Acetamidine-Based iNOS Inhibitors as Molecular Tools to Counteract Inflammation in BV2 Microglial Cells

We investigated whether two newly synthesized acetamidine based inducible nitric oxide synthase inhibitors, namely CM292 and CM544, could inhibit lipopolysaccharide -induced BV2 microglial cell activation, focusing on both inflammatory and metabolic profiles

Silvia Grottelli; Rosa Amoroso; Lara Macchioni; Fiorella D’Onofrio; Katia Fettucciari; Ilaria Bellezza; Cristina Maccallini

2020

Scholarcy highlights

  • Nitric oxide is a radical diffusible compound, which exerts several physiological functions, acting as a biological messenger
  • In this study we show that two newly synthesized compounds, namely CM292 and CM544, reduce LPS-induced NO production in BV2 microglial cells, and, with different efficacy, they are capable of counteracting LPS-induced microglial activation and metabolic switch induced by LPS
  • In order to understand whether CM292- and CM544-induced decrease in NO levels could result in a metabolic switch, we focused our attention on the glycolytic enzyme PKM2, since it is a critical modulator of glycolytic reprogramming in LPS-stimulated macrophages
  • Two newly synthesized inducible nitric oxide synthase inhibitors, i.e., CM292 and CM544, were used to investigate the potential usefulness of iNOS inhibition in the recovery of oxidative metabolism in LPS stimulated BV2 cells. Both the compounds inhibit iNOS enzymatic activity leading to a significant reduction in NO levels, CM292 seems to exert a stronger metabolic action that relies on a decrease in PKM2 nuclear translocation
  • Since activated microglia augments reliance on glycolysis by increasing lactate production and decreasing mitochondrial oxygen consumption, it appears that CM292, possibly by reverting these metabolic actions, can revert microglial activation, as confirmed by the reacquisition of the ameboid morphology
  • The collected results prompt the research of new potent and selective iNOS inhibitors able to affect cell energetic metabolism, and potentially useful to treat neuroinflammatory diseases

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