Antiinflammatory effects of 5‐HT<sub>3</sub>receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes

Fiebich, BL; Akundi, RS; Lieb, K; Candelario‐Jalil, Eduardo; Gmeiner, Doris; Haus, Ulrike; Müller, Wolfgang; Stratz, T; Muñóz, Eduardo

doi:10.1080/03009740410006998

Cited by 79 publications

(62 citation statements)

References 4 publications

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“…We became interested in reports that some serotonin (5-HT) receptor antagonists can inhibit LPS (TLR4 ligand)-induced TNF production from human monocytes (12) and other studies showing anti-inflammatory properties in animal models of inflammation. One particular example is mianserin, a tetracyclic 5-HT2 A/C receptor antagonist which has been shown to decrease PMA-induced edema in the mouse (13) and B 1 kinin receptor-induced paw edema formation in rodents (14).…”

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confidence: 99%

Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures

Sacre

Gregory

et al. 2008

The Journal of Immunology

113

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The advent of anti-TNF biologicals has been a seminal advance in the treatment of rheumatoid arthritis (RA) and has confirmed the important role of TNF in disease pathogenesis. However, it is unknown what sustains the chronic production of TNF. In this study, we have investigated the anti-inflammatory properties of mianserin, a serotonin receptor antagonist. We discovered mianserin was able to inhibit the endosomal TLRs 3, 7, 8, and 9 in primary human cells and inhibited the spontaneous release of TNF and IL-6 from RA synovial membrane cultures. This suggested a role for these TLRs in production of TNF and IL-6 from RA which was supported by data from chloroquine, an inhibitor of endosomal acidification (a prerequisite for TLRs 3, 7, 8, and 9 activation) which also inhibited production of these cytokines from RA synovial cultures. Only stimulation of TLR 3 or 8 induced TNF from these cultures, indicating that TLR7 and TLR9 were of less consequence in this model. The key observation that indicated the importance of TLR8 was the inhibition of spontaneous TNF production by imiquimod, which we discovered to be an inhibitor of TLR8. Together, these data suggest that TLR8 may play a role in driving TNF production in RA. Because this receptor can be inhibited by small m.w. molecules, it may prove to be an important therapeutic target.

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confidence: 99%

Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures

Sacre

Gregory

et al. 2008

The Journal of Immunology

113

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“…Several researchers including us reported the essential role of MAPK pathway in the regulation of MMP-9 and iNOS expression in immunostimulated glial cells (Fiebich et al, 2004;Koistinaho et al, 2005;Shin et al, 2007). Therefore, we investigated whether C. japonica alkaloids affect ERK1/2 phosphorylation by Western blot.…”

Section: Effects Of C Japonica Alkaloids On Lps-stimulated Mmp-9 Actmentioning

confidence: 96%

Inhibitory Effects of Coptis japonica Alkaloids on the LPS-Induced Activation of BV2 Microglial Cells

Jeon¹,

Kwon²,

Shin³

et al. 2009

Biomolecules and Therapeutics

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-Coptis japonica (C. japonica) is a perennial medicinal plant that has anti-inflammatory activity. C. japonica contains numerous biologically active alkaloids including berberine, palmatine, epi-berberine, and coptisine. The most well-known anti-inflammatory principal in C. japonica is berberine. For example, berberine has been implicated in the inhibition of iNOS induction by cytokines in microglial cells. However, the efficacies of other alkaloids components on microglial activation were not investigated yet. In this study, we investigated the effects of three alkaloids (palmatine, epi-berberine and coptisine) from C. japonica on lipopolysaccharide (LPS)-induced microglial activation. BV2 microglial cells were immunostimulated with LPS and then the production of several inflammatory mediators such as nitric oxide (NO), reactive oxygen species (ROS) and matrix metalloproteinase-9 (MMP-9) were examined as well as the phosphorylation status of Erk1/2 mitogen activated protein kinase (MAPK). Palmatine and to a lesser extent epi-berberine and coptisine, significantly reduced the release of NO, which was mediated by the inhibition of LPS-stimulated mRNA and protein induction of inducible nitric oxide synthase (iNOS) from BV2 microglia. In addition to NO, palmatine inhibited MMP-9 enzymatic activity and mRNA induction by LPS. Palmatine also inhibited the increase in the LPS-induced MMP-9 promoter activity determined by MMP-9 promoter luciferase reporter assay. LPS stimulation increased Erk1/2 phosphorylation in BV2 cells and these alkaloids inhibited the LPS-induced phosphorylation of Erk1/2. The anti-inflammatory effect of palmatine in LPS-stimulated microglia may suggest the potential use of the alkaloids in the modulation of neuroinflammatory responses, which might be important in the pathophysiological events of several neurological diseases including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD) and stroke.

