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.
Highlights
Of ERT concerns the inefficient enzyme dissemination to all occupied sites in the body, including its ineffective delivery to the central nervous system (CNS) due to an ineffective delivery of proteins through the blood-brain barrier[2]
It has been previously demonstrated that acetaminophen, indomethacin and nimesulide are among analgesics and NSAIDs which inhibit GAG synthesis[13,14,25]
phosphoinositide 3-kinase (PI3K) activity decrease in fibroblasts treated with NSAIDs and genistein. In this part of the work we studied further how the inhibition of epidermal growth factor receptor (EGFR) phosphorylation by investigated NSAIDs influences the activity of phosphatidylinositol-3-kinase, a downstream effector of epidermal growth factor (EGF) receptor, in fibroblasts treated with particular indomethacin and nimesulide alone or with their mixture with genistein
Summary
Of ERT concerns the inefficient enzyme dissemination to all occupied sites in the body, including its ineffective delivery to the central nervous system (CNS) due to an ineffective delivery of proteins through the blood-brain barrier[2]. This strategy relates to the partial inhibition of enzymes of the lysosomal substrate biosynthetic pathway by low molecular weight inhibitor, leading to reduction of these de novo synthesized substrates The purpose of this is to restore in pathologically changed cells the equilibrium between the processes of synthesis and degradation of these substrates. This work led us to revise the action of the other EGFR inhibitors, which could be considered as putative drugs in MPS treatment, even more efficient in treating the neurological symptoms This will be a milestone in the development of substrate reduction therapy and crucial in view of fact that the SRT is a promising strategy for treatment of mucopolysaccharidoses, and what is most important, it gives chance to be effective for their neurodegenerative forms, for which no treatment is available at the moment. Among different cells types (such as keratinocytes, melanocytes, lymphocytes, glial, lens and endothelial cells), fibroblasts from normal and MPS individuals exhibit most limited replicative life span in the culture, and remain a powerful tool for our studies
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