Abstract
Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug, can induce neuronal differentiation, promote neurite extension and exert a neuroprotective effect in central nervous system (CNS) injuries; however, comparatively little is known regarding its action on mouse embryonic neural stem cells (NSCs) and the underlying molecular mechanism. Recent studies suggested that c-Jun N-terminal kinase (JNK) is required for neurite outgrowth and neuronal differentiation during neuronal development. In the present study, we cultured mouse embryonic NSCs and treated the cells with 1 mM VPA for up to 7 days. The results indicate that VPA promotes the neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons; moreover, VPA induces the phosphorylation of c-Jun by JNK. In contrast, the specific JNK inhibitor SP600125 decreased the VPA-stimulated increase in neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons. Taken together, these results suggest that VPA promotes neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons. Moreover, JNK activation is involved in the effects of VPA stimulation.
Highlights
Neural stem cells (NSCs) have the ability to proliferate; self-renew; and differentiate into oligodendrocytes, astrocytes, and neurons; NSCs are considered a potential therapeutic tool for treating central nervous system (CNS) injuries [1,2,3]
A multitude of factors have been shown to promote NSC differentiation into neurons, such as neurotrophin-3 (NT-3), NG2, Mash1, bone morphogenetic protein 4, and all-trans retinoic acid (RA) [7,8,9,10]; more recent studies reported that valproic acid (VPA), an effective and safe mood stabilizer that has been used in the treatment of bipolar diseases and different epilepsy syndromes for several decades [11, 12]
To differentiate NSCs, third-passage neurospheres were dissociated, transferred to coverslips coated with PLL, and cultured in differentiation medium for up to 7 days; these cells differentiated into β-III-tubulin-positive neurons (Fig. 3a), glial fibrillary acidic protein (GFAP)-positive astrocytes (Fig. 3b), and CNPase-positive oligodendrocytes (Fig. 3c)
Summary
Neural stem cells (NSCs) have the ability to proliferate; self-renew; and differentiate into oligodendrocytes, astrocytes, and neurons; NSCs are considered a potential therapeutic tool for treating central nervous system (CNS) injuries [1,2,3]. It is important to explore strategies to promote more efficient neuronal differentiation of NSCs. neurite outgrowth is a key cellular aspect of neuronal differentiation and is crucial for neural plasticity and synaptic formation [6]. A multitude of factors have been shown to promote NSC differentiation into neurons, such as neurotrophin-3 (NT-3), NG2, Mash, bone morphogenetic protein 4, and all-trans retinoic acid (RA) [7,8,9,10]; more recent studies reported that valproic acid (VPA), an effective and safe mood stabilizer that has been used in the treatment of bipolar diseases and different epilepsy syndromes for several decades [11, 12]. Increasing in vitro and in vivo evidence demonstrated that VPA acts as a neurotrophic compound through its ability to increase neurite
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