Brain IL-6 Levels Research Articles

Leaky gut and inflammatory biomarkers in a medication overuse headache model in male rats.

Medication overuse is common among chronic migraine patients and nonsteroidal antiinflammatory drugs (NSAIDs) are the most frequently overused drugs. The pathophysiological mechanisms underlying medication overuse headache (MOH) are not completely understood. Intestinal hyperpermeability and leaky gut are reported in patients using NSAIDs. The aim of the study is to investigate the role of leaky gut and inflammation in an MOH model MOH model in male rats. The study was conducted in male Sprague Dawley rats. There were two experimental groups. The first group was the chronic NSAID group in which the rats received mefenamic acid (n = 8) for four weeks intraperitoneally (ip) and the second group was the vehicle group (n = 8) that received 5% dimethyl sulfoxide+sesame oil (ip) for 4 weeks. We assessed spontaneous pain-like behavior, periorbital mechanical withdrawal thresholds, and anxiety-like behavior using an elevated plus maze test. After behavioral testing, serum levels of occludin and lipopolysaccharide-binding protein (LBP) and brain levels of IL-17, IL-6, and high mobility group box 1 protein (HMGB1) were evaluated with ELISA.Results: Serum LBP and occludin levels and brain IL-17 and HMGB1 levels were significantly elevated in the chronic NSAID group compared to its vehicle (p = 0.006, p = 0.016, p = 0.016 and p = 0.016 respectively) while brain IL-6 levels were comparable (p = 0.67) between the groups. The chronic NSAID group showed pain-like and anxiety-like behavior in behavioral tests. Brain IL-17 level was positively correlated with number of head shakes (r = 0.64, p = 0.045), brain IL-6 level was negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.71, p = 0.049), and serum occludin level was positively correlated with grooming duration (r = 0.73, p = 0.032) in chronic NSAID group. Elevated serum occludin and LBP levels and brain IL-17 and HMGB1 levels indicate a possible role of leaky gut and inflammation in an MOH model in male rats. Additionally, a significant correlation between pain behavior and markers of inflammation and intestinal hyperpermeability, supports the role of inflammation and leaky gut in MOH pathophysiology.

#6078 MODULATION OF TRYPTOPHAN METABOLISM IN SEPSIS-INDUCED ACUTE KIDNEY INJURY (AKI): A NEW THERAPEUTIC APPROACH TO PREVENT NEUROCOGNITIVE IMPAIRMENT

Abstract Background and Aims Partial recovery following AKI could lead to long-term consequences that predispose to chronic dysfunction and may also accelerate progression of neurocognitive impairment. In this scenario, a tight crosstalk between kidney and brain named “kidney-brain axis” seems to play a pivotal role leading to detrimental outcome for AKI patients. Notably, many studies suggest a high relationship between kidney damage and brain dysfunction (cognitive impairment, taste and olfactory dysfunction, peripheral nerve dysfunction) even after the resolution of AKI. Furthermore, patients who suffered AKI may afterward show a disturbance of arousal, also called “brain fog”. Although major advances have been made in our understanding of the pathophysiology of AKI and brain dysfunction, there are no available preventive and therapeutic strategies in this field. Recent findings have revealed remarkable link existing between dyslipidemia/low High-density lipoprotein (HDL) levels and Kynurenine pathway (KP) alterations that lead to the production of neuroactive metabolites such as kynurenine (KYN) and quinolinic acid (QA) in AKI setting. Method Sepsis-induced AKI (SI-AKI) was induced in a porcine model by intravenous infusion of a saline solution containing 300 μg/kg of LPS. After LPS injection, 12 animals were treated with different doses of recombinant HDL (rHDL) (20–40 mg/kg) (rHDL group), while 6 animals did not receive treatment (LPS group). Animals were sacrificed after 24h from the start of experimental procedure. Results Endotoxemic pigs developed oliguric AKI with increased tubular and glomerular damage and interstitial inflammatory infiltrate. We found that rHDL treatment significantly decreased the inflammatory process and tubular damage, preventing AKI, especially in the rHDL 40 mg/kg group. Then, we evaluated the Indolamine-2,3-dioxygenase 1 (IDO1) enzyme activation, which is the first and rate-limiting step of KP, upregulated during inflammation in both sera and brain tissue, and has been linked to cognitive dysfunction. In our model, LPS induced an increased activation of the IDO-1 gene expression at brain level in endotoxemic animals, meanwhile it appears to be reduced in both treated arms (p<0.005). Furthermore, sera from the rHDL group showed a significant reduction in IDO1 activity (KYN/Trp ratio) (p<0.05) and QA levels (p<0.005) compared with the LPS group. Moreover, a significant decrease of both systemic and brain IL-6 levels was observed after rHDL treatments. Conclusion Our preliminary data indicated that HDL-enhancing therapies may decrease the inflammatory response, the retention of waste products and neuroactive compounds, improving renal and cognitive function in SI-AKI.

