Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice

Sorafenib is FDA-approved for the treatment of primary kidney or liver cancer, but its ability to inhibit many types of kinases suggests it may have potential for treating other diseases. Here, the effects of sorafenib on neuroinflammatory responses in vitro and in vivo and the underlying mechanisms were assessed. Sorafenib reduced the induction of mRNA levels of the proinflammatory cytokines COX-2 and IL-1β by LPS in BV2 microglial cells, but in primary astrocytes, only COX-2 mRNA levels were altered by sorafenib. Interestingly, sorafenib altered the LPS-mediated neuroinflammatory response in BV2 microglial cells by modulating AKT/P38-linked STAT3/NF-kB signaling pathways. In LPS-stimulated wild-type mice, sorafenib administration suppressed microglial/astroglial kinetics and morphological changes and COX-2 mRNA levels by decreasing AKT phosphorylation in the brain. In 5xFAD mice (an Alzheimer’s disease model), sorafenib treatment daily for 3 days significantly reduced astrogliosis but not microgliosis. Thus, sorafenib may have therapeutic potential for suppressing neuroinflammatory responses in the brain.

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Role of RPTPβ/ζ in neuroinflammation and microglia-neuron communication

Scientific Reports ◽

10.1038/s41598-020-76415-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rosalía Fernández-Calle ◽

Milagros Galán-Llario ◽

Esther Gramage ◽

Begoña Zapatería ◽

Marta Vicente-Rodríguez ◽

...

Keyword(s):

Tyrosine Phosphatase ◽

Conditioned Media ◽

Microglial Cells ◽

Receptor Protein ◽

Mrna Levels ◽

Bv2 Cells ◽

The Central Nervous System ◽

Bv2 Microglial Cells ◽

The Brain

AbstractPleiotrophin (PTN) is a cytokine that is upregulated in different neuroinflammatory disorders. Using mice with transgenic PTN overexpression in the brain (Ptn-Tg), we have found a positive correlation between iNos and Tnfα mRNA and Ptn mRNA levels in the prefrontal cortex (PFC) of LPS-treated mice. PTN is an inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, which is mainly expressed in the central nervous system. We aimed to test if RPTPβ/ζ is involved in the modulation of neuroinflammatory responses using specific inhibitors of RPTPβ/ζ (MY10 and MY33-3). Treatment with MY10 potentiated LPS-induced microglial responses in the mouse PFC. Surprisingly, MY10 caused a decrease in LPS-induced NF-κB p65 expression, suggesting that RPTPβ/ζ may be involved in a novel mechanism of potentiation of microglial activation independent of the NF-κB p65 pathway. MY33-3 and MY10 limited LPS-induced nitrites production and iNos increases in BV2 microglial cells. SH-SY5Y neuronal cells were treated with the conditioned media from MY10/LPS-treated BV2 cells. Conditioned media from non-stimulated and from LPS-stimulated BV2 cells increased the viability of SH-SY5Y cultures. RPTPβ/ζ inhibition in microglial cells disrupted this neurotrophic effect of microglia, suggesting that RPTPβ/ζ plays a role in the neurotrophic phenotype of microglia and in microglia-neuron communication.

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VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice

Molecular Neurodegeneration ◽

10.1186/s13024-020-0357-x ◽

2020 ◽

Vol 15 (1) ◽

Cited By ~ 9

Author(s):

Farida El Gaamouch ◽

Mickael Audrain ◽

Wei-Jye Lin ◽

Noam Beckmann ◽

Cheng Jiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rna Sequencing ◽

Microglial Cells ◽

Wild Type ◽

Primary Microglia ◽

Murine Microglia ◽

5Xfad Mice ◽

Transcriptomic Changes ◽

Bv2 Microglial Cells

Abstract Background Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) identified VGF as a major driver of Alzheimer’s disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression. Methods We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human. Results We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA- and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21. Conclusions These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.

