Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used
as an in vitro model for neurotoxicity experiments. Although the neuroblastoma is
usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and
undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the
changes in neuronal properties triggered by RA as well as the subsequent responsiveness
to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate
the differentiation property of RA on this cell line. We hypothesize that modulation
of signaling pathways and neuronal properties during RA-mediated differentiation in
SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation
property of RA was confirmed by showing an extensive outgrowth of neurites, increased
expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic
associated protein-97, and decreased expression of inhibitor of differentiation-1.
While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation
conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling,
including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against
6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells.
Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity
or neuroprotection in experimental Parkinson's disease research.