Mouse Adapted SARS-CoV-2 (MA10) Viral Infection Induces Neuroinflammation in Standard Laboratory Mice.

Increasing evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacts neurological function both acutely and chronically, even in the absence of pronounced respiratory distress. Developing clinically relevant laboratory mouse models of the neuropathogenesis of SARS-CoV-2 infection is an important step toward elucidating the underlying mechanisms of SARS-CoV-2-induced neurological dysfunction. Although various transgenic models and viral delivery methods have been used to study the infection potential of SARS-CoV-2 in mice, the use of commonly available laboratory mice would facilitate the study of SARS-CoV-2 neuropathology. Herein we show neuroinflammatory profiles of immunologically intact mice, C57BL/6J and BALB/c, as well as immunodeficient (Rag2-/-) mice, to a mouse-adapted strain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 (MA10)). Our findings indicate that brain IL-6 levels are significantly higher in BALB/c male mice infected with SARS-CoV-2 MA10. Additionally, blood-brain barrier integrity, as measured by the vascular tight junction protein claudin-5, was reduced by SARS-CoV-2 MA10 infection in all three strains. Brain glial fibrillary acidic protein (GFAP) mRNA was also elevated in male C57BL/6J infected mice compared with the mock group. Lastly, immune-vascular effects of SARS-CoV-2 (MA10), as measured by H&E scores, demonstrate an increase in perivascular lymphocyte cuffing (PLC) at 30 days post-infection among infected female BALB/c mice with a significant increase in PLC over time only in SARS-CoV-2 MA10) infected mice. Our study is the first to demonstrate that SARS-CoV-2 (MA10) infection induces neuroinflammation in laboratory mice and could be used as a novel model to study SARS-CoV-2-mediated cerebrovascular pathology.

Anesthesia and surgery induce age-dependent changes in behaviors and microbiota.

The neuropathogenesis of postoperative delirium remains mostly unknown. The gut microbiota is implicated in the pathogenesis of neurological disorders. We, therefore, set out to determine whether anesthesia/surgery causes age-dependent gut microbiota dysbiosis, changes in brain IL-6 level and mitochondrial function, leading to postoperative delirium-like behavior in mice. Female 9 or 18 months old mice received abdominal surgery under 1.4% isoflurane for two hours. The postoperative delirium-like behavior, gut microbiota, levels of brain IL-6, PSD-95 and synaptophysin, and mitochondrial function were determined by a battery of behavioral tests, 16s rRNA sequencing, ELISA, Western blot and Seahorse XFp Extracellular Flux Analyzer. Intragastric administration of Lactobacillus (10 days) and probiotic (20 days) were used to mitigate the anesthesia/surgery-induced changes. Anesthesia/surgery caused different alterations in gut microbiota, including change rate of reduction in the levels of gut lactobacillus, between the 18 and 9 months old mice. The anesthesia/surgery induced greater postoperative delirium-like behavior, increased brain IL-6 levels, decreased PSD-95 and synaptophysin levels, and mitochondrial dysfunction in 18 than 9 months old mice. Treatments with Lactobacillus and probiotic mitigated the anesthesia/surgery-induced changes. These data suggest that microbiota dysbiosis may contribute to neuropathogenesis of postoperative delirium and treatment with Lactobacillus or a probiotic could mitigate postoperative delirium.

Effects of Rat Anti-mouse Interleukin-6 Receptor Antibody on the Recovery of Cognitive Function in Stroke Mice.

