Effect of Sevoflurane Anesthesia on Brain Is Mediated by lncRNA HOTAIR
Postoperative cognitive dysfunction in elderly patients has been related to neurodegenerative disorders and mortality. Sevoflurane anesthesia has been implicated in both postoperative cognitive dysfunction and neurotoxicity. Given the advantages of using inhaled anesthetics like sevoflurane, it is important to understand how their usage results in neurotoxicity and subsequently devise ways to circumvent or attenuate the anesthetic-mediated induction in neurotoxicity. Long noncoding RNAs (LncRNAs) are a group of > 200 bp long RNAs and show specific spatiotemporal expression profiles. Several recent reports suggest that lncRNAs are involved in responses of the central nervous system (CNS) following acute injuries. However, their role in sevoflurane anesthesia-mediated cognitive dysfunction has not been studied. RNA immunoprecipitation (RIP) combined with qRT-PCR detection of six different lncRNAs showed that the HOTAIR lncRNAs were significantly more bound to both Sin3A and coREST, both corepressors of the RE-1 silencing transcription factor, within rat hippocampus following sevoflurane anesthesia compared with sham. Sevoflurane inhalation resulted in significant inhibition of brain-derived neurotrophic factor (BDNF) and cognitive impairment. Treatment with a combination of siRNAs targeting HOTAIR rescued BDNF expression and improved cognitive responses. Taken together, our results suggest that sevoflurane-mediated brain function impairment is at least in part mediated by the HOTAIR lncRNA.
KeywordsLong noncoding RNA HOTAIR Sevoflurane Cognitive impairment
Compliance with Ethical Standards
All procedures were approved by the Local Ethics Committee at Binzhou People’s Hospital.
Conflict of Interest
The authors declare that they have no conflict of interest.
- Abe Y, Kikuchi A, Kobayashi S, Wakusawa K, Tanaka S, Inui T, Kunishima S, Kure S, Haginoya K (2014) Xq26.1-26.2 gain identified on array comparative genomic hybridization in bilateral periventricular nodular heterotopia with overlying polymicrogyria. Dev Med Child Neurol 56(12):1221–1224. https://doi.org/10.1111/dmcn.12553 CrossRefPubMedGoogle Scholar
- Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25(18):1915–1927. https://doi.org/10.1101/gad.17446611 CrossRefPubMedCentralPubMedGoogle Scholar
- Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmannbroz D, Khalil AM, Zuk O, Amit I, Rabani M (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142(3):409–419. https://doi.org/10.1016/j.cell.2010.06.040 CrossRefPubMedCentralPubMedGoogle Scholar
- Kesslak JP, So V, Choi J, Cotman CW, Gomezpinilla F (1998) Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance? Behav Neurosci 112(4):1012–1019. https://doi.org/10.1037/0735-7044.112.4.1012 CrossRefPubMedGoogle Scholar
- Liang G, Ward C, Peng J, Zhao Y, Huang B, Wei H (2010) Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology 112(6):1325–1334. https://doi.org/10.1097/ALN.0b013e3181d94da5 CrossRefPubMedCentralPubMedGoogle Scholar
- Maisonpierre PC, Belluscio L, Friedman B, Alderson RF, Wiegand SJ, Furth ME, Lindsay RM, Yancopoulos GD (1990) NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 5(4):501–509. https://doi.org/10.1016/0896-6273(90)90089-X CrossRefPubMedGoogle Scholar
- Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, Rabbitt P, Jolles J, Larsen K, Hanning CD (1998) Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 351:857CrossRefPubMedGoogle Scholar
- Petrovics G, Zhang W, Makarem M, Street JP, Connelly R, Sun L, Sesterhenn IA, Srikantan V, Moul JW, Srivastava S (2004) Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients. Oncogene 23(2):605–611. https://doi.org/10.1038/sj.onc.1207069 CrossRefPubMedGoogle Scholar
- Rasmussen LS, Johnson T, Kuipers HM, Kristensen D, Siersma VD, Vila P, Jolles J, Papaioannou A, Abildstrom H, Silverstein JH (2003) Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand 47(3):260–266. https://doi.org/10.1034/j.1399-6576.2003.00057.x CrossRefPubMedGoogle Scholar
- Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C, Sanchez-Gomez DB, Hacisuleyman E, Li E, Spence M, Liapis SC, Mallard W, Morse M, Swerdel MR, D'Ecclessis MF, Moore JC, Lai V, Gong G, Yancopoulos GD, Frendewey D, Kellis M, Hart RP, Valenzuela DM, Arlotta P, Rinn JL (2013) Multiple knockout mouse models reveal lincRNAs are required for life and brain development. elife 2:e01749CrossRefPubMedCentralPubMedGoogle Scholar
- Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, Livezey JR, Connell T, Sesterhenn IA, Yoshino K (2000) PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci U S A 97(22):12216–12221. https://doi.org/10.1073/pnas.97.22.12216 CrossRefPubMedCentralPubMedGoogle Scholar
- Xiong WX, Zhou GX, Wang B, Xue ZG, Wang L, Sun HC, Ge SJ (2013) Impaired spatial learning and memory after sevoflurane-nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling. PLoS One 8(11):e79408. https://doi.org/10.1371/journal.pone.0079408 CrossRefPubMedCentralPubMedGoogle Scholar