory role. The protein expression of THBS1, GDNF, and ORM2 was increased by 4R. Our data show that 4R preserves the integrity of hippocampal neurons against LPS-induced neuroinflammation in mice.

Danggui Shaoyao San: comprehensive modulation of the microbiota-gut-brain axis for attenuating Alzheimer's disease-related pathology.

Background: Alzheimer's disease (AD), an age-associated neurodegenerative disorder, currently lacks effective clinical therapeutics. Traditional Chinese Medicine (TCM) holds promising potential in AD treatment, exemplified by Danggui Shaoyao San (DSS), a TCM formulation. The precise therapeutic mechanisms of DSS in AD remain to be fully elucidated. This study aims to uncover the therapeutic efficacy and underlying mechanisms of DSS in AD, employing an integrative approach encompassing gut microbiota and metabolomic analyses. Methods: Thirty Sprague-Dawley (SD) rats were allocated into three groups: Blank Control (Con), AD Model (M), and Danggui Shaoyao San (DSS). AD models were established via bilateral intracerebroventricular injections of streptozotocin (STZ). DSS was orally administered at 24g·kg-1·d-1 (weight of raw herbal materials) for 14 days. Cognitive functions were evaluated using the Morris Water Maze (MWM) test. Pathological alterations were assessed through hematoxylin and eosin (HE) staining. Bloodstream metabolites were characterized, gut microbiota profiled through 16S rDNA sequencing, and cortical metabolomics analyzed. Hippocampal proinflammatory cytokines (IL-1β, IL-6, TNF-α) were quantified using RT-qPCR, and oxidative stress markers (SOD, CAT, GSH-PX, MDA) in brain tissues were measured with biochemical assays. Results: DSS identified a total of 1,625 bloodstream metabolites, predominantly Benzene derivatives, Carboxylic acids, and Fatty Acyls. DSS significantly improved learning and spatial memory in AD rats and ameliorated cerebral tissue pathology. The formulation enriched the probiotic Ligilactobacillus, modulating metabolites like Ophthalmic acid (OA), Phosphocreatine (PCr), Azacridone A, Inosine, and NAD. DSS regulated Purine and Nicotinate-nicotinamide metabolism, restoring balance in the Candidatus Saccharibacteria-OA interplay and stabilizing gut microbiota-metabolite homeostasis. Additionally, DSS reduced hippocampal IL-1β, IL-6, TNF-α expression, attenuating the inflammatory state. It elevated antioxidative enzymes (SOD, CAT, GSH-PX) while reducing MDA levels, indicating diminished oxidative stress in AD rat brains. Conclusion: DSS addresses AD pathology through multifaceted mechanisms, encompassing gut microbiome regulation, specific metabolite modulation, and the mitigation of inflammation and oxidative stress within the brain. This holistic intervention through the Microbial-Gut-Brain Axis (MGBA) underscores DSS's potential as an integrative therapeutic agent in combatting AD.

Hippocampal and gut AMPK activation attenuates enterocolitis-like symptoms and co-occurring depressive-like behavior in ulcerative colitis model mice: Involvement of brain-gut autophagy

Patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease, have a high incidence of psychiatric disorders, including depression and anxiety. However, the underlying pathogenic mechanism remains unknown. Dextran sulfate sodium (DSS)-treated mice, a model of UC, exhibit depressive-like behavior and reduced adenosine monophosphate-activated protein kinase (AMPK) activity, which regulates various physiological functions in the brain and gut. However, comprehensive studies on UC pathophysiology with co-occurring depression focused on brain-gut AMPK activity are lacking. Therefore, we aimed to investigate whether resveratrol (RES), an AMPK activator, prevented DSS-induced UC-like symptoms and depressive-like behavior. DSS treatment induced UC-like pathology and depressive-like behavior, as assessed via the tail suspension test. Moreover, western blotting and immunohistochemical studies revealed that DSS increased p-p70S6 kinase (Thr389), p62, tumor necrosis factor-α, interleukin (IL)-1β, IL-18, NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, cleaved Gasdermin-D (GSDMD), and cleaved caspase-3 expression levels in the rectum and hippocampus, and increased CD40, iNOS, and Kelch-like ECH-associated protein 1 expression levels, and the number of Iba1-positive cells in the hippocampus, and decreased p-AMPK and LC3II/I expression levels, and the number of NF-E2-related factor 2 (Nrf2)-positive cells, and reduced neurogenesis in the hippocampus. These changes were reversed by the RES administration. RES also enhanced PGC1α and SOD1 expression in the hippocampus of DSS-treated male mice. Moreover, NLRP3 staining was observed in the neurons and microglia, and cleaved GSDMD staining in neurons in the hippocampus of DSS-treated mice. Notably, RES prevented UC-like pathology and depressive-like behavior and enhancement of autophagy, decreased rectal and hippocampal inflammatory cytokines and inflammasome, and induced the Nrf2-PGC1α-SOD1 pathway in the hippocampus, resulting in neurogenesis in the hippocampal dentate gyrus. Our findings suggest that brain-gut AMPK activation may be an important therapeutic strategy in patients with UC and depression.

