Effect of Dexamethasone on Mammalian Target of Rapamycin Expression of Astrocytes in Hippocampus of Rats with Sepsis Associated Encephalopathy_West China Medical Journal

Authors：

 ChenBin , LiYafei , SunYunjie ,  LiXihong

Department of Emergency Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LiXihong, Email: hilixihong@163.com

Keywords：

Sepsis associated encephalopathy; Hippocampus; Glial fibrillary acidic protein; Mammalian target of rapamycin; Rat

DOI：

10.7507/1002-0179.201600273

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Objective To investigate the effect of dexamethasone on mammalian target of rapamycin (mTOR) expression of astrocytes in hippocampus of rats with sepsis associated encephalopathy (SAE). Methods Totally, 90 cases of 30-day-old male Wistar rats were randomly divided into sham-operation group (n=10) and cecal ligation and puncture (CLP) group (n=80). Models of rats with sepsis were established by CLP. At 12 hours after CLP, if rats appeared lower neurobehavioral scores, abnormal electroencephalogram (EEG) and somatosensory evoked potential (SEP), they were diagnosed with SAE. And then, they were randomly divided into non-treated group and dexamethasone group. Rats in the dexamethasone group were injected with dexamethasone (1 mg/kg) via tail vein every other day for a total of 3 times. The same dose of saline was used in the non-treated group. The neurobehavioral score was measured, SEP and EEG were examined in the age of 40 days, and then the rats were killed and the hippocampus was taken. Expressions of mTOR protein were measured by Western blot. The glial fibrillary acidic protein (GFAP) and mTOR were detected by immunofluorescence assay, and the number of positive cells was calculated by image analysis system software. Results Six of 80 CLP rats died in 12 hours after operation, and 28 of 74 rats were diagnosed as SAE because they appeared lower neurobehavioral scores, abnormal EEG and SEP at 12 hours after CLP. The incidence of SAE was 37.84% (28/74). In the age of 40 days, compared with non-treated group, neurobehavioral score of rats in the dexamethasone group was low, the amount of alpha waves in EEG reduced, delta waves increased, the amplitude of P1 waves in SEP was decreased, and the latencies of P1 and N1 waves were prolonged (P＜0.05). GFAP immunofluorescence staining showed astrocytic body and processes were small in the sham operation group. However, astrocytes in the non-treated group had large body and hypertrophic processes, and compared with the sham operation group, the number of these cells increased significantly (P＜0.05). Astrocytic body and processes were small in the dexamethasone group compared with the non-treated group, and the number of cells also decreased (P＜0.05). The mTOR positive astrocytes in the non-treated group were more than those in the sham operation group (P＜0.05). But mTOR positive astrocytes in the dexamethasone group were fewer than those in the non-treated group (P＜0.05). Conclusions Astrocytes are activated in the hippocampus of rats with SAE. They show features of reactive hyperplasia, and the expression of mTOR is up-regulated, while dexamethasone can inhibit effects on these.

Citation： ChenBin, LiYafei, SunYunjie, LiXihong. Effect of Dexamethasone on Mammalian Target of Rapamycin Expression of Astrocytes in Hippocampus of Rats with Sepsis Associated Encephalopathy. West China Medical Journal, 2016, 31(6): 1013-1018. doi: 10.7507/1002-0179.201600273 Copy

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2.	Berg RM, Møller K, Bailey DM. Neuro-oxidative-nitrosative stress in sepsis[J]. J Cereb Blood Flow Metab, 2011, 31(7): 1532-1544.
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14.	Sofroniew M. Vinters HV. Astrocytes:biology and pathology[J]. Acta Neuropathol, 2010, 119(1): 7-35.
15.	Hennessy E, Griffin ÉW, Cunningham C. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL- 1β and TNF-α[J]. J Neurosci, 2015, 35(22): 8411-8422.
16.	Kalashnyk O, Lykhmus O, Oliinyk O, et al. α7 nicotinic acetylcholine receptor-specific antibody stimulates interleukin-6 production in human astrocytes through p38-dependent pathway[J]. Int Immunopharmacol, 2014, 23(2): 475-479.
17.	Bockaert J, Marin P. mTOR in brain physiology and pathologies[J]. Physiol Rev, 2015, 95(4): 1157-1187.
18.	Gao S, Duan C, Gao G, et al. Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling[J]. Int J Biochem Cell Biol, 2015, 64: 25-33.
19.	Dáňová K, Klapetková A, Kayserová J, et al. NF-κB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment[J]. Oncotarget, 2015, 6(16): 14123- 14138.
20.	Xu Y, Li Z, Yin Y, et al. Ghrelin inhibits the differentiation of T helper 17 cells through mTOR/STAT3 signaling pathway[J]. PLoS One, 2015, 10(2): e0117081.
21.	Park J, Kim M, Kang SG, et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway[J]. Mucosal Immunol, 2015, 8(1): 80-93.
22.	Minneci PC, Deans KJ, Banks SM, et al. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose[J]. Ann Intern Med, 2004, 141(1): 47-56.
23.	Levy M, Antunes A, Fiette L, et al. Impact of corticosteroids on experimental meningococcal sepsis in mice[J]. Steroids, 2015, 101: 96-102.
24.	Atkinson SJ, Cvijanovich NZ, Thomas NJ, et al. Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis[J]. PLoS One, 2014, 9(11): e112702.
25.	Casserly B, Gerlach H, Phillips GS, et al. Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign[J]. Intensive Care Med, 2012, 38(12): 1946-1954.

