Effect of itraconazole on mouse mesencephalic neurons

Abstract

Neuronal cells have complex geometrical shapes, long processes such as axons and dendrites, and as a response to specific stimuli, they go through polarized neuronal migration that influences connectivity and information processing. Recently, it has been discovered that itraconazole, a widely used systemic antifungal drug, has an effect on cell morphology, acting as an inhibitor of the morphogen Sonic Hedgehog (Shh) and of the mammalian target of rapamycin mTOR pathways. In this paper we evaluated the effect of itraconazole on mouse mesencephalic dopaminergic neurons following their neurite outgrowth and functional activity by [(3)H] DA uptake. Furthermore the expression of several neural markers, the activation of the mTOR and of the morphogenic Shh pathways in the neuronal population was examined. Our results show for the first time a strong alteration of neurons morphology and an inhibitory effect of differentiation by itraconazole, probably due to cholesterol trafficking reduction, mTOR and Shh pathways inhibition. The inhibition of mTOR and Shh pathways by this drug has also been found in other cellular systems such as endothelial cells and lung cancer cells, suggesting a conserved mechanism of intercellular communication. As itraconazole is currently involved in multiple human clinical trials as a prospective anticancer agent, the effect on neuronal differentiation should be taken into account.

Effect of itraconazole on Staphylococcus aureus biofilm and extracellular vesicles formation

“…In our work, we chose to test the fungicide IT as antibacterial agent because of its versatile spectrum of action already observed on several different biological system (7). We demonstrated that IT disaggregates biofilm structure, starting from sub-lethal doses.…”

“…IT is a triazole antifungal drug, approved by Food and Drug Administration, inhibitor of the sterol 14α-demethylase activity produced by the cytochrome p450 gene (CYP51), essential for the biosynthesis of ergosterol, the main fungal membrane sterol [6]. Moreover, IT has been described to be a versatile and multifunctional remedy for various diseases [7] but it has not yet tested on bacterial infections [6,8]. In our investigation, an evident bacterial biofilm degradation and a strong increase of extracellular vesicles (EV) size have been observed when bacterial cells were exposed to IT starting from sublethal doses.…”

Rho-inhibition and neuroprotective effect on rotenone-treated dopaminergic neurons in vitro

“…Brains were obtained from 13-day-old mouse embryos and placed in cold, sterile, phosphate-buffered saline (PBS). As previously described (Giorgi et al, 2015), the midbrain was dissected out under microscopic control and placed in a nutrient medium composed of F12 and Eagle's minimal essential medium (ratio1:1), supplemented with 2 mM glutamine, 10% of Nu-serum and 33.3 mM glucose. The tissue was mechanically dispersed, centrifuged at 800 g for 3 min, and suspended in the culture medium.…”