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Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-021-02297-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Avijit Banik ◽

Radhika Amaradhi ◽

Daniel Lee ◽

Michael Sau ◽

Wenyi Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Complete Blood Count ◽

Cardiovascular Effects ◽

Mrna Levels ◽

Proinflammatory Mediators ◽

Model Of Alzheimer’S Disease ◽

Cox 2 ◽

5Xfad Mice

Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.

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Abstract MP06: Kinin B1 Receptor Mediates Orexin System Hyperactivity In Salt-sensitive Hypertension

Hypertension ◽

10.1161/hyp.76.suppl_1.mp06 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Rohan U Parekh ◽

Abdel A Abdel-rahman ◽

Srinivas Sriramula

Keyword(s):

Radio Telemetry ◽

Mrna Levels ◽

Wild Type ◽

Salt Treatment ◽

Neurogenic Hypertension ◽

B1 Receptor ◽

Kinin B1 Receptor ◽

Salt Sensitive Hypertension ◽

The Brain

Hyperactivity of the orexin system contributes to several animal models of hypertension and enhances arginine vasopressin (AVP) release. We previously reported higher neuronal kinin B1 receptor (B1R) expression and brain AVP levels in hypertensive mice. However, the role of B1R and its interaction with orexin system in neurogenic hypertension have not been studied. In the present study, we tested the hypothesis that kinin B1R contributes to hypertension by upregulation of orexin-AVP signaling in the brain. Deoxycorticosterone acetate (DOCA)-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of wild-type (WT) male mice produced a significant increase in mean arterial pressure (MAP; radio-telemetry) (138 ±3 mmHg, n=8, p<0.01) that was blunted in B1R knockout mice (121±2 mmHg, P <0.05 vs. WT+DOCA). In WT mice, DOCA-salt, compared to vehicle, increased mRNA levels of orexin receptor 1 (2.5 fold, n=9, p<0.001), orexin receptor 2 (3 fold, n=9, p<0.001) and AVP (3 fold, n=9, p<0.01) in the hypothalamic paraventricular nucleus (PVN), and these DOCA-salt evoked effects were attenuated in B1RKO mice. Similarly, DOCA-salt evoked increases in protein expression of orexin receptor 1 and 2 in the hypothalamic PVN of WT mice were attenuated by 25±5% and 33±5% (p<0.05), respectively, in B1RKO vs WT+DOCA mice. Furthermore, DOCA-salt treatment increased plasma AVP levels in WT mice compared to vehicle treated mice (13.69±1.1 vs. 47.86±8.7 pg/ml, p<0.05), but not in B1RKO mice. Together, these data provide novel evidence that kinin B1R plays an important role in mediating DOCA-salt induced hypertension possibly via upregulating the orexin-AVP signaling in the brain.

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Anti-inflammatory Activity of 8-Hydroxydaidzein in LPS-Stimulated BV2 Microglial Cells via Activation of Nrf2-Antioxidant and Attenuation of Akt/NF-κB-Inflammatory Signaling Pathways, as Well As Inhibition of COX-2 Activity

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.8b00437 ◽

2018 ◽

Vol 66 (23) ◽

pp. 5790-5801 ◽

Cited By ~ 17

Author(s):

Pei-Shan Wu ◽

Hsiou-Yu Ding ◽

Jui-Hung Yen ◽

Shu-Fen Chen ◽

Kuan-Han Lee ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Activity ◽

Microglial Cells ◽

Inflammatory Signaling ◽

Cox 2 ◽

Anti Inflammatory ◽

Bv2 Microglial Cells

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Cytosolic phospholipase A2α regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00815.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. R1774-R1782 ◽

Cited By ~ 34

Author(s):

Adam Sapirstein ◽

Hideyuki Saito ◽

Sarah J. Texel ◽

Tarek A. Samad ◽

Eileen O’Leary ◽

...