This study aimed to investigate the effects of rat anti-mouse interleukin (IL)-6 receptor antibody (MR16-1) on the recovery of cognitive function in stroke mice. Adult male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO). Mice were randomly assigned into three groups: sham group, model group, and MR16-1 group. After the treatment of MR16-1, spatial learning and memory performance of mice were evaluated by the Morris water maze (MWM) and Y-maze tests. Then, brain slices were obtained and infarct volume and neuronal apoptosis were assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining and Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, respectively. Protein expression levels of apoptosis-associated proteins and multiple inflammatory cytokines were determined by Western blot analysis. Real-time quantitative PCR (RT-PCR) was used to examine the mRNA levels of various inflammatory cytokines in brain slices and cerebrospinal fluid (CSF). The results showed that MR16-1 improved performances of stroke mice in MWM and Y-maze tests. Moreover, MR16-1 ameliorated MCAO-induced infarct, neuronal apoptosis, and inflammatory response. Furthermore, MR16-1 promoted the expression of Bcl-2 and inhibited the expression of Bax in stroke mice, which revealed the inhibitory effect of MR16-1 on neuronal apoptosis. IL-6 levels in brain and CSF were both decreased by MR16-1 treatment in stroke mice. MR16-1 ameliorated cognitive dysfunction and apoptosis in stroke mice, involving the inhibition of inflammatory response and pro-apoptotic Bax, and the up-regulation of anti-apoptotic Bcl-2. The data supported that MR16-1 might be a potential therapeutic drug for the treatment of stroke.

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

BackgroundLysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.FindingsHere we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.ConclusionsThis study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.

Inflammatory Cascades Driven by Tumor Necrosis Factor-Alpha Play a Major Role in the Progression of Acute Liver Failure and Its Neurological Complications

Background/aimsAcute liver failure (ALF) due to ischemic or toxic liver injury is a clinical condition that results from massive loss of hepatocytes and may lead to hepatic encephalopathy (HE), a serious neuropsychiatric complication. Although increased expression of tumor necrosis factor-alpha (TNF-α) in liver, plasma and brain has been observed, conflicting results exist concerning its roles in drug-induced liver injury and on the progression of HE. The present study aimed to investigate the therapeutic value of etanercept, a TNF-α neutralizing molecule, on the progression of liver injury and HE in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity.Methods/Principal FindingsMice were administered saline or etanercept (10 mg/kg; i.p.) 30 minutes prior to, or up to 6 h after AOM. Etanercept-treated ALF mice were sacrificed in parallel with vehicle-treated comatose ALF mice and controls. AOM induced severe hepatic necrosis, leading to HE, and etanercept administered prior or up to 3 h after AOM significantly delayed the onset of coma stages of HE. Etanercept pretreatment attenuated AOM-induced liver injury, as assessed by histological examination, plasma ammonia and transaminase levels, and by hepatic glutathione content. Peripheral inflammation was significantly reduced by etanercept as shown by decreased plasma IL-6 (4.1-fold; p<0.001) and CD40L levels (3.7-fold; p<0.001) compared to saline-treated ALF mice. Etanercept also decreased IL-6 levels in brain (1.2-fold; p<0.05), attenuated microglial activation (assessed by OX-42 immunoreactivity), and increased brain glutathione concentrations.ConclusionsThese results indicate that systemic sequestration of TNF-α attenuates both peripheral and cerebral inflammation leading to delayed progression of liver disease and HE in mice with ALF due to toxic liver injury. These results suggest that etanercept may provide a novel therapeutic approach for the management of ALF patients awaiting liver transplantation.

An analysis of the role of paulinia cupana (Guaraná) in blood IL-1b and brain IL-6 levels as well as brain IL-6 and TNF-a mRNA expression in mice.