Neuro‐immune and behavioral consequences of low dose radiation, social isolation and sex differences in the longevity MCAT mouse model

AbstractBackgroundThe multi‐organ physiological responses to spaceflight stressors resemble aging on Earth. We simulate space environment together with environmental stress, as a model of accelerated aging. Redox dys‐homeostasis was shown to contribute to aging‐related pathologies such as Alzheimer’s and Parkinson’s. The MCAT transgenic mice (overexpressing human catalase in the mitochondria), have increased life span, delayed age‐related pathology and enhanced hippocampal spatial learning and memory.MethodOur study uses 1‐year old C57BL/6NJ male and female mice that underwent exposure to 0.5 gray of gamma radiation together with social isolation. In order to determine ROS contribution to neuro‐behavioral stress response, we used the longevity MCAT mouse model in which human catalase is overexpressed in the mitochondria. We aimed to determine whether in older mice quenching ROS, will mitigate the neuro‐behavioral consequences of low dose ionizing radiation and social isolation and whether sex differences will be detected. We have performed multiple behavioral tests which focused on performance, memory, physical stance, and stress, together with plasma and hippocampal neuro‐immune panels.ResultWe have detected both sex and radiation/isolation effects; the older females look physically better, are faster and perform better almost in all behavioral tasks compared to their male counterparts. On the other hand, they are more sensitive to low dose radiation and isolation in many cases. Interestingly, many of the neuro‐immune changes caused by radiation and social isolation were mitigated in the MCAT mice. In a plasma multiplex cytokine panel, corticosterone (7‐ and 90‐days post radiation), and hippocampal cytokine and microglial activation at the end of the experiment, we have detected significant changes due to radiation, isolation, sex and genotype in both short and long post radiation period. Our focus is now on applying advanced statistical modeling to correlate the behavioral tests with our recent molecular findings to look for specific biomarkers that could predict behavioral deficits caused by various environmental stresses.ConclusionQuenching ROS in older mice partially mitigates neuro‐immune consequences of environmental stresses. Significant sex differences were detected, pointing out the importance of examining both sexes, for better personal medicine. The study points out that anti‐oxydant meassures could help older isolated population.

Protection of p-Coumaric acid against chronic stress-induced neurobehavioral deficits in mice via activating the PKA-CREB-BDNF pathway

There is a body of evidence to suggest that chronic stress modulates neurochemical homeostasis, alters neuronal structure, inhibits neurogenesis and contributes to development of mental disorders. Chronic stress-associated mental disorders present common symptoms of cognitive impairment and depression with complex disease mechanisms. P-coumaric acid (p-CA), a natural phenolic compound, is widely distributed in vegetables, cereals and fruits. p-CA exhibits a wide range of health-related effects, including anti-oxidative-stress, anti-mutagenesis, anti-inflammation and anti-cancer activities. The current study aims to evaluate the therapeutic potential of p-CA against stress-associated mental disorders. We assessed the effect of p-CA on cognitive deficits and depression-like behavior in mice exposed to chronic restraint stress (CRS); we used network pharmacology, biochemical and molecular biological approaches to elucidate the underlying molecular mechanisms. CRS exposure caused memory impairments and depression-like behavior in mice; p-CA administration attenuated these CRS-induced memory deficits and depression-like behavior. Network pharmacology analysis demonstrated that p-CA was possibly involved in multiple targets and a variety of signaling pathways. Among them, the protein kinase A (PKA) - cAMP-response element binding protein (CREB) - brain derived neurotrophic factor (BDNF) signaling pathway was predominant and further characterized. The levels of PKA, phosphorylated CREB (pCREB) and BDNF were significantly lowered in the hippocampus of CRS mice, suggesting disruption of the PKA-CREB-BDNF signaling pathway; p-CA treatment restored the signaling pathway. Furthermore, CRS upregulated expression of proinflammatory cytokines in hippocampus, while p-CA reversed the CRS-induced effects. Our findings suggest that p-CA will offer therapeutic benefit to patients with stress-associated mental disorders.

