Establishment and evaluation of animal models of sepsis-associated encephalopathy

doi:10.5847/wjem.j.1920-8642.2023.088

Abstract

Abstract:

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a critical disease caused by sepsis. In addition to high mortality, SAE can also adversely affect life quality and lead to significant socioeconomic costs. This review aims to explore the development of evaluation animal models of SAE, giving insight into the direction of future research in terms of its pathophysiology and therapy.
METHODS: We performed a literature search from January 1, 2000, to December 31, 2022, in MEDLINE, PubMed, EMBASE, and Web of Science using related keywords. Two independent researchers screened all the accessible articles based on the inclusion and exclusion criteria and collected the relevant data of the studies.
RESULTS: The animal models for sepsis are commonly induced through cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) injection. SAE can be evaluated using nervous reflex scores and sepsis evaluation during the acute phase, or through Morris water maze (MWM), open-field test, fear condition (FC) test, inhibitory avoidance, and other tests during the late phase.
CONCLUSION: CLP and LPS injection are the most common methods for establishing SAE animal models. Nervous reflexs cores, MWM, FC test, and inhibitory avoidance are widely used in SAE model analysis. Future research should focus on establishing a standardized system for SAE development and analysis.

Key words: Sepsis, Sepsis-associated encephalopathy, Animal model, Systematic review

Mubing Qin, Yanxia Gao, Shigong Guo, Xin Lu, Qian Zhao, Zengzheng Ge, Huadong Zhu, Yi Li. Establishment and evaluation of animal models of sepsis-associated encephalopathy[J]. World Journal of Emergency Medicine, 2023, 14(5): 349-353.

