Topiramate Reverses Physiological and Behavioral Alterations by Postoperative Cognitive Dysfunction in Rat Model Through Inhibiting TNF Signaling Pathway
This study aimed to investigate the effects of topiramate (TPM) on rats with postoperative cognitive dysfunction (POCD) and elucidate the underlying mechanism. Differentially expressed genes in propofol-treated group and vehicle control group were filtered out and visualized in heatmap based on R program. POCD rat models were established for validation of TPM’s anti-inflammatory action and Morris water maze (MWM) test was employed for assessment of spatial learning and memory ability of rats. Hematoxylin and eosin (HE) staining was applied to detect the neurodegeneration, and the apoptosis status was detected using TUNEL assay. In vitro, hippocampal microglia was treated with lipopolysaccharide or TPM to validate the TPM’s anti-inflammatory action. Cell apoptosis was detected with flow cytometry. Inflammatory factors were detected by enzyme-linked immunosorbent assay, and factor-associated suicide (Fas), Fas-associated protein with death domain (FADD) expression were detected by western blot. As results, TPM administration improved the spatial learning and memory ability in POCD rat by decreasing the expression levels of Fas, FADD, and inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-1β, IL-1β; interleukin-6, IL-6) in POCD rats. In addition, TPM down-regulated cell apoptotic rate to suppress POCD by decreasing the expression of Caspase8, Bcl2-associated X (Bax), and poly ADP-ribose polymerase-1 (PARP1) yet enhancing B-cell lymphoma-2 (Bcl-2) expression. Besides, inhibition of Fas enhanced TPM-induced down-regulation of apoptosis of neuronal cell in hippocampus tissues of POCD rats. Our results revealed that treatment of POCD rats with TPM could suppress neuronal apoptosis in the hippocampus tissues, and the neuroprotective effects of TPM may relate with the regulation of tumor necrosis factor (TNF) signaling pathway.
KeywordsTopiramate Postoperative cognitive dysfunction Propofol TNF signaling pathway Neuroinflammation Apoptosis Fas/Fas-L
Analysis of variance
Enzyme-linked immunosorbent assay
Fas-associated protein with death domain
Gene expression omnibus
Gene set enrichment analysis
Hematoxylin and eosin
Mitogen-activated protein kinase
Morris water maze
Poly ADP-ribose polymerase-1
Postoperative cognitive dysfunction
Tumor necrosis factor
TdT-mediated dUTP Nick-End labeling
Contributing to the conception and design: WS, JL, and MX; Analyzing and interpreting the data: YL, MX, and XG; drafting the article: WS, YL, and JL; revising it critically for important intellectual content: JL, XG, and WS; and approving the final version to be published: All authors.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants performed by any of the authors. All procedures performed in studies involving animals were in accordance with the ethical standards of Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital.
Informed consent was obtained from all individual participants included in the study.
- Andrzejczak, D., Woldan-Tambor, A., Bednarska, K., & Zawilska, J. B. (2016). The effects of topiramate on lipopolysaccharide (LPS)-induced proinflammatory cytokine release from primary rat microglial cell cultures. Epilepsy Research,127, 352–357. https://doi.org/10.1016/j.eplepsyres.2016.09.020.CrossRefPubMedGoogle Scholar
- Cascella, M., & Bimonte, S. (2017). The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research,12(11), 1780–1785. https://doi.org/10.4103/1673-5374.219032.CrossRefPubMedPubMedCentralGoogle Scholar
- Cascella, M., Muzio, M. R., Bimonte, S., Cuomo, A., & Jakobsson, J. G. (2018). Postoperative delirium and postoperative cognitive dysfunction: Updates in pathophysiology, potential translational approaches to clinical practice and further research perspectives. Minerva Anestesiologica,84(2), 246–260. https://doi.org/10.23736/S0375-9393.17.12146-2.CrossRefPubMedGoogle Scholar
- Chandradasa, M., Champika, L., de Silva, S., & Kuruppuarachchi, K. (2017). Topiramate’s effectiveness on weight reduction in overweight/obese persons with schizophrenia: Study protocol for a randomized controlled trial. Trials,18(1), 435. https://doi.org/10.1186/s13063-017-2162-6.CrossRefPubMedPubMedCentralGoogle Scholar
