Abstract
We have previously demonstrated the potential of biologically synthesized silver nanoparticles (AgNP) in the induction of neuronal differentiation of human neuroblastoma, SH-SY5Y cells; we aimed herein to unveil its molecular mechanism in comparison to the well-known neuronal differentiation-inducing agent, all-trans-retinoic acid (RA). AgNP-treated SH-SY5Y cells showed significantly higher reactive oxygen species (ROS) generation, stronger mitochondrial membrane depolarization, lower dual-specificity phosphatase expression, higher extracellular-signal-regulated kinase (ERK) phosphorylation, lower AKT phosphorylation, and lower expression of the genes encoding the antioxidant enzymes than RA-treated cells. Notably, pretreatment with N-acetyl-l-cysteine significantly abolished AgNP-induced neuronal differentiation, but not in that induced by RA. ERK inhibition, but not AKT inhibition, suppresses neurite growth that is induced by AgNP. Taken together, our results uncover the pivotal contribution of ROS in the AgNP-induced neuronal differentiation mechanism, which is different from that of RA. However, the negative consequence of AgNP-induced neurite growth may be high ROS generation and the downregulation of the expression of the genes encoding the antioxidant enzymes, which prompts the future consideration and an in-depth study of the application of AgNP-differentiated cells in neurodegenerative disease therapy.
Highlights
Neuronal differentiation involves the growth, elongation, and bifurcation of neuronal branches out of the neuronal cell body. This process is characterized by various cellular changes, such as morphological changes and the increased expression of neuronal differentiation markers, such as β-tubulin III and microtubule-associated protein 2 (MAP2), which are indispensable for the promotion of neurite growth and maturation [1]
Our results show a marked difference in the mechanism of the neuronal differentiation induced after the exposure to AgNP or retinoic acid (RA) and open the door for further studies on NP-induced neuronal differentiation and further clinical applications
The average zeta potential of our synthesized AgNP was −29.10 mV, which confirms the stability of our AgNP solution
Summary
Neuronal differentiation involves the growth, elongation, and bifurcation of neuronal branches (neurites) out of the neuronal cell body. This process is characterized by various cellular changes, such as morphological changes and the increased expression of neuronal differentiation markers, such as β-tubulin III and microtubule-associated protein 2 (MAP2), which are indispensable for the promotion of neurite growth and maturation [1]. SH-SY5Y cells possess the capacity for the dopaminergic phenotype [4], and are considered to be a suitable in vitro neurotoxicity model for the study of amyotrophic lateral sclerosis, Parkinson’s disease (PD), and Alzheimer’s disease [5,6]. PD, which is a common neurodegenerative disease, is characterized by the accumulation of α-synuclein-containing abnormal protein aggregates (Lewy bodies) and the loss of dopaminergic neurons from the substantia nigra [7]
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