Abstract
Our previous studies have shown that the maternal hyperinflammatory response in pre-eclampsia lowered the eclampsia-like seizure threshold. Cyclosporin A (CsA), which is an effective immunosuppressant, could attenuate the inflammatory responses in LPS-induced pre-eclampsia rats. Here, we hypothesized that CsA may ameliorate seizure severity through reducing systemic inflammation in pre-eclampsia/eclampsia. In the current study, the effects of CsA on pre-eclampsia manifestation, eclampsia-like seizure activities and systemic inflammation were examined in a pre-eclampsia model. Pregnant rats were given an intraperitoneal injection of the epileptogenic drug pentylenetetrazol (PTZ) following a tail vein injection of lipopolysaccharide to establish the eclampsia-like seizure model. CsA (5 mg/kg) was administered intravenously through the tail after LPS infusion. Mean systolic blood pressure and proteinuria in pre-eclampsia were detected. After PTZ injection, seizure activity was assessed, inflammatory responses were determined and pregnancy outcomes were analyzed. The results showed that CsA treatment significantly decreased blood pressure and proteinuria and increased the fetal and placental weight (P < 0.01). Meanwhile, CsA treatment significantly reduced serum IL-1β, TNF-α, and IL-17 levels (P < 0.01), decreased the seizure scores and prolonged the latency to seizure (P < 0.01). CsA effectively attenuated pre-eclampsia manifestation and eclampsia-like seizure severity. In addition, CsA treatment significantly reduced the inflammatory cytokine levels and improved pregnancy outcomes following eclampsia-like seizures. The decreased inflammatory cytokines in pre-eclampsia are coincident with attenuated pre-eclampsia manifestation after CsA treatment, suggesting that CsA treatment might decrease the eclampsia-like seizure severity through decreasing systemic inflammation in pre-eclasmpsia/eclampsia.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Podjarny E, Losonczy G, Baylis C. Animal models of preeclampsia. Semin Nephrol. 2004;24:596–606.
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376:631–44.
Sargent IL, Germain SJ, Sacks GP, Kumar S, Redman CW. Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol. 2003;59:153–60.
Mihu D, Razvan C, Malutan A, Mihaela C. Evaluation of maternal systemic inflammatory response in preeclampsia. Taiwan J Obstet Gynecol. 2015;54:160–6.
Cotechini T, Graham CH. Aberrant maternal inflammation as a cause of pregnancy complications: A potential therapeutic target? Placenta. 2015;36:960–6.
Cipolla MJ, Pusic AD, Grinberg YY, Chapman AC, Poynter ME, Kraig RP. Pregnant serum induces neuroinflammation and seizure activity via TNFα. Exp Neurol. 2012;234:398–404.
Huang Q, Liu L, Hu B, Di X, Brennecke SP, Liu H. Decreased seizure threshold in an eclampsia-like model induced in pregnant rats with lipopolysaccharide and pentylenetetrazol treatments. PLoS ONE. 2014;9:e89333.
Hu B, Yang J, Huang Q, Bao J, Brennecke SP, Liu H. Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model. Cytokine. 2016;81:77–81.
Liu L, Han X, Huang Q, Zhu X, Yang J, Liu H. Increased neuronal seizure activity correlates with excessive systemic inflammation in a rat model of severe preeclampsia. Hypertens Res. 2016;39:701–8.
Domañska-Janik K, Buzañska L, Dłuzniewska J, Kozłowska H, Sarnowska A, Zabłocka B. Neuroprotection by cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome C to cytoplasm. Brain Res Mol Brain Res. 2004;121:50–59.
Kountouras J, Zavos C, Chatzopoulos D. Immunomodulatory benefits of cyclosporine A in inflammatory bowel disease. J Cell Mol Med. 2004;8:317–28.
Pino-Lagos K, Michea P, Sauma D, Alba A, Morales J, Bono MR, et al. Cyclosporin A-treated dendritic cells may affect the outcome of organ transplantation by decreasing CD4+CD25+ regulatory T cell proliferation. Biol Res. 2010;43:333–7.
Tang C, Chen L, Gu W, Du M, Li M, Chen Q, et al. Cyclosporin A enhances the ability of trophoblasts to displace the activated human umbilical vein endothelial cell monolayers. Int J Clin Exp Pathol. 2013;6:2441–50.
Piao HL, Wang SC, Tao Y, Zhu R, Sun C, Fu Q, et al. Cyclosporine A enhances Th2 bias at the maternal-fetal interface in early human pregnancy with aid of the interaction between maternal and fetal cells. PloS ONE. 2012;7:e45275.
Jung S, Yang H, Kim BS, Chu K, Lee SK, Jeon D. The immunosuppressant cyclosporin A inhibits recurrent seizures in an experimental model of temporal lobe epilepsy. Neurosci Lett. 2012;529:133–8.
Albensi BC, Sullivan PG, Thompson MB, Scheff SW, Mattson MP. Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity. Exp Neurol. 2000;162:385–9.
Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol. 1994;171:158–64.
Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol. 1972;32:281–94.
Ramma W, Ahmed A. Is inflammation the cause of pre-eclampsia? Biochem Soc Trans. 2011;39:1619–27.
Neroli S, Annemarie H, Angela M. Animal models of pre-eclampsia. Am J Reprod Immunol. 2010;65:533–41.