Keyword(s):

Arachidonic Acid ◽

Inflammatory Responses ◽

Arachidonic Acid Metabolism ◽

Cyclooxygenase 2 ◽

Phospholipase A ◽

Wild Type ◽

Cytosolic Phospholipase ◽

The Central Nervous System ◽

Cox 2 ◽

The Brain

The products of arachidonic acid metabolism are key mediators of inflammatory responses in the central nervous system, and yet we do not know the mechanisms of their regulation. The phospholipase A2 enzymes are sources of cellular arachidonic acid, and the enzymes cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) are essential for the synthesis of inflammatory PGE2 in the brain. These studies seek to determine the function of cytosolic phospholipase A2α (cPLA2α) in inflammatory PGE2 production in the brain. We wondered whether cPLA2α functions in inflammation to produce arachidonic acid or to modulate levels of COX-2 or mPGES-1. We investigated these questions in the brains of wild-type mice and mice deficient in cPLA2α (cPLA2α−/−) after systemic administration of LPS. cPLA2α−/− mice had significantly less brain COX-2 mRNA and protein expression in response to LPS than wild-type mice. The reduction in COX-2 was most apparent in the cells of the cerebral blood vessels and the leptomeninges. The brain PGE2 concentration of untreated cPLA2α−/− mice was equal to their wild-type littermates. After LPS treatment, however, the brain concentration of PGE2 was significantly less in cPLA2α−/− than in cPLA2α+/+ mice (24.4 ± 3.8 vs. 49.3 ± 11.6 ng/g). In contrast to COX-2, mPGES-1 RNA levels increased equally in both mouse genotypes, and mPGES-1 protein was unaltered 6 h after LPS. We conclude that cPLA2α regulates COX-2 levels and modulates inflammatory PGE2 levels. These results indicate that cPLA2α inhibition is a novel anti-inflammatory strategy that modulates, but does not completely prevent, eicosanoid responses.

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Streptococcus pneumoniae-Induced Inhibition of Rat Ependymal Cilia Is Attenuated by Antipneumolysin Antibody

Infection and Immunity ◽

10.1128/iai.72.11.6694-6698.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6694-6698 ◽

Cited By ~ 19

Author(s):

Robert A. Hirst ◽

Bashir J. Mohammed ◽

Timothy J. Mitchell ◽

Peter W. Andrew ◽

Christopher O'Callaghan

Keyword(s):

Streptococcus Pneumoniae ◽

Therapeutic Potential ◽

Ependymal Cell ◽

Ex Vivo ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Ependymal Cells ◽

Wild Type ◽

Ependymal Cilia ◽

The Brain

ABSTRACT Ciliated ependymal cells line the ventricular surfaces and aqueducts of the brain. In ex vivo experiments, pneumolysin caused rapid inhibition of the ependymal ciliary beat frequency and caused ependymal cell disruption. Wild-type pneumococci and pneumococci deficient in pneumolysin caused ciliary slowing, but penicillin lysis of wild-type, not pneumolysin-deficient, pneumococci increased the extent of ciliary inhibition. This effect was abolished by antipneumolysin antibody. Ependymal ciliary stasis by purified pneumolysin was also blocked by the addition of antipneumolysin monoclonal antibodies. These data show that antibiotic lysis of Streptococcus pneumoniae can be detrimental to the ciliated ependyma and that antipneumolysin antibody may have a therapeutic potential.

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Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice

10.21203/rs.2.17199/v2 ◽

2019 ◽

Author(s):

Xin-chun Ye ◽

Qi Hao ◽

Wei-jing Ma ◽

Qiu-chen Zhao ◽

Wei-wei Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Infarct Volume ◽

Inos Expression ◽

Microglial Cells ◽

Brain Infarct ◽

Tnf Α ◽

Bv2 Microglial Cells ◽

The Brain

Abstract Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer's disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model. Adult male C57BL/6J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test and foot-fault test were evaluated on days 1, 3, 5 and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl’s and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention. Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5 and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk and p-Syk expression was increased following the 3-h OGD and 0, 3 and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction. Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

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