- Feng, P. P., Deng, P., Liu, L. H., Ai, Q., Yin, J., Liu, Z., et al. (2017). Electroacupuncture alleviates postoperative cognitive dysfunction in aged rats by inhibiting hippocampal neuroinflammation activated via microglia/TLRs pathway. Evidence-Based Complementary and Alternative Medicine,2017, 6421260. https://doi.org/10.1155/2017/6421260.CrossRefPubMedPubMedCentralGoogle Scholar
- Himmerich, H., Bartsch, S., Hamer, H., Mergl, R., Schonherr, J., Petersein, C., et al. (2013). Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro. Journal of Psychiatric Research,47(11), 1751–1759. https://doi.org/10.1016/j.jpsychires.2013.07.026.CrossRefPubMedGoogle Scholar
- Hovens, I. B., Schoemaker, R. G., van der Zee, E. A., Absalom, A. R., Heineman, E., & van Leeuwen, B. L. (2014). Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning. Brain, Behavior, and Immunity,38, 202–210. https://doi.org/10.1016/j.bbi.2014.02.002.CrossRefPubMedGoogle Scholar
- Lee, J. H., Lee, D. S., Nam, H., Lee, G., Seo, B. M., Cho, Y. S., et al. (2012). Dental follicle cells and cementoblasts induce apoptosis of ameloblast-lineage and Hertwig’s epithelial root sheath/epithelial rests of Malassez cells through the Fas-Fas ligand pathway. European Journal of Oral Sciences,120(1), 29–37. https://doi.org/10.1111/j.1600-0722.2011.00895.x.CrossRefPubMedGoogle Scholar
- McDonagh, D. L., Mathew, J. P., White, W. D., Phillips-Bute, B., Laskowitz, D. T., Podgoreanu, M. V., et al. (2010). Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype, and biomarkers of brain injury. Anesthesiology,112(4), 852–859. https://doi.org/10.1097/ALN.0b013e3181d31fd7.CrossRefPubMedPubMedCentralGoogle Scholar
- Milanovic, D., Pesic, V., Loncarevic-Vasiljkovic, N., Pavkovic, Z., Popic, J., Kanazir, S., et al. (2016). The Fas Ligand/Fas death receptor pathways contribute to propofol-induced apoptosis and neuroinflammation in the brain of neonatal rats. Neurotoxicity Research,30(3), 434–452. https://doi.org/10.1007/s12640-016-9629-1.CrossRefPubMedGoogle Scholar
- Moller, J. T., Cluitmans, P., Rasmussen, L. S., Houx, P., Rasmussen, H., Canet, J., et al. (1998). Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet,351(9106), 857–861.CrossRefGoogle Scholar
- Motaghinejad, M., Motevalian, M., Abdollahi, M., Heidari, M., & Madjd, Z. (2017). Topiramate confers neuroprotection against methylphenidate-induced neurodegeneration in dentate gyrus and CA1 regions of hippocampus via CREB/BDNF pathway in rats. Neurotoxicity Research,31(3), 373–399. https://doi.org/10.1007/s12640-016-9695-4.CrossRefPubMedGoogle Scholar
- Rasmussen, L. S. (2006). Postoperative cognitive dysfunction: Incidence and prevention. Best Practice & Research: Clinical Anaesthesiology,20(2), 315–330.Google Scholar
- Sin, Y. Y., Ballantyne, L. L., Mukherjee, K., St Amand, T., Kyriakopoulou, L., Schulze, A., et al. (2013). Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism. PLoS ONE,8(11), e80001. https://doi.org/10.1371/journal.pone.0080001.CrossRefPubMedPubMedCentralGoogle Scholar
- Su, X., Feng, X., Terrando, N., Yan, Y., Chawla, A., Koch, L. G., et al. (2013). Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of the metabolic syndrome. Molecular Medicine,18, 1481–1490. https://doi.org/10.2119/molmed.2012.00351.CrossRefPubMedPubMedCentralGoogle Scholar
- Terrando, N., Monaco, C., Ma, D., Foxwell, B. M., Feldmann, M., & Maze, M. (2010). Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proceedings of the National Academy of Sciences of the United States of America,107(47), 20518–20522. https://doi.org/10.1073/pnas.1014557107.CrossRefPubMedPubMedCentralGoogle Scholar
- Tian, Y., Guo, S. X., Li, J. R., Du, H. G., Wang, C. H., Zhang, J. M., et al. (2015). Topiramate attenuates early brain injury following subarachnoid haemorrhage in rats via duplex protection against inflammation and neuronal cell death. Brain Research,1622, 174–185. https://doi.org/10.1016/j.brainres.2015.06.007.CrossRefPubMedGoogle Scholar
- Wang, L., Liu, B. J., Cao, Y., Xu, W. Q., Sun, D. S., Li, M. Z., et al. (2018). Deletion of Type-2 cannabinoid receptor induces alzheimer’s disease-like tau pathology and memory impairment through AMPK/GSK3beta pathway. Molecular Neurobiology,55(6), 4731–4744. https://doi.org/10.1007/s12035-017-0676-2.CrossRefPubMedGoogle Scholar
- Zhou, C., Zhu, Y., Liu, Z., & Ruan, L. (2016). Effect of dexmedetomidine on postoperative cognitive dysfunction in elderly patients after general anaesthesia: A meta-analysis. Journal of International Medical Research,44(6), 1182–1190. https://doi.org/10.1177/0300060516671623.CrossRefPubMedGoogle Scholar