m -Terphenylamines, Acting as Selective COX-1 Inhibitors, Block Microglia Inflammatory Response and Exert Neuroprotective Activity.
Damiano RocchiJuan-Francisco GonzálezOlmo Martín-CámaraMaria Grazia PerroneMorena MiciacciaAntonio ScilimatiCeline Decouty-PérezEsther ParadaJavier EgeaJosé Carlos MenéndezPublished in: Molecules (Basel, Switzerland) (2023)
Inhibition of cyclooxygenase-2 (COX-2) has been extensively studied as an approach to reduce proinflammatory markers in acute brain diseases, but the anti-neuroinflammatory role of cyclooxygenase-1 (COX-1) inhibition has been rather neglected. We report that m -terphenylamine derivatives are selective COX-1 inhibitors, able to block microglia inflammatory response and elicit a neuroprotective effect. These compounds were synthesized via a three-component reaction of chalcones, β-ketoesters, and primary amines, followed by hydrolysis/decarboxylation of the ester group. Together with their synthetic intermediates and some urea derivatives, they were studied as inhibitors of COX-1 and COX-2. The m -terphenylamine derivatives, which were selective COX-1 inhibitors, were also analyzed for their ability to block microglia inflammatory and oxidative response. Compound 3b presented an interesting anti-inflammatory and neuroprotective profile by reducing nitrite release, ROS overproduction, and cell death in organotypic hippocampal cultures subjected to LPS. We thus show that COX-1 inhibition is a promising approach to provide enhanced neuroprotection against acute inflammatory processes, which are crucial in the development of a plethora of acute neurodegenerative injuries.
Keyphrases
- inflammatory response
- cerebral ischemia
- cell death
- liver failure
- lipopolysaccharide induced
- respiratory failure
- anti inflammatory
- toll like receptor
- nitric oxide
- brain injury
- cell proliferation
- intensive care unit
- immune response
- signaling pathway
- resting state
- subarachnoid hemorrhage
- hepatitis b virus
- functional connectivity
- extracorporeal membrane oxygenation
- spinal cord
- mechanical ventilation
- nitric oxide synthase