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Article

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

1
Department of Experimental Medicine, University of Perugia, Polo Unico Sant’Andrea delle Fratte, 06132 Perugia, Italy
2
Department of Pharmacy, University G. d’Annunzio, Via dei Vestini 31, 66100 Chieti, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Paola Barraja, Alessandra Montalbano and Virginia Spanò
Molecules 2020, 25(11), 2646; https://doi.org/10.3390/molecules25112646
Received: 22 April 2020 / Revised: 3 June 2020 / Accepted: 4 June 2020 / Published: 6 June 2020
(This article belongs to the Special Issue Bioactive Molecules in Medicinal Chemistry)
Neurodegenerative diseases are associated with increased levels of nitric oxide (NO) mainly produced by microglial cells through inducible nitric oxide synthase (iNOS) whose expression is induced by inflammatory stimuli. NO can both exert cytotoxic functions and induce a metabolic switch by inhibiting oxidative phosphorylation and upregulating glycolytic flux. Here, we investigated whether two newly synthesized acetamidine based iNOS inhibitors, namely CM292 and CM544, could inhibit lipopolysaccharide (LPS)-induced BV2 microglial cell activation, focusing on both inflammatory and metabolic profiles. We found that CM292 and CM544, without affecting iNOS protein expression, reduced NO production and reverted LPS-induced inflammatory and cytotoxic response. Furthermore, in the presence of the inflammatory stimulus, both the inhibitors increased the expression of glycolytic enzymes. In particular, CM292 significantly reduced nuclear accumulation of pyruvate kinase M2, increased mitochondrial membrane potential and oxygen consumption rate, and augmented the expression of pyruvate dehydrogenase, pointing to a metabolic switch toward oxidative phosphorylation. These data confirm the role played by NO in the connection between cell bioenergetics profile and inflammation, and suggest the potential usefulness of iNOS inhibitors in redirecting microglia from detrimental to pro-regenerative phenotype. View Full-Text
Keywords: acetamidine; iNOS inhibitor; nitric oxide; inflammation; pyruvate kinase M2; glycolytic enzymes; mitochondrial function acetamidine; iNOS inhibitor; nitric oxide; inflammation; pyruvate kinase M2; glycolytic enzymes; mitochondrial function
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MDPI and ACS Style

Grottelli, S.; Amoroso, R.; Macchioni, L.; D’Onofrio, F.; Fettucciari, K.; Bellezza, I.; Maccallini, C. Acetamidine-Based iNOS Inhibitors as Molecular Tools to Counteract Inflammation in BV2 Microglial Cells. Molecules 2020, 25, 2646. https://doi.org/10.3390/molecules25112646

AMA Style

Grottelli S, Amoroso R, Macchioni L, D’Onofrio F, Fettucciari K, Bellezza I, Maccallini C. Acetamidine-Based iNOS Inhibitors as Molecular Tools to Counteract Inflammation in BV2 Microglial Cells. Molecules. 2020; 25(11):2646. https://doi.org/10.3390/molecules25112646

Chicago/Turabian Style

Grottelli, Silvia, Rosa Amoroso, Lara Macchioni, Fiorella D’Onofrio, Katia Fettucciari, Ilaria Bellezza, and Cristina Maccallini. 2020. "Acetamidine-Based iNOS Inhibitors as Molecular Tools to Counteract Inflammation in BV2 Microglial Cells" Molecules 25, no. 11: 2646. https://doi.org/10.3390/molecules25112646

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