e21002 Background: Paulinia cupana also known as Guaraná is an amazonic plant which has been used for centuries as a tonic by indigenous populations. We have recently demonstrated that the dry crude extract of Guaraná is effective in preventing the treatment of cancer related fatigue (CRF) in breast cancer patients undergoing adjuvant chemotherapy. Of note, CRF patients have been associated with high blood levels of IL-1beta and IL-6. Methods: female Balb/c mice were divided in 8 groups each with 6 to 8 animals each and treated as follows: 1) Normal Saline PO; 2) Excipient PO; 3) Dexamethasone 1mg/kg subcutaneously (SC) (positive control group; 4-6) Guaraná purified Extract (PC18) at 30, 100 and 300 mg/kg PO; 7-8) Gurana dry crude extract at 100 and 300 mg/kg PO. All animals, except those from Group 1 received 100 ml (2.5 µg/mice) of intraperitoneal Escherichia coli Lipopolyssacaride (LPS). Animals were evaluated for social and exploratory interaction (Fishkin and Winslow, 1997) and motor activity (Dunn e Swiergiel, 2005) before (0) and at 2, 4, 8 and 24 hours after the LPS treatment. Levels of IL-1 beta and IL-6 were measured in the blood by ELISA 2 hours after LPS injection (N=5 animals per group) and the mRNA expression of IL-6, IL-12, TNF-alpha and INF-gama in the brain by quantitative real time RT-PCR 2 hours after LPS injection (N=5 animals per group). Results: We observed a statistically significant improvement in social interaction in animals treated with Guaraná extract. We observed no significant change in the IL-6 levels in the blood from animals that received Guarana extract, whereas plasma IL1-beta levels were significantly lower in the animals treated with Guaraná. Interestingly, Guaraná significantly suppressed the increase in brain IL-6 and TNF-alpha mRNA levels induced by LPS. Conclusions: Guaraná extract is effective to improve social behavior in animals treated with LPS which is associated with suppression of blood IL-1beta as well as IL-6 and TNF-alpha mRNA expression in the brain. Therefore, guarana extract may exhibit orally anti-inflammatory effects that might explain its anti-fatigue activity observed clinically in cancer patients.

Involvement of monoamines and proinflammatory cytokines in mediating the anti-stress effects of Panax quinquefolium

Panax quinquefolium (PQ) is well acclaimed in literature for its effects on central and peripheral nervous system. The present study explores the effects of PQ on stress induced changes of corticosterone level in plasma, monoamines (NA, DA and 5-HT) and interleukin (IL-2 and IL-6) levels in cortex and hippocampus regions of brain and also indicate their possible roles in modulating stress. Mice subjected to chronic unpredictable stress (CUS, for 7 days) showed significant increase in plasma corticosterone level and depletion of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in cortex and hippocampal regions along with an increased level of IL-2 and IL-6 in the same areas. Aqueous suspension of PQ was administered daily at a dose of 100 and 200 mg/kg p.o. prior to the stress regimen and its effects on selected stress markers in plasma and brain was evaluated. PQ at a dose of 200 mg/kg p.o. was found to be effective in normalizing the CUS induced elevation of plasma corticosterone and IL-2, IL-6 levels in brain. Moreover, it was significantly effective in reinstating the CUS induced depletion of NA, DA and 5-HT in hippocampus, while NA and 5-HT in cortex of brain. However, PQ at a dose of 100 mg/kg p.o. was found ineffective in regulating any of these CUS induced changes. Present study provides an insight into the possible role of PQ on hyperactive HPA axis in the regulation of immediate stress effectors like corticosterone, cytokines and brain monoamines. In this study, PQ has emerged as a potential therapeutic in the cure of stress related disorders and needs to be evaluated in clinical studies to ascertain its efficacy.

LPS INDUCES IL-6 IN THE BRAIN AND IN SERUM LARGELY THROUGH TNF PRODUCTION

We investigated the relative contribution of IL-6 and PGE2 directly induced by LPS and indirectly induced via TNF, using in vivo and in vitro models in the mouse. In these models we have used as tools an anti-TNF antibody and a cyclooxygenase inhibitor, the S enantiomer of ketoprofen (S-KPF). Anti-TNF antibodies inhibited LPS-induced IL-6 production in three different models: IL-6 production by mouse peritoneal macrophages in vitro; serum IL-6 levels induced by intraperitoneal LPS; and brain IL-6 levels induced by an intracerebroventricular injection of LPS. However, in vitro anti-TNF antibodies, did not inhibit LPS-induced PGE2, indicating that this effect is not mediated by TNF. Since PGE2 has an opposite effect on TNF and IL-6 production, inhibiting that of TNF but inducing that of IL-6, we investigated the effect of S-KPF on TNF and IL-6 production in vivo following LPS injection. Both TNF and IL-6 induction was augmented by S-KPF, but anti-TNF antibodies abolished the augmentation of IL-6 production. Thus, the effect of anti-inflammatory drugs on IL-6 production in some models can be secondary to their effect on TNF production.