Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure

Abstract

BackgroundDeveloping brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains.MethodsThe behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism.ResultsBehavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both in vivo and in vitro. Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.ConclusionsTaken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.

Effect of Different Propofol Concentrations on Rat Lung Mesenchymal Stem Cells

“…These pathways play an important role in the autocrine and paracrine functions of the cell membrane and cell proliferation activities (15,16). Chen et al concluded that low-dose (10 µM) propofol activated hippocampal neurogenesis, increased the number of viable cells and expressed higher mitochondrial metabolism genes in cultured neural stem cells, while highdose (100 µM) propofol did not affect these cells (17). However, Lv et al indicated that 5 and 25 µM propofol inhibited lipopolysaccharide-induced apoptosis in lung epithelial cell cultures, while 1 µM propofol had no effect (18).…”

The Long-Term Neuroprotective Effect of the Endocannabinoid 2-AG and Modulation of the SGZ’s Neurogenic Response after Neonatal Hypoxia-Ischemia

“…The possibility of tissue repair in the developing brain by enhancing the proliferative potential of the neurogenic niches is currently under active investigation [ 26 , 27 , 28 ]. The modulation of the ECS to activate the neurogenic response after adult ischemia has been postulated [ 29 , 30 ], so we wondered if the administration of the endocannabinoid 2-AG could generate a neuroprotective and/or neuroregenerative response after neonatal HI.…”