Metformin attenuates brain damage in mouse model of lipopolysaccharide-induced sepsis

Jing TIAN; Yan DONG; Gang LIU; Li ZHANG; Ling TANG

doi:10.16016/j.1000-5404.201902108

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Metformin attenuates brain damage in mouse model of lipopolysaccharide-induced sepsis

更新时间：2026-01-09

- Metformin attenuates brain damage in mouse model of lipopolysaccharide-induced sepsis
- Journal of Third Military Medical University Vol. 41, Issue 15, Pages: 1423-1430(2019)
- 作者机构：
- 作者简介：
- 基金信息：
  
  the Project of Scientific and Technological Research of Chongqing Municipal Education Commission(2015X9517)
- DOI：10.16016/j.1000-5404.201902108
  CLC：
- Received：24 February 2019，
  
  Published：15 August 2019
- 稿件说明：
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Jing TIAN, Yan DONG, Gang LIU, et al. Metformin attenuates brain damage in mouse model of lipopolysaccharide-induced sepsis[J]. Journal of Third Military Medical University, 2019, 41(15): 1423-1430.
DOI：

Jing TIAN, Yan DONG, Gang LIU, et al. Metformin attenuates brain damage in mouse model of lipopolysaccharide-induced sepsis[J]. Journal of Third Military Medical University, 2019, 41(15): 1423-1430. DOI： 10.16016/j.1000-5404.201902108.

摘要

Abstract

Objective

To explore the mitigative effect of metformin on brain damage in mice with lipopolysaccharide (LPS)-induced sepsis.

Methods

A total of 104 male BALB/c mice were randomly divided into 4 groups (

=26)

that is

control

metformin

LPS and LPS+metformin group. LPS of 20 mg/kg was intraperitoneally injected to mice to induce sepsis-like systemic inflammation

and metformin (400 mg/kg) was given intraperitoneally in 0.5 h before LPS injection. Serum and brain

samples were harvested 18 h after LPS administration. HE staining was performed for the histological observation in the brain tissues. Evans blue staining was used to evaluate the permeability of the blood-brain barrier (BBB). The activity of Caspase-3

content of malondialdehyde (MDA)

and levels of IL-6

TNF-α and myeloperoxidase (MPO) in brain samples

and the levels of neuron-specific enolase (NSE) and soluble protein100-β (S100-β) in serum were determined with corresponding reagent testing kits.

Results

In the morphological observation on hippocampal CA1 and CA3 regions and cerebral cortex

the results indicated that LPS exposure induced large quantities of widespreading degenerative neurons

and these abnormalities were attenuated in mice receiving metformin administration. The elevated Evans blue content in the brain from LPS-insulted mice was decreased by metformin (

0.05). Treatment with metformin suppressed LPS-induced elevation of NSE and S100-β in the serum (

0.05). The activity of Caspase-3 was significantly higher in LPS group than the control group (

0.01)

while the activity of Caspase-3 in LPS+metformin group was lower than in LPS group (

0.05)

which was higher than that in control group and metformin group (

0.05). Metformin treatment decreased the contents of IL-6

TNF-α and MPO in the brain tissue from LPS-insulted mice (

0.05). In addition

metformin treatment inhibited LPS-induced increase of MDA in brain tissue (

0.01).

Conclusion

Metformin alleviates LPS-induced brain damage

which may associated with protection of BBB

inhibition of apoptosis

suppressed inflammatory response and attenuated oxidative stress. Metformin might have therapeutic value in sepsis-associated brain damage.

关键词

Keywords

references

SHANKAR-HARI M PHILLIPS G S LEVY M L Developing a new definition and assessing new clinical criteria for septic shock:For the third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA 2016 315 8 775 787 10.1001/jama.2016.0289 SHANKAR-HARI M, PHILLIPS G S, LE VY M L, et al .Developing a new definition and assessing new clinical criteria for septic shock:For the third international consensus definitions for sepsis and septic shock (Sepsis-3)[J ] .JAMA, 2016, 315(8):775-787.DOI:10.1001/jama.2016.0289.

