Enhanced Hippocampal Neurogenesis Mediated by PGC-1α-activated OXPHOS After Neonatal Low-dose Propofol Exposure

Overview

Journal Front Aging Neurosci

Specialty Geriatrics

Date 2022 Aug 15

PMID 35966788

Authors

Keyu Chen

Dihan Lu

Xiaoyu Yang

Rui Zhou

Liangtian Lan

Yan Wu

Chen Wang

Xuanxian Xu

Mei Hua Jiang

Ming Wei

Xia Feng

Affiliations

Soon will be listed here.

Abstract

Background: Developing 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.

Methods: The 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.

Results: Behavioral 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 and . Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.

Conclusions: Taken 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.

Citing Articles

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

Beldarrain G, Hilario E, Lara-Celador I, Chillida M, Catalan A, Alvarez-Diaz A Pharmaceutics. 2023; 15(6).

PMID: 37376115 PMC: 10300731. DOI: 10.3390/pharmaceutics15061667.

References

McMeekin L, Fox S, Boas S, Cowell R . Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities. Cells. 2021; 10(2). PMC: 7915819. DOI: 10.3390/cells10020352. View

Finck B, Kelly D . Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) regulatory cascade in cardiac physiology and disease. Circulation. 2007; 115(19):2540-8. DOI: 10.1161/CIRCULATIONAHA.107.670588. View

Deyama S, Duman R . Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacol Biochem Behav. 2019; 188:172837. PMC: 6997025. DOI: 10.1016/j.pbb.2019.172837. View

Gao Y, Zhang R, Wei G, Dai S, Zhang X, Yang W . Long Non-coding RNA Maternally Expressed 3 Increases the Expression of Neuron-Specific Genes by Targeting miR-128-3p in All-Trans Retinoic Acid-Induced Neurogenic Differentiation From Amniotic Epithelial Cells. Front Cell Dev Biol. 2020; 7:342. PMC: 6936004. DOI: 10.3389/fcell.2019.00342. View

Chen H, Xu D, Zhang Y, Yan Y, Liu J, Liu C . Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol. Front Neurosci. 2021; 15:636901. PMC: 7985178. DOI: 10.3389/fnins.2021.636901. View

Jevtovic-Todorovic V, Brambrick A . General Anesthesia and Young Brain: What is New?. J Neurosurg Anesthesiol. 2017; 30(3):217-222. PMC: 5732095. DOI: 10.1097/ANA.0000000000000432. View

Uittenbogaard M, Chiaramello A . Mitochondrial biogenesis: a therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr Pharm Des. 2014; 20(35):5574-93. PMC: 4823001. DOI: 10.2174/1381612820666140305224906. View

Favaro R, Valotta M, Ferri A, Latorre E, Mariani J, Giachino C . Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci. 2009; 12(10):1248-56. DOI: 10.1038/nn.2397. View

Zhao T, Shi Z, Ling N, Qin J, Zhou Q, Wu L . Sevoflurane Ameliorates Schizophrenia in a Mouse Model and Patients: A Pre-Clinical and Clinical Feasibility Study. Curr Neuropharmacol. 2022; 20(12):2369-2380. PMC: 9890293. DOI: 10.2174/1570159X20666220310115846. View

10.

LeBleu V, OConnell J, Gonzalez Herrera K, Wikman H, Pantel K, Haigis M . PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014; 16(10):992-1003, 1-15. PMC: 4369153. DOI: 10.1038/ncb3039. View

11.

Tao T, Zhao Z, Hao L, Gu M, Chen L, Tang J . Propofol promotes proliferation of cultured adult rat hippocampal neural stem cells. J Neurosurg Anesthesiol. 2013; 25(3):299-305. DOI: 10.1097/ANA.0b013e31828baa93. View

12.

Qiao H, Li Y, Xu Z, Li W, Fu Z, Wang Y . Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis. Anesthesiology. 2017; 127(3):490-501. PMC: 5561483. DOI: 10.1097/ALN.0000000000001730. View

13.

Armand E, Li J, Xie F, Luo C, Mukamel E . Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes. Neuron. 2021; 109(1):11-26. PMC: 7808568. DOI: 10.1016/j.neuron.2020.12.010. View

14.

Zywitza V, Misios A, Bunatyan L, Willnow T, Rajewsky N . Single-Cell Transcriptomics Characterizes Cell Types in the Subventricular Zone and Uncovers Molecular Defects Impairing Adult Neurogenesis. Cell Rep. 2018; 25(9):2457-2469.e8. DOI: 10.1016/j.celrep.2018.11.003. View

15.

Toda T, Parylak S, Linker S, Gage F . The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry. 2018; 24(1):67-87. PMC: 6195869. DOI: 10.1038/s41380-018-0036-2. View

16.

Chen C, Shen F, Zhao X, Zhou T, Xu D, Wang Z . Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats. ASN Neuro. 2015; 7(2). PMC: 4720175. DOI: 10.1177/1759091415575845. View

17.

Shi S, Yang W, Chen Y, Chen J, Tu X . Propofol reduces inflammatory reaction and ischemic brain damage in cerebral ischemia in rats. Neurochem Res. 2014; 39(5):793-9. DOI: 10.1007/s11064-014-1272-8. View

18.

Iwata R, Vanderhaeghen P . Regulatory roles of mitochondria and metabolism in neurogenesis. Curr Opin Neurobiol. 2021; 69:231-240. PMC: 8415079. DOI: 10.1016/j.conb.2021.05.003. View

19.

Schraag S, Petscher M, Wachter U, Kreuer S, Kenny G, Wagner F . Performance of target-controlled infusion of propofol in plasma versus effect-site control during induction in elderly patients: A Letter To The Editor. J Clin Anesth. 2019; 58:9-11. DOI: 10.1016/j.jclinane.2019.04.013. View

20.

Zhong Y, Chen J, Li L, Qin Y, Wei Y, Pan S . PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats. Brain Res. 2018; 1691:64-74. DOI: 10.1016/j.brainres.2018.04.022. View