Gadonski G, LaMarca BB, Sullivan E, Bennett W, Chandler D, Granger JP. Hypertension produced by reductions in uterine perfusion in the pregnant rat: role of interleukin 6. Hypertension. 2006;48:711–6.
LaMarca BB, Cockrell K, Sullivan E, Bennett W, Granger JP. Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats. Hypertension. 2005;46:82–6.
Zenclussen AC, Fest S, Joachim R, Klapp BF, Arck PC. Introducing a mouse model for pre-eclampsia: adoptive transfer of activated Th1 cells leads to pre-eclampsia-like symptoms exclusively in pregnant mice. Eur J Immunol. 2004;34:377–87.
Sharma A, Satyam A, Sharma JB. Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women. Am J Reprod Immunol. 2007;58:21–30.
Tinsley JH, Chiasson VL, South S, Mahajan A, Mitchell BM. Immunosuppression improves blood pressure and endothelial function in a rat model of pregnancy-induced hypertension. Am J Hypertens. 2009;22:1107–14.
Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449–60.
Borlongan CV, Yu G, Matsukawa N, Xu L, Hess DC, Sanberg PR, et al. Acute functional effects of cyclosporine-A and methylprednisolone treatment in adult rats exposed to transient ischemic stroke. Life Sci. 2005;76:1503–12.
Santos JB, Schauwecker PE. Protection provided by cyclosporin A against excitotoxic neuronal death is genotype dependent. Epilepsia. 2003;44:995–1002.
Setkowicz Z, Ciarach M. Neuroprotectants FK-506 and cyclosporin A ameliorate the course of pilocarpine-induced seizures. Epilepsy Res. 2007;73:151–5.
Ziylan YZ, Ates N. Age-related changes in regional patterns of blood-brain barrier breakdown during epileptiform seizures induced by pentylenetetrazol. Neurosci Lett. 1989;96:179–84.
Asanuma M, Nishibayashi S, Kondo Y, Iwata E, Tsuda M, Ogawa N. Effects of single cyclosporin A pretreatment on pentylenetetrazol-induced convulsion and on TRE-binding activity in the rat brain. Brain Res Mol Brain Res. 1995;33:29–36.
Hardie DG, Ross FA, Hawley SA. Ampk: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol cell Biol. 2012;13:251–62.
Fakharnia F, Khodagholi F, Dargahi L, Ahmadiani A. Prevention of cyclophilin D-mediated mPTP opening using cyclosporine-A alleviates the elevation of necroptosis, autophagy and apoptosis-related markers following global cerebral ischemia-reperfusion. J Mol Neurosci. 2017;61:52–60.
Aronica E, Crino PB. Inflammation in epilepsy: clinical observations. Epilepsia. 2011;52:26–32.
Auvin S, Shin D, Mazarati A, Sankar R. Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA. Epilepsia. 2010;51:34–38.
Vezzani A, Ravizza T, Balosso S, Aronica E. Glia as a source of cytokines: implications for neuronal excitability and survival. Epilepsia. 2008;49:24–32.
Li X, Han X, Yang J, Bao J, Di X, Zhang G, et al. Magnesium sulfate provides neuroprotection in eclampsia-like seizure model by ameliorating neuroinflammation and brain edema. Mol Neurobiol. 2017;54:7938–48.
Li X, Han X, Bao J, Liu Y, Ye A, Thakur M, et al. Nicotine increases eclampsia-like seizure threshold and attenuates microglial activity in rat hippocampus through the α7 nicotinic acetylcholine receptor. Brain Res. 2016;1642:487–96.
Steiner S, Daniel C, Fischer A, Atreya I, Hirschmann S, Waldner M, et al. Cyclosporine A regulates pro-inflammatory cytokine production in ulcerative colitis. Arch Immunol Ther Exp. 2015;63:53–63.
Coscia LA, Constantinescu S, Moritz MJ, Frank AM, Ramirez CB, Maley WR, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2010:65–85.
Miniero R, Tardivo I, Curtoni ES, Segoloni GP, La Rocca E, Nino A, et al. Pregnancy after renal transplantation in Italian patients: focus on fetal outcome. J Nephrol. 2002;15:626–32.
Bar OzB, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation. 2001;71:1051–5.
Zhou WH, Dong L, Du MR, Zhu XY, Li DJ. Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4. Reproduction. 2008;135:385–95.
Acknowledgements
The authors thank Lijun Dai and Chengjie Liang from Guangzhou Medical University for their help with the animal experiments. This study was supported by the National Natural Sciences Foundation of China (81871181), the Guangzhou Science and Technology Project (201607010222), and the Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center/(YIP-2019-029).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Huang, Q., Hu, B., Han, X. et al. Cyclosporin A ameliorates eclampsia seizure through reducing systemic inflammation in an eclampsia-like rat model. Hypertens Res 43, 263–270 (2020). https://doi.org/10.1038/s41440-019-0387-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41440-019-0387-3
This article is cited by
-
Preeclampsia up to date—What’s going on?
Hypertension Research (2023)
-
The preventive effects of aspirin on preeclampsia based on network pharmacology and bioinformatics
Journal of Human Hypertension (2022)
-
The bioflavonoid troxerutin prevents gestational hypertension in mice by inhibiting STAT3 signaling
Hypertension Research (2021)
-
Neurology of Preeclampsia and Related Disorders: an Update in Neuro-obstetrics
Current Pain and Headache Reports (2021)