Anti-inflammatory activity of a new class of nitric oxide synthase inhibitors that release nitric oxide.
Nitric oxide (NO) is a gaseous mediator that exerts key regulatory functions in mammalian cells. Low levels of NO exert homeostatic functions and counteract inflammation, whereas high amounts of NO cause tissue destruction and cellular death. Herein we describe a new class of nitric oxide synthase (NOS) inhibitor NO-donating drugs (NI-NODs). Human endothelial cells and human monocyte-based activity screening showed that NI-NODs inhibit IL-1beta production, modulate PGE(2) production, and protect against apoptosis. In a rodent model of colitis, NI-NOD1 and NI-NOD2 potently decreased inflammation. These data show that NI-NODs are effective in both in vitro and in vivo models of inflammation, mimicking the positive effects of low levels of NO and suppressing NOS-induced NO production.
Botta
Maurizio
M
Dipartimento Farmaco-Chimico-Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, 53100 Siena, Italy. botta@unisi.it
Distrutti
Eleonora
E
Mencarelli
Andrea
A
Parlato
Maria Cristina
MC
Raffi
Francesco
F
Cipriani
Sabrina
S
Fiorucci
Stefano
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D003092:Colitis / Q000188:drug therapy; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D015232:Dinoprostone