1. Zhang LN, Wang XT, Ai YH, et al. Epidemiological features and risk factors of sepsis-associated encephalopathy in intensive care unit patients: 2008-2011[J]. Chin Med J (Engl), 2012, 125(5): 828-831.
2. Berg RM, Møller K, Bailey DM. Neuro-oxidative-nitrosative stress in sepsis[J]. J Cereb Blood Flow Metab, 2011, 31(7): 1532-1544.
3. Jacob A, Brorson JR, Alexander JJ. Septic encephalopathy: inflammation in man and mouse[J]. Neurochem Int, 2011, 58(4): 472-476.
4. Liu TF, Vachharajani V, Millet P, et al. Sequential actions of SIRT1- RELB-SIRT3 coordinate nuclear-mitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis[J]. J Biol Chem, 2015, 290(1): 396-408.
5. Liu MW, Su MX, Zhang W, et al. Rhodiola rosea suppresses thymus T-lymphocyte apoptosis by downregulating tumor necrosis factor- α-induced protein 8-like-2 in septic rats[J]. Int J Mol Med, 2015, 36(2): 386-398.
6. Patel GP, Balk RA. Systemic steroids in severe sepsis and septic shock[J]. Am J Respir Crit Care Med, 2012, 185(2): 133-139.
7. Allen KS, Kinasewitz GT. The pendulum of corticosteroids in sepsis swings again?[J]. Crit Care Med, 2014, 42(11): 2442-2443.
8. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review[J]. JAMA, 2009, 301(22): 2362-2375.
9. Das T, Hoarau JJ, Jaffar Bandjee MC, et al. Multifaceted innate immune responses engaged by astrocytes, microglia and resident dendritic cells against Chikungunya neuroinfection[J]. J Gen Virol, 2015, 96(Pt 2): 294-310.
10. De los Reyes LM, Céspedes ÁE. Atorvastatin-meloxicam association inhibits neuroinflammation and attenuates the cellular damage in cerebral ischemia by arterial embolism[J]. Biomedica, 2014, 34(3): 366-378.
11. Araki K, Youngblood B, Ahmed R. The role of mTOR in memory CD8 T-cell differentiation[J]. Immunol Rev, 2010, 235(1): 234-243.
12. Su Y, Qu Y, Zhao F, et al. Regulation of autophagy by the nuclear factor κB signaling pathway in the hippocampus of rats with sepsis[J]. J Neuroinflammation, 2015, 12: 116.
13. Maramattom BV. Sepsis associated encephalopathy[J]. Neurol Res, 2007, 29(7): 643-646.
14. Sofroniew M. Vinters HV. Astrocytes:biology and pathology[J]. Acta Neuropathol, 2010, 119(1): 7-35.
15. Hennessy E, Griffin ÉW, Cunningham C. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL- 1β and TNF-α[J]. J Neurosci, 2015, 35(22): 8411-8422.
16. Kalashnyk O, Lykhmus O, Oliinyk O, et al. α7 nicotinic acetylcholine receptor-specific antibody stimulates interleukin-6 production in human astrocytes through p38-dependent pathway[J]. Int Immunopharmacol, 2014, 23(2): 475-479.
17. Bockaert J, Marin P. mTOR in brain physiology and pathologies[J]. Physiol Rev, 2015, 95(4): 1157-1187.
18. Gao S, Duan C, Gao G, et al. Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling[J]. Int J Biochem Cell Biol, 2015, 64: 25-33.
19. Dáňová K, Klapetková A, Kayserová J, et al. NF-κB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment[J]. Oncotarget, 2015, 6(16): 14123- 14138.
20. Xu Y, Li Z, Yin Y, et al. Ghrelin inhibits the differentiation of T helper 17 cells through mTOR/STAT3 signaling pathway[J]. PLoS One, 2015, 10(2): e0117081.
21. Park J, Kim M, Kang SG, et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway[J]. Mucosal Immunol, 2015, 8(1): 80-93.
22. Minneci PC, Deans KJ, Banks SM, et al. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose[J]. Ann Intern Med, 2004, 141(1): 47-56.
23. Levy M, Antunes A, Fiette L, et al. Impact of corticosteroids on experimental meningococcal sepsis in mice[J]. Steroids, 2015, 101: 96-102.
24. Atkinson SJ, Cvijanovich NZ, Thomas NJ, et al. Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis[J]. PLoS One, 2014, 9(11): e112702.
25. Casserly B, Gerlach H, Phillips GS, et al. Low-dose steroids in adult septic shock: results of the Surviving Sepsis Campaign[J]. Intensive Care Med, 2012, 38(12): 1946-1954.

West China Medical Journal

Effect of Dexamethasone on Mammalian Target of Rapamycin Expression of Astrocytes in Hippocampus of Rats with Sepsis Associated Encephalopathy

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