Nonsteroidal anti-inflammatory drugs modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways

Abstract

In this report, selected non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and nimesulide, and analgesics acetaminophen, alone, as well as in combination with isoflavone genistein as potential glycosaminoglycan (GAG) metabolism modulators were considered for the treatment of mucopolysaccharidoses (MPSs) with neurological symptoms due to the effective blood-brain barrier (BBB) penetration properties of these compounds. We found that indomethacin and nimesulide, but not acetaminophen, inhibited GAG synthesis in fibroblasts significantly, while the most pronounced impairment of glycosaminoglycan production was observed after exposure to the mixture of nimesulide and genistein. Phosphorylation of the EGF receptor (EGFR) was inhibited even more effective in the presence of indomethacin and nimesulide than in the presence of genistein. When examined the activity of phosphatidylinositol-3-kinase (PI3K) production, we observed its most significant decrease in the case of fibroblast exposition to nimesulide, and afterwards to indomethacin and genistein mix, rather than indomethacin used alone. Some effects on expression of individual GAG metabolism-related and lysosomal function genes, and significant activity modulation of a number of genes involved in intracellular signal transduction pathways and metabolism of DNA and proteins were detected. This study documents that NSAIDs, and their mixtures with genistein modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways.

Molecular action of isoflavone genistein in the human epithelial cell line HaCaT

“…Previous work has reported the importance of the PI3K pathway as an important regulator of growth and inflammation in inflammation-mediated diseases such as psoriasis [ 58 ]. Moreover, studies indicated that genistein, alone or even in combination with various pharmaceutical agents (e.g., selected non-steroidal anti-inflammatory drugs), inhibits EGF receptor kinase and its downstream effector PI3K, which in turn might also be implicated in NF-κB transcriptional activation [ 59 , 60 ]. Thus, to test these correlations, we primarily examined the activity of PI3K.…”

Genistein Ameliorates Scopolamine-Induced Amnesia in Mice Through the Regulation of the Cholinergic Neurotransmission, Antioxidant System and the ERK/CREB/BDNF Signaling

“…Previous studies found that the neuroprotective effects of GE mainly involved several mechanisms such as resisting the oxidative stress damage, alleviating neuroinflammation, reducing Aβ deposition, activating the neurotrophins and antiapoptotic factors ( Yang et al, 2014 ). Besides, as a lipid-soluble flavonoid compound, GE has the effective BBB penetration properties ( Mozolewski et al, 2017 ). All these studies together suggest that GE may be a potential agent for the treatment of the neurodegenerative disease and it is noteworthy to further explore the neuroprotective effects of GE.…”

PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions

“…Epidemiological studies indicate that anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), have a beneficial effect on AD, and several reports have shown that NSAIDs protect against inflammation in transgenic AD models [56]. It has been shown that some NSAIDs can exert their actions by modulating PI3K [75,76,77]. Thus, an interesting line of investigation is now directed at analyzing the relationship between inflammation, PI3K signaling, and AD.…”