ZHAO L AN R YANG Y Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress:the role of SIRT1 signaling J Pineal Res 2015 59 2 230 239 10.1111/jpi.12254 ZHAO L, AN R, YANG Y, et al .Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress:the role of SIRT1 signaling[J ] .J Pineal Res, 2015, 59(2):230-239.DOI:10.1111/jpi.12254.

YANG Y JIANG S DONG Y S Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice J Pineal Res 2015 58 1 61 70 10.1111/jpi.12193 YANG Y, JIANG S, DONG Y S, et al .Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice[J ] .J Pineal Res, 2015, 58(1):61-70.DOI:10.1111/jpi.12193.

DU MOULIN G C PATERSON D HEDLEY-WHYTE J E.coli peritonitis and bacteremia cause increased blood-brain barrier permeability Brain Res 1985 340 2 261 268 10.1016/0006-8993(85)90922-9 DU MOULIN G C, PATERSON D, HEDLEY-WHYTE J, et al . E.coli peritonitis and bacteremia cause increased blood-brain barrier permeability[J ] .Brain Res, 1985, 340(2):261-268.DOI:10.1016/0006-8993(85)90922-9.

YANG Y DONG R L HU D L Liver kinase B1/AMP-activated protein kinase pathway activation attenuated the progression of endotoxemia in the diabetic mice Cell Physiol Biochem 2017 42 2 761 779 10.1159/000478068 YANG Y, DONG R L, HU D L, et al .Liver kinase B1/AMP-activated protein kinase pathway activation attenuated the progression of endotoxemia in the diabetic mice[J ] .Cell Physiol Biochem, 2017, 42(2):761-779.DOI:10.1159/000478068.

YUAN H M LI L J ZHENG W P Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice Int Immunopharmacol 2012 12 4 682 688 10.1016/j.intimp.2012.01.015 YUAN H M, LI L J, ZHENG W P, et al .Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice[J ] .Int Immunopharmacol, 2012, 12(4):682-688.DOI:10.1016/j.intimp.2012.01.015.

WANG X N XUE G X LIU W C Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice Aging Cell 2017 16 2 414 421 10.1111/acel.12572 WANG X N, XUE G X, LIU W C, et al .Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice[J ] .Aging Cell, 2017, 16(2):414-421.DOI:10.1111/acel.12572.

NATH N KHAN M PAINTLIA M K Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis J Immunol 2009 182 12 8005 8014 10.4049/jimmunol.0803563 NATH N, KHAN M, PAINTLIA M K, et al .Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis[J ] .J Immunol, 2009, 182(12):8005-8014.DOI:10.4049/jimmunol.0803563.

张锟李仁杰刘涛两种脓毒症小鼠模型的比较中华临床医师杂志(电子版) 2012 6 8 1998 2001 10.3877/cma.j.issn.1674-0785.2012.08.006 张锟, 李仁杰, 刘涛, 等.两种脓毒症小鼠模型的比较[J].中华临床医师杂志(电子版), 2012, 6(8):1998-2001.DOI:10.3877/cma.j.issn.1674-0785.2012.08.006.

ZHANG K LI R J LIU T Comparison of two distinct animal models for polymicrobial sepsis in mice Chin J Clinicians (Electr Ed) 2012 6 8 1998 2001 10.3877/cma.j.issn.1674-0785.2012.08.006 ZHANG K, LI R J, LIU T, et al .Comparison of two distinct animal models for polymicrobial sepsis in mice[J ] .Chin J Clinicians (Electr Ed), 2012, 6(8):1998-2001.DOI:10.3877/cma.j.issn.1674-0785.2012.08.006.

YOKOO H CHIBA S TOMITA K Neurodegenerative evidence in mice brains with cecal ligation and puncture-induced sepsis:preventive effect of the free radical scavenger edaravone PLoS ONE 2012 7 12 e51539 10.1371/journal.pone.0051539 YOKOO H, CHIBA S, TOMITA K, et al .Neurodegenerative evidence in mice brains with cecal ligation and puncture-induced sepsis:preventive effect of the free radical scavenger edaravone[J ] .PLoS ONE, 2012, 7(12):e51539.DOI:10.1371/journal.pone.0051539.

