The activation of nitric oxide (NO) production is an analgesic mechanism shared by drugs such as morphine and diclofenac. Therefore, the controlled release of low amounts of NO seems to be a promising analgesic approach. In the present study, the antinociceptive effect of the ruthenium NO donor [Ru(bpy)2(NO)SO3](PF6) (complex I) was investigated. It was observed that complex I inhibited in a dose (0.3-10mg/kg)-dependent manner the acetic acid-induced writhing response. At the dose of 1mg/kg, complex I inhibited the phenyl-p-benzoquinone-induced writhing response and formalin- and complete Freund's adjuvant-induced licking and flinch responses. Additionally, complex I also inhibited transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent overt pain-like behavior induced by capsaicin. Complex I also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity (MPO) in paw skin samples. The inhibitory effect of complex I in the carrageenin-induced hyperalgesia, MPO activity and formalin was prevented by the treatment with ODQ, KT5823 and glybenclamide, indicating that complex I inhibits inflammatory hyperalgesia by activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. The present study demonstrates the efficacy of a novel ruthenium NO donor and its analgesic mechanisms.

Proposed catalytic cycle for ROS production in the vicinity of DNA after reduction of [Cu(phen)(van)2] by glutathion.

O processo redox da metaloproteína cyt c foi observado através da utilização de eletrodos de ouro modificados com os complexos [Ru(CNPy)(NH 3) 4 (1,4-dt)] 2+ e [Ru(CNPy)(NH 3) 4 (pyS)] 2+ , onde CNPy = 4-cianopiridina, pyS = 4-mercaptopiridina e 1,4dt = ditiano. Os valores dos potenciais redox observados indicam a forma in natura da proteína. A forma dos voltamogramas, todavia, é dependente da conformação do complexo modificador sobre a superfície que, por sua vez, foi determinada por SERS. Os potenciais de dessorção redutiva, observados em-0,52 e-0,64 V vs Ag|AgCl|Clpara os complexos [Ru(CNPy)(NH 3) 4 (1,4-dt)] 2+ e [Ru(CNPy)(NH 3) 4 (pyS)] 2+ , respectivamente, são indicativos do tipo de ligação com a superfície e da capacidade π retiradora do ligante CNpy. The redox process of the cyt c metalloprotein was assessed by the cationic SAMs formed with [Ru(CNPy)(NH 3) 4 (1,4-dt)] 2+ and [Ru(CNPy)(NH 3) 4 (pyS)] 2+ complexes on gold, where CNPy = 4-cyanopyridine, pyS = 4-mercaptopyridine and 1,4-dt = dithiane. The observed cyt c redox potentials are indicative of the native protein form. The voltammograms, however, were observed to be affected by the conformation of the modifiers, determined by SERS spectroscopy. The [Ru(CNPy)(NH 3) 4 (pyS)] 2+ complex, which exhibits trans conformation on the surface, presented a well-defined voltammogram. On the other hand, the gauche conformation of the [Ru(CNPy)(NH 3) 4 (1,4-dt)] 2+ SAM seems to make the assessment of the cyt c hET reaction difficult. The reductive desorption potentials, at-0.52 and-0.64 V vs Ag|AgCl|Clfor the [Ru(CNPy)(NH 3) 4 (1,4-dt)] 2+ and [Ru(CNPy)(NH 3) 4 (pyS)] 2+ SAMs, respectively, are indicative of the bonding mode with the surface and the π withdrawing capability of the CNpy ligand.

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