Role of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cgmp) in oxidative metabolism, inflammation and cell death: case amphotericin b

Abstract

Amphotericin B (AmB) is an important antibiotic agent; however, nephrotoxicity is one of the main adverse effects. The purpose of this study was to evaluate the effect of cAMP and cGMP in nephrotoxicity caused by AmB from the assessment of cytokines, stress oxidative, nitric oxide production and cell death in MDCK cells line. Our results showed an increase of IL-6 production by AmB, and an inhibitory effect was observed when cells were incubated with AmB plus cAMP. Results with TNF-α showed that cAMP is able to produce TNF-α only up to the basal level similar to AmB. In contrast, cGMP was able to revert the production of TNF-α Also, AmB decreases IL-10 production but that incubation with cAMP and cGMP was able to reverse this inhibition. Both hydrogen peroxide and AmB were able to induced reactive oxygen species (ROS) generation and cAMP and cGMP were able to reduce ROS production. AmB decreases NO production and cAMP and cGMP increase NO production by reversing the effect generated by AmB. cAMP and cGMP were able to decrease the fragmentation of the DNA generated by AmB. Our findings open new perspectives in the clinical management of invasive fungal diseases. The alternative contributory intracellular mechanism of action of AmB should be considered in the rationale of combined therapy. Combinations of AmB and cAMP and cGMP can be based on that additional effect, as therapy can target both the membrane and the oxidative burst of the fungal cells.