Abstract
Activated microglia secrete an array of pro-inflammatory factors, such as prostaglandins, whose accumulation contributes to neuronal damages. Prostaglandin endoperoxide synthases or cyclooxygenases (COX-1 and COX-2), which play a critical role in the inflammation, are the pharmacological targets of non-steroidal anti-inflammatory drugs, used to treat pain and inflammation. Since it was reported that COX-1 is the major player in mediating the brain inflammatory response, the aim of this study was to evaluate the effects of highly selective COX-1 inhibitors, such as P6 and mofezolac, in neuroinflammation models. Lipopolysaccharide (LPS)-activated mouse BV-2 microglial cells and LPS intracerebroventricular-injected mice as in vitro and in vivo neuroinflammation models, respectively, were used to probe the antiinflammatory efficacy of P6 and mofezolac. Both P6 and mofezolac reduce COX-1 expression in LPS-activated BV-2 cells. This reduction was accompanied with PGE2 release reduction and NF-kB activation downregulation. Coextensively, in the in vivo model, both glial fibrillary acidic protein and ionized calcium-binding adapter molecule-1 expression, two markers of inflammation, were reduced by mofezolac to a rank depending on the encephalon area analyzed. The increase of COX-1 expression observed in all the brain sections of LPS-treated mice was selectively downregulated by the in vivo treatment with mofezolac as well as PGE2 release and Ikβα phosphorylation amount assayed in the brain areas tested. These results indicate the capability of P6 and mofezolac to modulate the NF-kB signaling pathway, emphasizing the neuroprotective effect and therapeutic potential of COX-1 inhibitors in the control of neuroinflammatory diseases.
Highlights
Neuroinflammation is widely recognized as an inflammatory response originated in the central nervous system (CNS)
None of the inhibitors used at the above indicated doses were toxic to BV2 microglial cells, when used in the absence of LPS
Inhibitors used at the same doses, resulted protective toward BV2 microglial cells after 48 h LPS treatment (1 μg/mL), being the percentage of cell viability comparable to that observed in control
Summary
Neuroinflammation is widely recognized as an inflammatory response originated in the central nervous system (CNS) It is a pathological condition mainly caused by the nervous tissue infiltration of host defense cells and molecules from the bloodstream. It implies a complex interplay of glia, in particular microglia, typically associated with neurological and COX-1 Inhibition in Neuroinflammation neurodegenerative diseases, triggering several concerns from a nosological viewpoint [1]. Epidemiological data-based link between neuroinflammation and neurodegenerative diseases increased the worldwide scientific interest aimed to determine whether reducing inflammation would reverse neurodegeneration Such data indicate an inverse relationship between the use of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and Alzheimer’s disease risk. Such data indicate an inverse relationship between the use of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and Alzheimer’s disease risk. tNSAIDs pharmacological action is due to their ability to inhibit the cyclooxygenase (COX) and, the biosynthesis of the prostaglandins (PG) involved in neuroinflammation [10]
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