Abstract
Neuronal differentiation appears to be dependent on oxidative phosphorylation capacity. Several drugs inhibit oxidative phosphorylation and might be detrimental for neuronal differentiation. Some pregnant women take these medications during their first weeks of gestation when fetal nervous system is being developed. These treatments might have later negative consequences on the offspring’s health. To analyze a potential negative effect of three widely used medications, we studied in vitro dopaminergic neuronal differentiation of cells exposed to pharmacologic concentrations of azidothymidine for acquired immune deficiency syndrome; linezolid for multidrug-resistant tuberculosis; and atovaquone for malaria. We also analyzed the dopaminergic neuronal differentiation in brains of fetuses from pregnant mice exposed to linezolid. The drugs reduced the in vitro oxidative phosphorylation capacity and dopaminergic neuronal differentiation. This differentiation process does not appear to be affected in the prenatally exposed fetus brain. Nevertheless, the global DNA methylation in fetal brain was significantly altered, perhaps linking an early exposure to a negative effect in older life. Uridine was able to prevent the negative effects on in vitro dopaminergic neuronal differentiation and on in vivo global DNA methylation. Uridine could be used as a protective agent against oxidative phosphorylation-inhibiting pharmaceuticals provided during pregnancy when dopaminergic neuronal differentiation is taking place.
Highlights
Late-onset Parkinson’s disease (PD) is a medical condition characterized by non-motor and motor signs
To analyze a potential negative effect of three widely used medications, we studied in vitro dopaminergic neuronal differentiation of cells exposed to pharmacologic concentrations of azidothymidine for acquired immune deficiency syndrome; linezolid for multidrug-resistant tuberculosis; and atovaquone for malaria
In the search for strategies to reverse their adverse consequences, we found that uridine, a necessary compound for cell proliferation of oxidative phosphorylation (OXPHOS)-dysfunctional cells [19], prevented these negative effects on dopaminergic neuronal differentiation
Summary
Late-onset Parkinson’s disease (PD) is a medical condition characterized by non-motor and motor signs. Motor signs are essentially due to the loss of dopaminergic neurons in the substantia nigra. These cells differ from less vulnerable neurons by having a higher basal rate of oxidative phosphorylation (OXPHOS) [1]. OXPHOS is the main energy provider to power neuronal activity [2]. PD is currently understood as a multietiological and multifactorial condition [3], numerous observations suggest that an OXPHOS defect may be a pathogenic event in many cases of PD [4]. Activities and levels of OXPHOS complexes were found to decrease in patients’ substantia nigra [4]
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