Small molecule inhibiting microglial nitric oxide release could become a potential treatment for neuroinflammation.
Philipp JordanAmanda CostaEdgar SpeckerOliver PoppAndrea VolkamerRegina PiskeTessa ObrusnikSabrina KleissleKevin StukeAndre RexMartin NeuenschwanderJens Peter von KriesMarc NazarePhillip MertinsHelmut KettenmannSusanne A WolfPublished in: PloS one (2023)
Microglia are the immune effector cells of the central nervous system (CNS) and react to pathologic events with a complex process including the release of nitric oxide (NO). NO is a free radical, which is toxic for all cells at high concentrations. To target an exaggerated NO release, we tested a library of 16 544 chemical compounds for their effect on lipopolysaccharide (LPS)-induced NO release in cell line and primary neonatal microglia. We identified a compound (C1) which significantly reduced NO release in a dose-dependent manner, with a low IC50 (252 nM) and no toxic side effects in vitro or in vivo. Target finding strategies such as in silico modelling and mass spectroscopy hint towards a direct interaction between C1 and the nitric oxide synthase making C1 a great candidate for specific intra-cellular interaction with the NO producing machinery.
Keyphrases
- lps induced
- nitric oxide
- inflammatory response
- nitric oxide synthase
- induced apoptosis
- small molecule
- lipopolysaccharide induced
- cell cycle arrest
- toll like receptor
- neuropathic pain
- signaling pathway
- hydrogen peroxide
- oxidative stress
- dendritic cells
- single molecule
- regulatory t cells
- photodynamic therapy
- endoplasmic reticulum stress
- spinal cord
- molecular docking
- spinal cord injury
- risk assessment
- brain injury
- mass spectrometry
- cognitive impairment
- smoking cessation