Memory deficits and hippocampal cytokine expression in a rat model of ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a complex behavioral disorder characterized by hyperactivity, impulsivity, inattention, and deficits in working memory and time perception. While animal models have advanced our neurobiological understanding of this condition, there are limited and inconsistent data on working and elapsed time memory function. Inflammatory signaling has been identified as a key factor in memory and cognitive impairments, but its role in ADHD remains unclear. Additionally, the disproportionate investigation of male subjects in ADHD research has contributed to a poor understanding of the disorder in females. This study sought to investigate the potential connections between memory, neuroimmunology, and ADHD in both male and female animals. Specifically, we utilized the spontaneously hypertensive rat (SHR), one of the most extensively studied animal models of ADHD. Compared to their control, the Wistar-Kyoto (WKY) rat, male SHR are reported to exhibit several behavioral phenotypes associated with ADHD, including hyperactivity, impulsivity, and poor sustained attention, along with impairments in learning and memory. As the hippocampus is a key brain region for learning and memory, we examined the behavior of male and female SHR and WKY rats in two hippocampal-dependent memory tasks. Our findings revealed that SHR have delay-dependent working memory deficits that were similar to, albeit less severe than, those seen in hippocampal-lesioned rats. We also observed impairments in elapsed time processing in female SHR, particularly in the discrimination of longer time durations. To investigate the impact of inflammatory signaling on memory in these rats, we analyzed the levels of several cytokines in the dorsal and ventral hippocampus of SHR and WKY. Although we found some sex and genotype differences, concentrations were generally similar between groups. Taken together, our results indicate that SHR exhibit deficits in spatial working memory and memory for elapsed time, as well as some differences in hippocampal cytokine concentrations. These findings contribute to a better understanding of the neurobiological basis of ADHD in both sexes and may inform future research aimed at developing effective treatments for the disorder. Nonetheless, the potential mediating role of neuroinflammation in the memory symptomatology of SHR requires further investigation.

HDAC3 inhibition protects against peripheral and central alterations in an animal model of obesity.

Obesity is a multifactorial disease with epigenetic manifestations that increases the prevalence of associated comorbidities such as metabolic syndrome, cardiovascular dysfunction, and major depression disorder. Given the aforementioned, a search for new pharmacological alternatives for the treatment of this disease is necessary. The current study aimed to evaluate the effects of histone deacetylase-3 (HDAC3) inhibition caused by RGFP966 (a benzamide-type HDAC inhibitor selective for HDAC3) administration, in an animal model of obesity induced by high-fat diet (HFD). Adult male mice C57BJ/6 were fed with a normal pellet diet (NPD) or HFD for 120days. The HDAC3 inhibitor (RGFP966; 10mg/kg; sc) was administered on the 91st to 120th day of the experiment (per 30days). After the last inhibitor administration, animals were euthanized, blood was collected, and the hippocampus was removed for biochemical determinations. In an overall manner, the administration of RGFP966 protected against changes in body weight gain, glucose, insulin, lipid profile, adipokines, and increase of hippocampal proinflammatory cytokines levels caused by HFD. Therefore, HDAC3 inhibition can represent a promising pharmacological target for the treatment of obesity.

Improvements of Age-Related Cognitive Decline in Mice by Lactobacillus helveticus WHH1889, a Novel Strain with Psychobiotic Properties.