VARATHARAJ A GALEA I The blood-brain barrier in systemic inflammation Brain Behav Immun 2017 60 1 12 10.1016/j.bbi.2016.03.010 VARATHARAJ A, GALEA I.The blood-brain barrier in systemic inflammation[J].Brain Behav Immun, 2017, 60:1-12.DOI:10.1016/j.bbi.2016.03.010.

GAO R TANG Y TONG J Systemic lipopolysaccharide administration-induced cognitive impairments are reversed by erythropoietin treatment in mice Inflammation 2015 38 5 1949 1958 10.1007/s10753-015-0175-4 GAO R, TANG Y, TONG J, et al .Systemic lipopolysaccharide administration-induced cognitive impairments are reversed by erythropoietin treatment in mice[J ] .Inflammation, 2015, 38(5):1949-1958.DOI:10.1007/s10753-015-0175-4.

LIU Y TANG G LI Y Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion J Neuroinflam 2014 11 1 177 10.1186/s12974-014-0177-4.DOI:10.1186/s12974-014-0177-4 LIU Y, TANG G, LI Y, et al .Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion[J ] .J Neuroinflam, 2014, 11(1):177.DOI:10.1186/s12974-014-0177-4.DOI:10.1186/s12974-014-0177-4.

FARBOOD Y SARKAKI A KHALAJ L Targeting adenosine monophosphate-activated protein kinase by metformin adjusts post-ischemic hyperemia and extracellular neuronal discharge in transient global cerebral ischemia Microcirculation 2015 22 7 534 541 10.1111/micc.12224 FARBOOD Y, SARKAKI A, KHALAJ L, et al .Targeting adenosine monophosphate-activated protein kinase by metformin adjusts post-ischemic hyperemia and extracellular neuronal discharge in transient global cerebral ischemia[J ] .Microcirculation, 2015, 22(7):534-541.DOI:10.1111/micc.12224.

TANG G YANG H CHEN J Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway Oncotarget 2017 8 58 97977 97989 10.18632/oncotarget.20105 TANG G, YANG H, CHEN J, et al .Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway[J ] .Oncotarget, 2017, 8(58):97977-97989.DOI:10.18632/oncotarget.20105.

GUO Y WANG F LI H Metformin Protects Against Spinal Cord Injury by Regulating Autophagy via the mTOR Signaling Pathway Neurochem Res 2018 43 5 1111 1117 10.1007/s11064-018-2525-8 GUO Y, WANG F, LI H, et al .Metformin Protects Against Spinal Cord Injury by Regulating Autophagy via the mTOR Signaling Pathway[J ] .Neurochem Res, 2018, 43(5):1111-1117.DOI:10.1007/s11064-018-2525-8.

DELKHOSH-KASMAIE F FARSHID AA TAMADDON-FARD E The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats:behavioral and hippocampal histopathological and biochemical evaluations Biomed Pharmacother 2018 107 203 211 10.1016/j.biopha.2018.07.165 DELKHOSH-KASMAIE F, FARSHID AA, TAMADDON-FARD E.The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats:behavioral and hippocampal histopathological and biochemical evaluations[J].Biomed Pharmacother, 2018, 107:203-211.DOI:10.1016/j.biopha.2018.07.165.

ZHOU C SUN R ZHUANG S Metformin prevents cerebellar granule neurons against glutamate-induced neurotoxicity Brain Res Bull 2016 121 241 245 10.1016/j.brainresbull.2016.02.009 ZHOU C, SUN R, ZHUANG S, et al .Metformin prevents cerebellar granule neurons against glutamate-induced neurotoxicity[J ] .Brain Res Bull, 2016, 121:241-245.DOI:10.1016/j.brainresbull.2016.02.009.

GE X H ZHU G J GENG D Q Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats Physiol Behav 2017 170 115 123 10.1016/j.physbeh.2016.12.021 GE X H, ZHU G J, GENG D Q, et al .Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats[J ] .Physiol Behav, 2017, 170:115-123.DOI:10.1016/j.physbeh.2016.12.021.

张莹范霞杨雪吴茱萸碱对脓毒症小鼠急性肺损伤的保护作用第三军医大学学报 2016 38 21 2309 2314 10.16016/j.1000-5404.201604138 http://aammt.tmmu.edu.cn/oa/DArticle.aspx?type=view&id=201604138 张莹, 范霞, 杨雪, 等.吴茱萸碱对脓毒症小鼠急性肺损伤的保护作用[J].第三军医大学学报, 2016, 38(21):2309-2314.DOI:10.16016/j.1000-5404.201604138.

