Abstract
This study investigated the mechanisms and kinetics of nitric oxide (NO) generation by derivatives of Piloty’s acid (NO-donors) under physiological conditions. In order to qualitatively and quantitatively measure NO release, electron paramagnetic resonance (EPR) was carried out with NO spin trapping. In addition, voltammetric techniques, including cyclic voltammetry and constant potential amperometry, were used to confirm NO release from Piloty’s acid and its derivatives. The resulting data showed that Piloty’s acid derivatives are able to release NO under physiological conditions. In particular, electron-withdrawing substituents favoured NO generation, while electron-donor groups reduced NO generation. In vitro microdialysis, performed on PC12 cell cultures, was used to evaluate the dynamical secretion of dopamine induced by the Piloty’s acid derivatives. Although all the studied molecules were able to induce DA secretion from PC12, only those with a slow release of NO have not determined an autoxidation of DA itself. These results confirm that the time-course of NO-donors decomposition and the amount of NO released play a key role in dopamine secretion and auto-oxidation. This information could drive the synthesis or the selection of compounds to use as potential drugs for the therapy of Parkinson’s disease (PD).
Highlights
Almost 20 years ago, the first reports concerning the endogenous generation of nitric oxide (NO) in mammalian systems appeared [1,2,3]
NO is a valuable lead compound of a family of well-established signalling molecules. It is bio-synthesized via oxidation of the amino group of L-arginine, yielding NO and citrulline, the reaction is catalysed by nitric oxide synthases
In this study the NO release from Piloty’s acid and its derivatives (4-NO2-PI and 4-OMe-PI) with different electronic properties have been investigated, and the results have been compared with a benchmark NO-donor (SNAP)
Summary
Almost 20 years ago, the first reports concerning the endogenous generation of nitric oxide (NO) in mammalian systems appeared [1,2,3]. DA release measured with perfusion of SNAP and 4-NO2-PI increased and did not return to Piloty’s acid had a similar effect to 4-MeO-PI, but resulted in a greater increase in dialysate DA levels. This greater increase could reflect the balance between DA release, due to NO passage through the cell membrane, and that arising from cell death due to the toxicity of PI. The higher amount of DA release with Piloty’s acid perfusion could be due to the relatively higher toxicity observed, even in long-time viability experiments These results can be applied to the development of new NO-donor drugs for neurodegenerative pathologies, involving a deficiency of dopamine and where an inflammatory component is overt, such as Parkinson’s disease. Therapies for such diseases should be able to slowly release NO at concentrations that allow entry of NO into the cells resulting in DA release, but that reduce DA auto-oxidation or cell death
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