References 42

1	Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315(8):801-10. doi: 10.1001/jama.2016.0287 pmid: 26903338
2	Sahu P, Raj Stanly EA, Simon Lewis LE, Prabhu K, Rao M, Kunhikatta V. Prediction modelling in the early detection of neonatal sepsis. World J Pediatr. 2022; 18(3):160-75. doi: 10.1007/s12519-021-00505-1 pmid: 34984642
3	Tauber SC, Djukic M, Gossner J, Eiffert H, Brück W, Nau R. Sepsis-associated encephalopathy and septic encephalitis: an update. Expert Rev Anti Infect Ther. 2021; 19(2):215-31. doi: 10.1080/14787210.2020.1812384
4	Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. 2012; 8(10):557-66.
5	Chung HY, Wickel J, Brunkhorst FM, Geis C. Sepsis-associated encephalopathy: from delirium to dementia? J Clin Med. 2020; 9(3):703. doi: 10.3390/jcm9030703
6	Pezzullo L, Streatfeild J, Hickson J, Teodorczuk A, Agar MR, Caplan GA. Economic impact of delirium in Australia: a cost of illness study. BMJ Open. 2019; 9(9):e027514. doi: 10.1136/bmjopen-2018-027514
7	Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013; 369(14):1306-16. doi: 10.1056/NEJMoa1301372
8	Saczynski JS, Marcantonio ER, Quach L, Fong TG, Gross A, Inouye SK, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012; 367(1):30-9. doi: 10.1056/NEJMoa1112923
9	Peng XY, Luo ZX, He S, Zhang LH, Li Y. Blood-brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy. Front Cell Infect Microbiol. 2021; 11:768108. doi: 10.3389/fcimb.2021.768108
10	Robba C, Crippa IA, Taccone FS. Septic encephalopathy. Curr Neurol Neurosci Rep. 2018; 18(12):82. doi: 10.1007/s11910-018-0895-6
11	Savi FF, de Oliveira A, de Medeiros GF, Bozza FA, Michels M, Sharshar T, et al. What animal models can tell us about long-term cognitive dysfunction following sepsis: a systematic review. Neurosci Biobehav Rev. 2021; 124:386-404. doi: 10.1016/j.neubiorev.2020.12.005
12	Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW, Bland KI, et al. Cecal ligation and puncture. Shock. 2005; 24(Supplement 1):52-7. doi: 10.1097/01.shk.0000191414.94461.7e
13	Wichterman KA, Baue AE, Chaudry IH. Sepsis and septic shock—a review of laboratory models and a proposal. J Surg Res. 1980; 29(2):189-201. doi: 10.1016/0022-4804(80)90037-2 pmid: 6997619
14	Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 2011; 19(4):198-208. doi: 10.1016/j.tim.2011.01.001 pmid: 21296575
15	Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 2009; 4(1):31-6. doi: 10.1038/nprot.2008.214 pmid: 19131954
16	Lee B, Sur B, Park J, Kim SH, Kwon S, Yeom M, et al. Ginsenoside Rg3 alleviates lipopolysaccharide-induced learning and memory impairments by anti-inflammatory activity in rats. Biomol Ther (Seoul). 2013; 21(5):381-90. doi: 10.4062/biomolther.2013.053
17	Yang Y, Yun D, Dong B, Geng Y, Wan Y. VIP alleviates sepsis-induced cognitive dysfunction as the TLR-4/NF-κB signaling pathway is inhibited in the hippocampus of rats. J Mol Histol. 2022; 53(2):369-77. doi: 10.1007/s10735-022-10068-8 pmid: 35239068
18	Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, et al. Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis. Infection. 2018; 46(5):687-91. doi: 10.1007/s15010-018-1183-8 pmid: 30105433
19	Huet O, Ramsey D, Miljavec S, Jenney A, Aubron C, Aprico A, et al. Ensuring animal welfare while meeting scientific aims using a murine pneumonia model of septic shock. Shock. 2013; 39(6):488-94. doi: 10.1097/SHK.0b013e3182939831 pmid: 23603767
20	Shrum B, Anantha RV, Xu SX, Donnelly M, Haeryfar SM, McCormick JK, et al. A robust scoring system to evaluate sepsis severity in an animal model. BMC Res Notes. 2014; 7:233. doi: 10.1186/1756-0500-7-233 pmid: 24725742
21	Xu XE, Liu L, Wang YC, Wang CT, Zheng Q, Liu QX, et al. Caspase-1 inhibitor exerts brain-protective effects against sepsis-associated encephalopathy and cognitive impairments in a mouse model of sepsis. Brain Behav Immun. 2019; 80:859-70. doi: 10.1016/j.bbi.2019.05.038
22	Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984; 11(1):47-60. doi: 10.1016/0165-0270(84)90007-4
