The purpose of this research was to explore the behavior of aquaporins (AQPs) in an in vitro model of Parkinson's disease that is a recurrent neurodegenerative disorder caused by the gradual, progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Because of postmortem studies have provided evidences for oxidative damage and alteration of water flow and energy metabolism, we carried out an investigation about AQP4 and 9, demonstrated in the brain to maintain water and energy homeostasis. As an appropriate in vitro cell model, we used SH-SY5Y cultures and induced their differentiation into a mature dopaminergic neuron phenotype with retinoic acid (RA) alone or in association with phorbol-12-myristate-13-acetate (MPA). The association RA plus MPA provided the most complete and mature neuron phenotype, as demonstrated by high levels of β-Tubulin III, MAP-2, and tyrosine hydroxylase. After validation of cell differentiation, the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and H2O2 were applied to reproduce a Parkinson's-like stress. The results confirmed RA/MPA differentiated SH-SY5Y as a useful in vitro system for studying neurotoxicity and for using in a MPTP and H2O2-induced Parkinson's disease cell model. Moreover, the data demonstrated that neuronal differentiation, neurotoxicity, neuroinflammation, and oxidative stress are strongly correlated with dynamic changes of AQP4 and 9 transcription and transduction. New in vitro and in vivo experiments are needed to confirm these innovative outcomes.