NSAIDs in the treatment and/or prevention of neurological disorders

Khansari, Parto S.; Coyne, Leanne

doi:10.1007/s10787-011-0116-2

Cited by 10 publications

(7 citation statements)

References 88 publications

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“…Extensive knowledge of ion channels targeted by FFA may revive interest in the use of this molecule for therapeutic purposes, as was suggested for NSAIDs, especially fenamates, in the treatment of neurological disorders (Khansari & Coyne, 2012). The recently developed FFA hydrophobic derivative nanoprodrugs show an increase in the drug efficiency (Lee et al ., 2011a).…”

Section: Discussionmentioning

confidence: 99%

Flufenamic acid as an ion channel modulator

Guinamard

Simard

Negro

2013

Pharmacology & Therapeutics

125

113

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Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10-6 M in TRPM4 channel inhibition to 10-3 M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and systems levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Flufenamic acid as an ion channel modulator

Guinamard

Simard

Negro

2013

Pharmacology & Therapeutics

125

113

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“…Epidemiological studies also indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in normal aging populations [ 6 , 7 ]. A primary action of NSAIDs is enzymatic inhibition of cyclooxygenases (COX)-1 and COX-2 activity which further leads to an inhibition of downstream prostaglandin signaling and also exerts multiple adverse side effects mainly characterized by gastrointestinal bleeding and cardiovascular events [ 8 , 9 ]. In prostaglandin (PG) signaling pathway, tissue-specific terminal prostaglandin synthases or isomerases convert PGH2 into biologically active prostaglandins (PGs), namely, PGD2, PGE2, PGF2a, and PGI2 (also known as prostacyclin), as well as thromboxane A2 (TxA2) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

PGE2-EP3 signaling pathway contributes to protective effects of misoprostol on cerebral injury in APP/PS1 mice

Tian

Luo

et al. 2016

Oncotarget

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Epidemiological studies indicate chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the enzymatic activity of the inflammatory cyclooxygenases (COX), reduces the risk of developing Alzheimer's disease (AD) in normal aging populations. Considering multiple adverse side effects of NSAIDs, findings suggest that COX downstream prostaglandin signaling function in the pre-clinical development of AD. Our previous study found that misoprostol, a synthetic prostaglandin E2 (PGE2) receptor agonist, has neuroprotection against brain injury induced by chronic aluminum overload. Here, we investigated the neuroprotective effects and mechanisms of misoprostol on neurodegeneration in overexpressing both amyloid precursor protein (APP) and mutant presenilin 1 (PS1) mice. Here were young group, elderly group, APP/PS1 group and misoprostol-treated group. Mice in misoprostol-treated group were administrated with misoprostol (200 μg·kg−1·d−1, p.o.) five days a week for 20 weeks. The spatial learning and memory function was impaired and karyopycnosis of hippocampal and cortical neurons was observed; amyloid beta (Aβ) deposition was increased; superoxide dismutase (SOD) activity was decreased and malondialdehyde (MDA) content was increased in APP/PS1 mice. However, misoprostol could significantly blunte these changes in APP/PS1 mic. Moreover, the expressions of microsomal PGE2 synthase (mPGES-1), PGE2, PGE2 receptor (EP) 2 and EP4 were increased and EP3 expression was decreased in APP/PS1 mice, while misoprostol reversed these changes. Our present experimental results indicate that misoprostol has a neuroprotective effect on brain injury and neurodegeneration of APP/PS1 mice and that the activation of PGE2-EP3 signaling and inhibition of oxidative stress contribute to the neuroprotective mechanisms of misoprostol.

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“…tients [12, 13, 28, 29]. Epidemiological studies have shown that NSAIDs act distinctly in different stages of AD.…”

Section: Discussionmentioning

confidence: 99%

“…However, many experiments found that although sustained administration of selective COX-2 inhibitor could prevent mild cognitive impairment caused by acute or chronic brain injury disease, it could not heal severe AD patients or reverse their cognitive defects. Additionally, the long-term use of these drugs increase the risk of bleeding, gastrointestinal ulcers, fatal heart and cerebrovascular side effects [12, 13]. Therefore, it was suggested that COX-2 downstream signaling needs to be further studied.…”

Section: Introductionmentioning

confidence: 99%

“…Our interest is in knowing how misoprostol, an EP3 agonist, affects the COX-2 downstream signaling cascades in aluminum-overload rats [20-23]. Furthermore, this study revealed that the COX-2 downstream prostaglandin signaling may be beneficial, including the modulation of a specific prostaglandin synthase or receptor for a superior therapeutic intervention compared with a generic block of the entire COX-2 signaling cascades [13, 14]. …”

Section: Introductionmentioning

confidence: 99%

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Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats

Guo

Lei

Wang

et al. 2016

CAR

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Although COX-2 inhibition in animal models of neurodegenerative diseases has shown neuroprotection, recent studies have revealed some serious side effects (ulcers, bleeding, fatal cerebrovascular diseases etc.) and the limited benefits of COX-2 inhibitors. A more focused approach is necessary to explore the therapeutic effect of the COX downstream signaling pathway in neurological research. The aim of this study was to explore the alterations of the PGES-PGE2-EP signal pathway and the effect of misoprostol on neurodegeneration by chronic aluminum-overload in rats. Adult rats were treated by intragastric administration of aluminum gluconate. The PGE2 content and expression of PGES and EPs in the hippocampi of rats were detected using ELISA, q-PCR and Western blot analysis, respectively. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the rat hippocampi were also detected. The misoprostol treatment dose-dependently improved spatial learning and memory function as well as healing after hippocampal neuron damage induced by chronic aluminum-overload in rats. Meanwhile, the administration of misoprostol resulted in a decrease in the PGE2 level and down-regulation of the mPGES-1, EP2 and EP4 expression levels, while there was a dose-dependent up-regulation of EP3 expression. These results suggest that misoprostol possesses a neuroprotective property, and the mechanism involves affecting the EP3 level and reducing the endogenous production of PGE2 through a negative feedback mechanism, increasing the EP3 expression level, decreasing the EP2 and EP4 expression levels, and rebuilding the mPGES-1-PGE2-EP1-4 signal pathway balance. In this way, misoprostol has a counteractive effect on oxidant stress and inflammation in the central nervous system. The PGES-PGE2-EPs signaling pathway is a potential therapeutic strategy for treating neurodegeneration in patients.

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NSAIDs in the treatment and/or prevention of neurological disorders

Cited by 10 publications

References 88 publications

Flufenamic acid as an ion channel modulator

Flufenamic acid as an ion channel modulator

PGE2-EP3 signaling pathway contributes to protective effects of misoprostol on cerebral injury in APP/PS1 mice

Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats

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