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“…Surface Plasmon Resonance (SPR) shows F03 also interacts directly with APP and this, combined with multifunctional receptor interactions, seems to be critical for efficacy. In addition, F03 has been reported as an anti-inflammatory agent [60][61][62]. As chronic inflammation may be a factor contributing to the onset of AD [63], this drug may be of even greater utility in the treatment or prevention of AD.…”

Section: Sappα or Adam10 Enhancers In Admentioning

confidence: 99%

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2015

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Citation: Spilman P, Jagodzinska B, Bredesen DE, John V (2015) Enhancement of sAPPα as a Therapeutic Strategy for Alzheimer's and Other Neurodegenerative Diseases. J Alzheimers Neurodegener Dis 1: 001. Introduction Therapeutics for Alzheimer's Disease (AD)The number of cases of Alzheimer's Disease (AD) -the most prevalent age-associated dementia -is expected to increase rapidly as society ages, rising from approximately 5 million at present to 15 million cases by 2050 in the US [1], and currently there are no treatments that prevent onset or alter the course of the disease. AD is a progressive neurodegenerative disorder characterized by the presence of senile plaques, composed mainly of Amyloid β peptide (Aβ) [2,3], and the development of neurofibrillary tangles of hyper-phosphorylated tau (ptau) in brain tissue [4,5]. AD patients suffer from deficits in cognition, learning and memory, and exhibit impaired Long-Term Potentiation (LTP) [6] and a consistent deficit in cholinergic neurotransmission. The currently approved therapeutics include the acetylcholinesterase inhibitors donepezil, galantamine, rivastigmine, and tacrine which inhibit the breakdown of acetylcholine at the neuronal junction, and the N-Methyl-D-Aspartate (NMDA) receptor antagonist memantine, which reduces the excitotoxicity that results from NMDA receptor overstimulation in AD. Recently, the FDA has approved a fixed-dose combination of memantine hydrochloride extended release (Namenda XR) and donepezil hydrochloride (Namzaric) for moderate to severe AD-related dementia. These current therapeutics offer only temporary improvement in cognition and/or delay in progress of the disease, thus there is clearly a need for new approaches to and discovery of new targets for AD therapeutic development.More recent approaches to AD therapeutic development include re-purposing the anti-epileptic drug levetiracetam to address the seizure-like activity manifest in many AD patients [7,8], use of anti-diabetic drugs including intranasal insulin [9,10], and development of BACE inhibitors [11][12][13], including our own APP-selective BACE inhibitors [14], to name a few. It is hoped that some of these new approaches will provide benefit in AD, but it is very likely that truly effective treatment for AD will require multiple therapeutics working in concert -similar to the approach used for AIDS therapy -to address the many deficits in the disease. One component of this multi-modal therapy should restore and promote normal neuronal function, rather than just arrest a single deleterious process underlying the disease. It is our hypothesis and that of others that enhancement of trophic peptide sAPPα, or the activity of the enzyme ADAM10, could play this key role in therapy. Aβ plaques and the amyloid hypothesis in ADThe original evidence pointing to amyloid as causative in AD came from the finding of amyloid plaques in the brains of AD patients. It was ultimately determined that these plaques were comprised of Amyloid-β (Aβ) peptides [15,16] and based on the presenc...

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Antiinflammatory effects of 5‐HT₃receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes

Cited by 79 publications

References 4 publications

Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures

Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures

Inhibitory Effects of Coptis japonica Alkaloids on the LPS-Induced Activation of BV2 Microglial Cells

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Antiinflammatory effects of 5‐HT3receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes

Cited by 79 publications

References 4 publications

Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures

Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures

Inhibitory Effects of Coptis japonica Alkaloids on the LPS-Induced Activation of BV2 Microglial Cells

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Antiinflammatory effects of 5‐HT₃receptor antagonists in lipopolysaccharide‐stimulated primary human monocytes