A gradual decline in cognitive function occurs with age. Accumulating evidence suggests that certain probiotic strains exert beneficial effects on age-related cognitive decline. Our previous study revealed that Lactobacillus helveticus WHH1889 attenuated symptoms of anxiety and depression in depressed mice via shaping the 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP) metabolism and gut microbial community, indicating the psychobiotic potential of WHH1889. In the present study, the effects of WHH1889 on age-related cognitive decline were investigated. WHH1889 was orally administrated (1 × 109 CFU/day) for twelve weeks in aged mice, and their cognitive behaviors, neurochemical factors, cognitive-related gene expressions, neuroinflammation, and serum tryptophan pathway-targeted metabolic profiling, as well as gut microbiome composition were assessed. WHH1889 demonstrated improvement of the cognitive behaviors via the novel object recognition test (NORT), the active shuttle avoidance test (ASAT), the Y-maze test, and the passive avoidance test (PAT). The hippocampal neuronal loss; the declined concentrations of BDNF, 5-HT, and 5-HTP; the decreased gene expressions of neurodegeneration biomarkers; and the increased production of hippocampal inflammatory cytokines in aged mice were restored by WHH1889. In addition, WHH1889 increased the 5-HT/5HTP levels and decreased the serum levels of tryptophan-derived metabolites (e.g., kynurenine, xanthurenic acid, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid). Furthermore, WHH1889 was revealed to shape the gut microbiota community by reversing the relative abundances of Bacteroidota and Firmicutes. The present findings suggest that L. helveticus WHH1889 exerted cognitive improving effects on aged mice, which was associated with the modulation of 5-HT and 5-HTP metabolism and gut microbial composition. The supplementation of WHH1889 may therefore be a promising therapeutic agent for age-related cognitive deficits.

Disordered gut microbiota and changes in short-chain fatty acids and inflammatory processes in stress-vulnerable mice

Long-term exposure to chronic stress increases the incidence of depression. However, chronic stress is an associated risk factor in only a subset of individuals. Inflammation has been identified as a putative mechanism promoting stress vulnerability. Because of the gut microbiota's potential role as a source of inflammatory substances, short-chain fatty acids (SCFAs) may exert their influence on inflammation, emotional states, and cognition via the gut-brain axis. In this study, Classic behavioral tests were used to categorize C57BL/6 J mice into a CUMS-vulnerable and a CUMS-resilient group after they were exposed to chronic unpredictable mild stress (CUMS). We compared the 16S ribosomal RNA (rRNA) gene sequences retrieved from fecal samples between control, CUMS-vulnerable, and CUMS-resilient mice. SCFAs in fecal samples were detected by liquid chromatography and gas chromatography–mass spectrometry. Hippocampal cytokine production and TLR4/MYD88/NF-κB inflammatory pathway activation were evaluated using enzyme-linked immunosorbent assays (ELISAs) and western blotting. Then, we supplemented SCFAs in CUMS mice. we observed depression-like behavior and the expression of TLR4/MYD88/NF-κB inflammatory pathway in hippocampus of SCFAs supplementation mice. Susceptible mice to CUMS showed more severe symptoms of depression and anxiety, α diversity was significantly different, as well as higher expression of interleukin (IL)-1β and TLR4/MYD88/NF-κB inflammatory pathway components in the hippocampus. SCFA levels in the feces were significantly higher in CUMS-resilient mice than in control mice. Depressive behavior was reversed in CUMS-SCFAs group, and the protein level of TLR4/MYD88/NF-κB in hippocampus was decreased. Overall, these results provide new light on the possible involvement of the microbiome in the gut-brain axis development in depressive disorder and provide a theoretical basis for identifying novel therapeutic targets.

Amyloid-β Pathology-Specific Cytokine Secretion Suppresses Neuronal Mitochondrial Metabolism

IntroductionNeuroinflammation and metabolic dysfunction are early alterations in Alzheimer’s disease (AD) brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in AD patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.MethodsWe used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of AD at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.ResultsWe identified a pattern of up-regulated IFNγ, IP-10/CXCL10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.ConclusionsWe identify a pattern of cytokine secretion predictive of progressing amyloid-β pathology in the 5xFAD mouse model of AD that reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in AD.

