Cardiac dysfunction including arrhythmias and myocardial ischemia have often been reported in carbon monoxide poisoning; scattered punctiform hemorrhages throughout the heart have been documented in autopsy samples. An appropriate diagnostic approach is crucial to assess carbon monoxide cardiac damage. This evaluation may be confounded by several factors, including the absence of overt symptoms and of specific ischemic changes in the electrocardiogram. In experimental studies, laboratory animals can develop cardiac changes similar to those seen in humans and therefore proved to be useful models to study the effects and the mechanisms of cardiac damage due to carbon monoxide. These investigations, as well as others performed in vitro, provide support for a direct action of carbon monoxide on the heart, in addition to systemic hypoxia produced by carboxyhemoglobin formation. This review focuses on the diagnostic aspects of carbon monoxide cardiotoxicity. Experimental results obtained in animals and in vitro models are also discussed.
Exposure of Pc 12 cells to styrene-7,8-oxide (SO) (0.5-1 mM) caused a rapid increase in cytosolic Ca2+, depletion of intracellular glutathione and ATP, DNA damage and loss of cell viability. Lower SO concentrations (less than or equal to 100 microM), did not cause loss of cell viability or affect cell growth rate. However, at 30 and 100 microM, SO stimulated the formation of alkali-sensitive, DNA single-strand breaks (SSB). DNA SSB were fully repaired when cells exposed to 30 microM SO were subsequently incubated for 3 h in fresh medium, whereas DNA repair was only partial after exposure to 100 microM SO. When cells exposed to 30 or 100 microM SO were incubated with the inhibitors of repair synthesis 1-beta-D-arabinofuranosyl-cytosine (AraC) and hydroxyurea (HU), SSB accumulated, indicating the involvement of the excision-repair system in the removal of DNA lesions. A SO adduct with guanine at the N7 position was detected in the DNA extracted from treated cells. SO did not induce the formation of double-strand breaks, interstrand cross-links, or DNA-protein cross-links. Although cells exposed to 30 or 100 microM SO underwent normal cell division, latent DNA damage was retained for up to 14 subsequent replicative cycles. In addition, SO-treated cells partially lost their normal ability to differentiate in response to nerve growth factor (NGF) stimulation. NGF failed to induce differentiation in cells that had replicated for 20 generations after exposure to 100 microM SO. Spontaneous differentiation stimulated by high-density culture was also inhibited in SO-treated cells. These results indicate that non-lethal concentrations of SO can cause modifications that compromise the ability of Pc 12 cells to respond to NGF and differentiate.
Biological barriers represent a stumbling block to the pharmacological treatment of lesions occurring in central nervous system or retina. The advent of nanodrugs was welcomed as a means to tide over and cross the barriers. Expectations, however, have not been completely fulfilled, as nanocarriers often accumulated at the endothelial frontier, rather than cross it over. The super-paramagnetism of iron oxide nanoparticles improved the diagnostic power of the magnetic resonance imaging and opened new perspectives. These nanoparticles, which can be addressed to the target organ by an external magnetic field, provide local imaging of the lesion, on-demand release of therapeutic agent, and subsequent imaging of the repair. Nanogels that present a sol–gel phase transition at body temperature are easy to inject and remain immobilized near the site of injection. There they promote prolonged and sustained release of drugs, or frame a shell for cell precursors to fully develop into mature neurons or glia.