23	Lin SP, Wei JX, Hu JS, Bu JY, Zhu LD, Li Q, et al. Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia. Acta Pharmacol Sin. 2021; 42(7):1069-79. doi: 10.1038/s41401-021-00634-3
24	Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc. 2006; 1(1):7-12. doi: 10.1038/nprot.2006.2 pmid: 17406205
25	Andonegui G, Zelinski EL, Schubert CL, Knight D, Craig LA, Winston BW, et al. Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment. JCI Insight. 2018; 3(9):99364.
26	Delcourt J, Miller NY, Couzin ID, Garnier S. Methods for the effective study of collective behavior in a radial arm maze. Behav Res Methods. 2018; 50(4):1673-85. doi: 10.3758/s13428-018-1024-9 pmid: 29464590
27	Ji MH, Qiu LL, Tang H, Ju LS, Sun XR, Zhang H, et al. Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. J Neuroinflammation. 2015; 12:182. doi: 10.1186/s12974-015-0401-x
28	Izquierdo I, Furini CR, Myskiw JC. Fear memory. Physiol Rev. 2016; 96(2):695-750. doi: 10.1152/physrev.00018.2015 pmid: 26983799
29	Tuon L, Comim CM, Petronilho F, Barichello T, Izquierdo I, Quevedo J, et al. Time-dependent behavioral recovery after sepsis in rats. Intensive Care Med. 2008; 34(9):1724-31. doi: 10.1007/s00134-008-1129-1
30	Blake MG, Boccia MM, Baratti CM. Behavioral differences on memory retrieval between two variants of step-through inhibitory avoidance task in mice. Neurosci Lett. 2008; 444(1):102-5. doi: 10.1016/j.neulet.2008.08.010 pmid: 18706479
31	Giridharan VV, Generoso JS, Lence L, Candiotto G, Streck E, Petronilho F, et al. A crosstalk between gut and brain in sepsis-induced cognitive decline. J Neuroinflammation. 2022; 19(1):114. doi: 10.1186/s12974-022-02472-4
32	Gao QZ, Hernandes MS. Sepsis-associated encephalopathy and blood-brain barrier dysfunction. Inflammation. 2021; 44(6):2143-50. doi: 10.1007/s10753-021-01501-3 pmid: 34291398
33	Michels M, Sonai B, Dal-Pizzol F. Polarization of microglia and its role in bacterial sepsis. J Neuroimmunol. 2017; 303:90-8. doi: S0165-5728(16)30309-5 pmid: 28087076
34	Hoogland ICM, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation. 2015; 12:114. doi: 10.1186/s12974-015-0332-6
35	Brownell AL, Kuruppu D, Kil KE, Jokivarsi K, Poutiainen P, Zhu AJ, et al. PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene. J Neuroinflammation. 2015; 12(1):1-8.
36	Zhu TX, Jiang JY, Xiao YT, Xu D, Liang ZB, Bi L, et al. Early diagnosis of murine sepsis-associated encephalopathy using dynamic PET/CT imaging and multiparametric MRI. Mol Imaging Biol. 2022; 24(6):928-39. doi: 10.1007/s11307-022-01743-z pmid: 35612771
37	Szöllösi D, Hegedűs N, Veres DS, Futó I, Horváth I, Kovács N, et al. Evaluation of brain nuclear medicine imaging tracers in a murine model of sepsis-associated encephalopathy. Mol Imaging Biol. 2018; 20(6):952-62. doi: 10.1007/s11307-018-1201-3 pmid: 29736562
38	Barichello T, Martins MR, Reinke A, Constantino LS, Machado RA, Valvassori SS, et al. Behavioral deficits in sepsis-surviving rats induced by cecal ligation and perforation. Braz J Med Biol Res. 2007; 40(6):831-7. pmid: 17581683
39	Ozcan PE, Senturk E, Orhun G, Gumru S, Arican N, Orhan N, et al. Effects of intravenous immunoglobulin therapy on behavior deficits and functions in sepsis model. Ann Intensive Care. 2015; 5(1):62. doi: 10.1186/s13613-015-0062-z pmid: 26228515
40	Yan C, Ma Z, Ma H, Li Q, Zhai Q, Jiang T, et al. Mitochondrial transplantation attenuates brain dysfunction in sepsis by driving microglial M2 polarization. Mol Neurobiol. 2020; 57(9):3875-90. doi: 10.1007/s12035-020-01994-3 pmid: 32613465
41	Zhang N, Zhao W, Hu ZJ, Ge SM, Huo Y, Liu LX, et al. Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats. Sci Rep. 2021; 11(1):14511. doi: 10.1038/s41598-021-93861-x pmid: 34267240
42	Saito M, Fujinami Y, Ono Y, Ohyama S, Fujioka K, Yamashita K, et al. Infiltrated regulatory T cells and Th2 cells in the brain contribute to attenuation of sepsis-associated encephalopathy and alleviation of mental impairments in mice with polymicrobial sepsis. Brain Behav Immun. 2021; 92:25-38. doi: 10.1016/j.bbi.2020.11.010 pmid: 33181271