Periodontitis-induced neuroinflammation impacts dendritic spine immaturity and cognitive impairment.

This study investigated the spinal changes in ligature-induced periodontitis and the role of periodontitis in cognitive impairment. Twenty mice were randomized into the control and chronic periodontitis (CP) groups, with the latter receiving ligature-induced periodontitis. Cognitive performance was assessed by fear conditioning test. Periodontal inflammation and alveolar bone resorption were evaluated by micro-computed tomography and histopathology. The hippocampal microglial activation was evaluated by immunohistochemistry (IHC). The expressions of hippocampal cytokines (TNF-α, iNOS, IL-1β, IL-4, IL-10, and TREM2) were measured by reverse transcription-polymerase chain reaction. The morphology and density of the dendritic spines were determined by Golgi-Cox staining. The CP mice reported significant inflammatory cell infiltration and alveolar bone resorption, with marked increases in cytokine levels (TNF-α, iNOS, IL-1β, and TREM2) in the brain. Moreover, the CP mice showed significantly reduced freezing to the conditioned stimulus in the cued and contextual tests, indicating impaired memory. Further analyses revealed, in the hippocampus of the CP mice, enhanced microglial activation, decreased dendritic spine density, and increased proportion of thin dendritic spines. Periodontitis-induced neuroinflammation may impair the cognitive function by activating hippocampal microglia and inducing dendritic spine immaturity.

Inhaled molecular hydrogen reduces hippocampal neuroinflammation, glial reactivity and ameliorates memory impairment during systemic inflammation

Sepsis is associated with numerous physiological and biochemical abnormalities that result in a life-threatening condition. The involvement of the Central Nervous System (CNS) during sepsis has received considerable attention, especially the hippocampus which plays a key role in the learning and memory processes. The increased interest in this limbic region during systemic inflammation (SI) is related to the number of sepsis survivor patients who have cognitive impairments. A single injection of lipopolysaccharide (LPS)-induced systemic inflammation is the most commonly used murine endotoxemia model because it replicates several pathophysiological changes observed in severe sepsis. Molecular hydrogen (H2) has been used as an anti-inflammatory therapeutic strategy to prevent neuroinflammation. However, the mechanisms by which inhaled H2 mitigate memory loss during SI remains unknown. To understand how H2 acts in the hippocampus, the current study focused on specific mechanisms that may be involved in reducing neuroinflammation in rats during SI. We hypothesized that inhaled H2 decreases LPS-induced hippocampal pro-inflammatory cytokines surges and this effect is associated with reduced memory loss. Using different and integrative approaches, i.e., from hippocampal cells electrophysiology to animal behavior, we report that inhaled H2 decreased LPS-induced peripheral and hippocampal inflammation, decreased microglial and astrocytic activation, lessen memory loss without affecting long-term potentiation (LTP). To our knowledge, this is the first evidence showing that inhaled H2 reduces hippocampal microglial and glial cells inflammation, which may be associated with a reduced memory impairment induced by SI.

Role of omentin-1 in susceptibility to anxiety and depression like behaviors

Neuro-inflammation and blood-brain barrier (BBB) dysfunction are associated with depression. Evidence shows that adipokines enter the brain from the circulation, which regulates depressive behaviors. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about its role in neuro-inflammation and mood-relevant behavior. Our results showed omentin-1 knockout mice (Omentin-1−/−) increased susceptibility to anxiety and depressive-like behaviors, which are associated with abnormalities of cerebral blood flow (CBF) and impaired BBB permeability. Moreover, omentin-1 depletion significantly increased hippocampal pro-inflammatory cytokines (IL-1β, TNFα, IL-6), caused microglial activation, inhibited hippocampus neurogenesis, and resulted in autophagy impairment by dysregulating ATG genes. Omentin-1 deficiency also sensitized mice to the behavioral changes induced by lipopolysaccharide (LPS), suggesting that omentin-1 could rescue neuro-inflammation by acting as an anti-depressant. Our in vitro microglia cell culture data confirmed that recombinant omentin-1 suppresses microglial activation and pro-inflammatory cytokine expression induced by LPS. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of depression by providing a barrier-promoting effect and an endogenous anti-inflammatory balance to downregulate the proinflammatory cytokines.

