Abstract
The present study aimed to investigate the effect of APAP treatment on the expression of pro-inflammatory cytokines in the astrocytes. The mouse astrocyte cells (C8-D1A) were treated with APAP at the concentration of 100 μM for 24 h, 16 and 28 days. The expressions of pro-inflammatory cytokines and NF-kB were determined using western blot analysis. Furthermore, the expression and localization of phosphorylation of NF-kB were detected by immunohistochemical and immunofluorescent analysis. The ultrastructure of C8-D1A cells was as well monitored. The results revealed that acute APAP treatment (24 h) had no effect on the expression of pro-inflammatory cytokines and pNF-kB. This treatment did not alter the ultrastructure of C8-D1A cells when compared with those in the control cells. However, the results obtained from the study on chronic APAP-treated cells (16 and 28 days) showed the different effect of APAP treatment. The results obtained from western blot analysis showed the increment of pro-inflammatory cytokine (IL-1β and TNF-α) expressions and the activation of NF-kB signaling pathway. Nuclear translocation of pNF-kB and alteration of several cell structures were well observed in the C8-D1A cells with chronic APAP treatment. The results obtained from this study suggest that chronic APAP treatment can induce an upregulation of pro-inflammatory cytokines (IL-1β and TNFα) in astrocytes. This alteration implies the involvement of the activation of NF-kB signaling pathway.
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References
Anderson BJ (2008) Paracetamol (acetaminophen): mechanisms of action. Paediatr Anaesth 18(10):915–921. https://doi.org/10.1111/j.1460-9592.2008.02764.x
Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336(15):1066–1071. https://doi.org/10.1056/nejm199704103361506
Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006) Paracetamol: new vistas of an old drug. CNS Drug Rev 12(3-4):250–275. https://doi.org/10.1111/j.1527-3458.2006.00250.x
Chantong C, Yisarakun W, Thongtan T, Maneesri-le Grand S (2013) Increase of pro-inflammatory cytokine expression in hippocampus following chronic paracetamol treatment in rats. Asian Arch Pathol 9:137–146
Combes V, Guillemin GJ, Chan-Ling T, Hunt NH, Grau GE (2012) The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes. Trends Parasitol 28(8):311–319. https://doi.org/10.1016/j.pt.2012.05.008
Dambach DM, Durham SK, Laskin JD, Laskin DL (2006) Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol 211(2):157–165. https://doi.org/10.1016/j.taap.2005.06.024
Dimova S, Hoet PH, Nemery B (2000) Paracetamol (acetaminophen) cytotoxicity in rat type II pneumocytes and alveolar macrophages in vitro. Biochem Pharmacol 59(11):1467–1475. https://doi.org/10.1016/S0006-2952(00)00257-4
Fakunle PB, AJA EBO, Alamu OA, Daramola AK (2011) Neurohistological degeneration of the hippocampal formation following chronic simultaneous administration of ethanol and acetaminophen in adult wistar rats (Rattus norvegicus). J Pharmacol Toxicol 6(8):701–709. https://doi.org/10.3923/jpt.2011.701.709
He Y, Yao Y, Tsirka SE, Cao Y (2014) Cell-culture models of the blood–brain barrier. Stroke 45(8):2514–2526. https://doi.org/10.1161/strokeaha.114.005427
van Kralingen C, Kho DT, Costa J, Angel CE, Graham ES (2013) Exposure to inflammatory cytokines IL-1β and TNFα induces compromise and death of astrocytes; implications for chronic neuroinflammation. PLoS One 8(12):e84269. https://doi.org/10.1371/journal.pone.0084269
Lawrence T (2009) The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 1(6). https://doi.org/10.1101/cshperspect.a001651
Moynagh PN (2005) The interleukin-1 signalling pathway in astrocytes: a key contributor to inflammation in the brain. J Anat 207(3):265–269. https://doi.org/10.1111/j.1469-7580.2005.00445.x
Nedergaard M, Verkhratsky A (2012) Artifact versus reality—how astrocytes contribute to synaptic events. Glia 60(7):1013–1023. https://doi.org/10.1002/glia.22288
Pacifici GM, Allegaert K (2015) Clinical pharmacology of paracetamol in neonates: a review. Curr Ther Res,Clin Exp 77:24–30. https://doi.org/10.1016/j.curtheres.2014.12.001
Posadas I, Santos P, Blanco A, Munoz-Fernandez M, Cena V (2010) Acetaminophen induces apoptosis in rat cortical neurons. PLoS One 5(12):e15360. https://doi.org/10.1371/journal.pone.0015360
Posadas I, Santos P, Cena V (2012) Acetaminophen induces human neuroblastoma cell death through NFKB activation. PLoS One 7(11):e50160. https://doi.org/10.1371/journal.pone.0050160
Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol (Clifton, NJ) 814:3–7. https://doi.org/10.1007/978-1-61779-452-0_1
Shih RH, Wang CY, Yang CM (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8. https://doi.org/10.3389/fnmol.2015.00077
Sofroniew MV (2014) Multiple roles for astrocytes as effectors of cytokines and inflammatory mediators. Neuroscientist Rev J Bringing Neurobiol, Neurol Psychiatry 20(2):160–172. https://doi.org/10.1177/1073858413504466
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35. https://doi.org/10.1007/s00401-009-0619-8
Sudano I, Flammer AJ, Periat D, Enseleit F, Hermann M, Wolfrum M, Hirt A, Kaiser P, Hurlimann D, Neidhart M, Gay S, Holzmeister J, Nussberger J, Mocharla P, Landmesser U, Haile SR, Corti R, Vanhoutte PM, Luscher TF, Noll G, Ruschitzka F (2010) Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation 122(18):1789–1796. https://doi.org/10.1161/circulationaha.110.956490
Tak PP, Firestein GS (2001) NF-κB: a key role in inflammatory diseases. J Clin Investig 107(1):7–11. https://doi.org/10.1172/JCI11830
Tripathy D, Grammas P (2009a) Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress. J Neuroinflammation 6(1):10. https://doi.org/10.1186/1742-2094-6-10
Tripathy D, Grammas P (2009b) Acetaminophen protects brain endothelial cells against oxidative stress. Microvasc Res 77(3):289–296. https://doi.org/10.1016/j.mvr.2009.02.002
Wongprom B, Maneesri-le Grand S, Thongtan T (2015) Long-term paracetamol treatment induces interleukin-1β expression in human microglial cells. Chula Med J 59(3):253–263
Yisarakun W, Supornsilpchai W, Chantong C, Srikiatkhachorn A, Maneesri-le Grand S (2014) Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model. Microvasc Res 94:36–46. https://doi.org/10.1016/j.mvr.2014.04.012
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This study was supported by the National Research Council of Thailand (NRCT, GB_B_60_071_30_15 and GB_B_60_074_30_18)
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Tantarungsee, N., Yisarakun, W., Thongtan, T. et al. Upregulation of Pro-inflammatory Cytokine Expression Following Chronic Paracetamol Treatment in Astrocyte. Neurotox Res 34, 137–146 (2018). https://doi.org/10.1007/s12640-018-9875-5
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DOI: https://doi.org/10.1007/s12640-018-9875-5