Propofol Regulates Neural Stem Cell Proliferation and Differentiation via Calmodulin-Dependent Protein Kinase II/AMPK/ATF5 Signaling Axis

Abstract

BACKGROUND: Propofol can cause degeneration of developing brain cells and subsequent long-term learning or memory impairment. However, at the early stage of embryonic development, the molecular mechanism of propofol-induced inhibition in neural stem cells (NSCs) neurogenesis is still unclear. The aim of this study was to determine the role of propofol in NSCs neurogenesis and, more importantly, to explore the underlying mechanism. METHODS: First, a single intraperitoneal injection of propofol was performed in pregnant mice, and 6 hours after administration of propofol, the hippocampus RNA and the protein of the embryos’ brains was extracted to analyze the expression of neuron-specific markers. Second, the primary NSCs were isolated from the hippocampus of mouse embryonic brain and then treated with propofol for cell viability, immunostaining, and transwell assays; more importantly, we performed RNA sequencing (RNA-seq) and q-reverse transcription polymerase chain reaction assays to identify genes regulated by propofol; the Western blot, small interfering RNA (SiRNA), and luciferase reporter assays were used to study the effects of propofol on calmodulin-dependent protein kinase (CaMk) II/5’ adenosine monophosphate-activated protein kinase (AMPK)/activating transcription factor 5 (ATF5) signaling pathway. RESULTS: Our results indicated that propofol treatment could inhibit the proliferation, migration, and differentiation of NSCs. The results of RNA-seq assays showed that propofol treatment resulted in downregulation of a group of Ca2+-dependent genes. The following mechanism studies showed that propofol regulates the proliferation, differentiation, and migration of NSCs through the CaMkII/phosphorylation of serine at amino acid position 485 (pS485)/AMPK/ATF5 signaling pathway. CONCLUSIONS: The results from study demonstrated that propofol inhibits the proliferation, differentiation, and migration of NSCs, and these effects are partially mediated by CaMkII/pS485/AMPK/ATF5 signaling pathway.

Long non-coding RNA Peg13 attenuates the sevoflurane toxicity against neural stem cells by sponging microRNA-128-3p to preserve Sox13 expression

“…In this study, we found that sevoflurane exposure inhibited the self-renewal and differentiation of mouse embryotic NSCs. These findings were consistent with previous observations with other anesthetic drugs [18,25] and support the notion that exposure to anesthesia in early life can inhibit neurogenesis and cause neurological impairments [1,3]. Although the central nervous system, particularly for the brain in humans and rodents, usually undergoes continual Quantitative RT-PCR revealed that sevoflurane exposure increased miR-128-3p transcripts in NSCs.…”

“…NSCs have potent self-renewal ability to form neurospheres and can differentiate into β-tubulin-III (Tuj1) + neurons, O4+ oligodendrocytes, and GFAP+ astrocytes [16,17]. Previous studies have shown that anesthesia, such as propofol, ketamine and isoflurane, can inhibit the self-renewal and differentiation of mouse NSCs [18,19]. Sevoflurane is commonly used in pediatric and obstetric anesthesia, and it is important to understand its potential neurotoxicity and mechanisms in NSCs.…”

Propofol Exposure Disturbs the Differentiation of Rodent Neural Stem Cells via an miR-124-3p/Sp1/Cdkn1b Axis

“…In previous studies, the data indicated that propofol would inhibit the proliferation of NSCs (Li et al, 2018;Liang et al, 2019). In our present study, propofol lengthened the G1 phase indicating a cell cycle arrest.…”

“…It has been suggested that propofol can disrupt neurogenesis by modulating apoptosis, proliferation, or the differentiation of neural stem cells (NSCs) (Zou et al, 2013). The potential mechanisms underlying these effects include regulation of the caspase-3 cascade (Karen et al, 2013), calmodulin-dependent protein kinase II, or microRNAs (miRNAs) (Hebert and De Strooper, 2009;Liang et al, 2019). However, the roles of miRNAs in the dysfunction of NSCs following propofol exposure are not fully understood.…”

Propofol activates AMPK to inhibit the growth of HepG2 cells in vitro and hepatocarcinogenesis in xenograft mouse tumor models by inducing autophagy

“…Metformin can induce the levels of DEP domain-containing mTORinteracting protein (DEPTOR), which intensifies binding to mTOR and exerts a suppressing effect on mTOR signaling in HCC (40). Previous research has shown that propofol suppresses the proliferation, differentiation, and migration of neural stem cells (NSCs), and these functions are partially mediated by the calmodulin-dependent protein kinase (CaMk) II/phosphorylation of serine at amino acid position 485 (pS485)/AMPK/activating transcription factor 5 (ATF5) signaling pathway (41). Importantly, the AMPK/ mTOR signaling pathway has been found to be activated in propofol-induced autophagosome accumulation in HeLa cells (42).…”