[1]	Jingyi Wang, Li Weng, Jun Xu, Bin Du. Blood gas analysis as a surrogate for microhemodynamic monitoring in sepsis [J]. World Journal of Emergency Medicine, 2023, 14(6): 421-427.
[2]	Saifeng Chen, Xuewei Hao, Guo Chen, Guorong Liu, Xiaoyan Yuan, Peiling Shen, Dongfeng Guo. Effects of mesencephalic astrocyte-derived neurotrophic factor on sepsis-associated acute kidney injury [J]. World Journal of Emergency Medicine, 2023, 14(5): 386-392.
[3]	Meng-meng An, Chen-xi Liu, Ping Gong. Effects of continuous renal replacement therapy on inflammation-related anemia, iron metabolism and prognosis in sepsis patients with acute kidney injury [J]. World Journal of Emergency Medicine, 2023, 14(3): 186-192.
[4]	Jue-xian Wei, Hui-lin Jiang, Xiao-hui Chen. Endothelial cell metabolism in sepsis [J]. World Journal of Emergency Medicine, 2023, 14(1): 10-16.
[5]	Hui Liu, Jie Hu, Jian-guo Xiao, Hong-jun Kang, Fei-hu Zhou. The procalcitonin-to-cortisol ratio is a potential prognostic predictor in sepsis with abdominal source: a retrospective observational study [J]. World Journal of Emergency Medicine, 2022, 13(6): 441-447.
[6]	Ralph Bou Chebl, Nadim Kattouf, Mohamad Assaf, Saadeddine Haidar, Gilbert Abou Dagher, Sarah Abdul Nabi, Rana Bachir, Mazen El Sayed. Comparing the demographic data and outcomes of septic shock patients presenting to teaching or non-teaching metropolitan hospitals in the United States [J]. World Journal of Emergency Medicine, 2022, 13(6): 433-440.
[7]	Shi-yuan Yu, Zeng-zheng Ge, Jun Xiang, Yan-xia Gao, Xin Lu, Joseph Harold Walline, Mu-bing Qin, Hua-dong Zhu, Yi Li. Is rosuvastatin protective against sepsis-associated encephalopathy? A secondary analysis of the SAILS trial [J]. World Journal of Emergency Medicine, 2022, 13(5): 367-372.
[8]	A-ling Tang, Mei-jia Shen, Guo-qiang Zhang. Intestinal microcirculation dysfunction in sepsis: pathophysiology, clinical monitoring, and therapeutic interventions [J]. World Journal of Emergency Medicine, 2022, 13(5): 343-348.
[9]	Xiao-kang Dai, Zhen-xing Ding, Yuan-yuan Tan, Hua-rui Bao, Dong-yao Wang, Hong Zhang. Neutrophils inhibit CD8⁺ T cells immune response by arginase-1 signaling in patients with sepsis [J]. World Journal of Emergency Medicine, 2022, 13(4): 266-273.
[10]	Xuan Fu, Xue Lin, Samuel Seery, Li-na Zhao, Hua-dong Zhu, Jun Xu, Xue-zhong Yu. Speckle-tracking echocardiography for detecting myocardial dysfunction in sepsis and septic shock patients: A single emergency department study [J]. World Journal of Emergency Medicine, 2022, 13(3): 175-181.
[11]	Mei-jia Shen, Li-chao Sun, Xiao-yu Liu, Meng-chen Xiong, Shan Li, A-ling Tang, Guo-qiang Zhang. Trichostatin A improves the inflammatory response and liver injury in septic mice through the FoxO3a/autophagy signaling pathway [J]. World Journal of Emergency Medicine, 2022, 13(3): 182-188.
[12]	Hai Hu, Jing-yuan Jiang, Ni Yao. Comparison of different versions of the quick sequential organ failure assessment for predicting in-hospital mortality of sepsis patients: A retrospective observational study [J]. World Journal of Emergency Medicine, 2022, 13(2): 114-119.
[13]	Yu-qing Cui, Xian-fei Ding, Huo-yan Liang, Dong Wang, Xiao-juan Zhang, Li-feng Li, Quan-cheng Kan, Le-xin Wang, Tong-wen Sun. Efficacy and safety of low-dose corticosteroids for acute respiratory distress syndrome: A systematic review and meta-analysis [J]. World Journal of Emergency Medicine, 2021, 12(3): 207-213.
[14]	Xin Lu, Wei Han, Yan-xia Gao, Shi-gong Guo, Shi-yuan Yu, Xue-zhong Yu, Hua-dong Zhu, Yi Li. Efficacy and safety of corticosteroids in immunocompetent patients with septic shock [J]. World Journal of Emergency Medicine, 2021, 12(2): 124-130.
[15]	Li-wei Duan, Jin-long Qu, Jian Wan, Yong-hua Xu, Yi Shan, Li-xue Wu, Jin-hao Zheng, Wei-wei Jiang, Qi-tong Chen, Yan Zhu, Jian Zhou, Wen-bo Yu, Lei Pei, Xi Song, Wen-fang Li, Zhao-fen Lin. Effects of viral infection and microbial diversity on patients with sepsis: A retrospective study based on metagenomic next-generation sequencing [J]. World Journal of Emergency Medicine, 2021, 12(1): 29-35.