Portulaca oleracea L. (purslane) improves the anti-inflammatory, antioxidant and autophagic actions of metformin in the hippocampus of diabetic demented rats

Great body of evidence links cognitive decline to diabetes/insulin resistance. In this study the effect of Portulaca oleracea (PUR) (100 mg/kg), Metformin (MET) (200 mg/kg), a first line diabetes mellitus type 2 therapy, and their combination on cognitive function and hippocampal markers in diabetic rats were assessed. Male rats were injected with streptozotocin (30 mg/kg on two successive weeks) followed by 4 weeks of treatment. Possible antioxidant, anti-inflammatory, and autophagy enhancing mechanisms of these drugs were investigated in the hippocampal tissue using spectrophotometry, ELISA, and western blotting. Diabetic rats suffered significant cognitive impairment in Morris's water maze, hippocampal TBARS elevation, GSH depletion, and SOD upregulation. In addition, diabetes promoted the secretion of hippocampal inflammatory cytokines, TNF-α and IL-1β, and depleted anti-inflammatory cytokines as IL-10. Such detrimental changes were reversed by MET and/or PUR. Notably, AMPK was upregulated by diabetes, then restored to normal by MET and/or PUR. The pattern of change in AMPK expression was concomitant with changes in oxidative and inflammatory burden. Hence, AMPK is believed to be a key mediator in most of the measured pre-AD markers in this study. However, from our results, PUR is believed to have non-AMPK dependent actions as well.In conclusion, antidiabetic agents as metformin and purslane extract proved to be invaluable in addressing the cognitive decline and hippocampal changes that arise as a complication of diabetes. They mainly acted through AMPK pathway; however, their usefulness was not limited to AMPK pathways since their combination was suggested to have a different mechanism.

Meloxicam Targets COX-2/NOX1/NOX4/Nrf2 Axis to Ameliorate the Depression-like Neuropathology Induced by Chronic Restraint Stress in Rats.

Meloxicam has shown significant neuroprotection in experimental models of stroke, Alzheimer's disease, and Parkinson's disease. However, the potential of meloxicam to treat depression-like neuropathology in a chronic restraint stress (CRS) model and the associated molecular changes has been insufficiently explored. The current work aimed to explore the potential neuroprotective actions of meloxicam against CRS-evoked depression in rats. In the current experiments, animals received meloxicam (10 mg/kg/day; i.p.) for 21 days, and CRS was instigated by restraining the animals for 6 h/day during the same period. The sucrose preference test and the forced swimming test were used to explore the depression-linked anhedonia/despair, whereas the open-field test examined the animals' locomotor activity. The current findings revealed that CRS elicited typical depression behavioral anomalies in the animals, including anhedonia, despair, and diminished locomotor activity; these findings were reinforced with Z-normalization scores. These observations were corroborated by brain histopathological changes and increased damage scores. In CRS-exposed animals, serum corticosterone spiked, and the hippocampi revealed decreased monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). Mechanistically, neuroinflammation was evident in stressed animals, as shown by elevated hippocampal TNF-α and IL-1β cytokines. Moreover, the hippocampal COX-2/PGE2 axis was activated in the rats, confirming the escalation of neuroinflammatory events. In tandem, the pro-oxidant milieu was augmented, as seen by increased hippocampal 8-hydroxy-2'-deoxyguanosine alongside increased protein expression of the pro-oxidants NOX1 and NOX4 in the hippocampi of stressed animals. In addition, the antioxidant/cytoprotective Nrf2/HO-1 cascade was dampened, as evidenced by the lowered hippocampal protein expression of Nrf2 and HO-1 signals. Interestingly, meloxicam administration mitigated depression manifestations and brain histopathological anomalies in the rats. These beneficial effects were elicited by meloxicam's ability to counteract the corticosterone spike and hippocampal neurotransmitter decrease while also inhibiting COX-2/NOX1/NOX4 axis and stimulating Nrf2/HO-1 antioxidant pathway. Together, the present findings prove the neuroprotective/antidepressant actions of meloxicam in CRS-induced depression by ameliorating hippocampal neuroinflammation and pro-oxidant changes, likely by modulating COX-2/NOX1/NOX4/Nrf2 axis.