ZHANG Y FAN X YANG X Evodiamine protects septic mice against acute lung injury J Third Mil Med Univ 2016 38 21 2309 2314 10.16016/j.1000-5404.201604138 http://aammt.tmmu.edu.cn/oa/DArticle.aspx?type=view&id=201604138 ZHANG Y, FAN X, YANG X, et al .Evodiamine protects septic mice against acute lung injury[J ] .J Third Mil Med Univ, 2016, 38(21):2309-2314.DOI:10.16016/j.1000-5404.201604138.

CHEN C Z HSU C H LI C Y Insulin use increases risk of asthma but metformin use reduces the risk in patients with diabetes in a Taiwanese population cohort J Asthma 2017 54 10 1019 1025 10.1080/02770903.2017.1283698 CHEN C Z, HSU C H, LI C Y, et al .Insulin use increases risk of asthma but metformin use reduces the risk in patients with diabetes in a Taiwanese population cohort[J ] .J Asthma, 2017, 54(10):1019-1025.DOI:10.1080/02770903.2017.1283698.

ZHU X C JIANG T ZHANG Q Q Chronic metformin preconditioning provides neuroprotection via suppression of NF-κB-Mediated inflammatory pathway in rats with permanent cerebral ischemia Mol Neurobiol 2015 52 1 375 385 10.1007/s12035-014-8866-7 ZHU X C, JIANG T, ZHANG Q Q, et al .Chronic metformin preconditioning provides neuroprotection via suppression of NF-κB-Mediated inflammatory pathway in rats with permanent cerebral ischemia[J ] .Mol Neurobiol, 2015, 52(1):375-385.DOI:10.1007/s12035-014-8866-7.

AN R ZHAO L XI C Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism Basic Res Cardiol 2016 111 1 8 10.1007/s00395-015-0526-1 AN R, ZHAO L, XI C, et al .Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism[J ] .Basic Res Cardiol, 2016, 111(1):8.DOI:10.1007/s00395-015-0526-1.

JI M H XIA D G ZHU L Y Short-and long-term protective effects of melatonin in a mouse model of sepsis-associated encephalopathy Inflammation 2018 41 2 515 529 10.1007/s10753-017-0708-0 JI M H, XIA D G, ZHU L Y, et al .Short-and long-term protective effects of melatonin in a mouse model of sepsis-associated encephalopathy[J ] .Inflammation, 2018, 41(2):515-529.DOI:10.1007/s10753-017-0708-0.

NING Q LIU Z WANG X Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice Neurol Res 2017 39 4 357 366 10.1080/01616412.2017.1281197 NING Q, LIU Z, WANG X, et al .Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice[J ] .Neurol Res, 2017, 39(4):357-366.DOI:10.1080/01616412.2017.1281197.

GHAVIMI H SHEIDAEI S VAEZ H Metformin-attenuated sepsis-induced oxidative damages:a novel role for metformin Iran J Basic Med Sci 2018 21 5 469 475 10.22038/IJBMS.2018.24610.6126 GHAVIMI H, SHEIDAEI S, VAEZ H, et al .Metformin-attenuated sepsis-induced oxidative damages:a novel role for metformin[J ] .Iran J Basic Med Sci, 2018, 21(5):469-475.DOI:10.22038/IJBMS.2018.24610.6126.

KESHAVARZI S KERMANSHAHI S KARAMI L Protective role of metformin against methamphetamine induced anxiety, depression, cognition impairment and neurodegeneration in rat:The role of CREB/BDNF and Akt/GSK3 signaling pathways Neurotoxicology 2019 72 74 84 10.1016/j.neuro.2019.02.004 KESHAVARZI S, KERMANSHAHI S, KARAMI L, et al .Protective role of metformin against methamphetamine induced anxiety, depression, cognition impairment and neurodegeneration in rat:The role of CREB/BDNF and Akt/GSK3 signaling pathways[J ] .Neurotoxicology, 2019, 72:74-84.DOI:10.1016/j.neuro.2019.02.004.

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