Abstract
Sepsis-associated encephalopathy (SAE) induces neuroinflammation, which is associated with cognitive impairment (CI). CI is also correlated with aging. We used contrast-enhanced magnetic resonance imaging (MRI), perfusion MRI, and MR spectroscopy to assess long-term alterations in BBB permeability, microvascularity, and metabolism, respectively, in a rat lipopolysaccharide-induced SAE model. Free radical-targeted molecular MRI was used to detect brain radical levels at 24 h and 1 week post-LPS injection. CE-MRI showed increased Gd-DTPA uptake in LPS rat brains at 24 h in cerebral cortex, hippocampus, thalamus, and perirhinal cortex regions. Increased MRI signal intensities were observed in LPS rat brains in cerebral cortex, perirhinal cortex, and hippocampus regions 1 week post-LPS. Long-term BBB dysfunction was detected in the cerebral cortex at 6 weeks post-LPS. Increased relative cerebral blood flow (rCBF) in cortex and thalamus regions at 24 h, decreased cortical and hippocampal rCBF at 6 weeks, decreased cortical rCBF at 3 and 12 weeks, and increased thalamus rCBF at 6 weeks post-LPS, were detected. MRS indicated that LPS-exposed rat brains had decreased: NAA/Cho metabolite ratios at 1, 3, 6, and 12 weeks; Cr/Cho at 1, 3, and 12 weeks; and Myo-Ins/Cho at 1, 3, and 6 weeks post-LPS. Free radical imaging detected increased radical levels in LPS rat brains at 24 h and 1 week post-LPS. LPS-exposed rats were compared to saline-treated controls. We clearly demonstrated BBB dysfunction, impaired vascularity, and decreased brain metabolites, as measures of long-term neuroinflammatory indicators, as well as increased free radicals in a LPS-induced rat SAE model.
Similar content being viewed by others
References
Banks WA, Erickson MA (2010) The blood-brain barrier and immune function and dysfunction. Neurobiol Dis 37(1):26–32. https://doi.org/10.1016/j.nbd.2009.07.031
Berg RM, Moller K, Bailey DM (2011) Neuro-oxidative-nitrosative stress in sepsis. J Cereb Blood Flow Metab 31(7):1532–1544. https://doi.org/10.1038/jcbfm.2011.48
Bettio LEB, Rajendran L, Gil-Mohapel J (2017) The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev 79:66–86. https://doi.org/10.1016/j.neubiorev.2017.04.030
Bozza FA, Garteiser P, Oliveira MF, Doblas S, Cranford R, Saunders D, Jones I, Towner RA, Castro-Faria-Neto HC (2010) Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 30(2):440–448. https://doi.org/10.1038/jcbfm.2009.215
Bozza FA, D’Avila JC, Ritter C, Sonneville R, Sharshar T, Dal-Pizzol F (2013) Bioenergetics, mitochondrial dysfunction, and oxidative stress in the pathophysiology of septic encephalopathy. Shock 39:10–16. https://doi.org/10.1097/SHK.0b013e31828fade1
Clement HW, Vasquez JF, Sommer O, Heiser P, Morawietz H, Hopt U, Schulz E, von Dobschutz E (2010) Lipopolysaccharide-induced radical formation in the striatum is abolished in Nox2 gp91phox-deficient mice. J Neural Transm (Vienna) 117(1):13–22. https://doi.org/10.1007/s00702-009-0327-5
Coutinho de Souza P, Smith N, Atolagbe O, Ziegler J, Nijoku C, Lerner M, Ehrenshaft M, Mason RP, Meek B, Plafker SM, Saunders D, Mamedova N, Towner RA (2015) OKN-007 decreases free radical levels in a preclinical F98 rat glioma model. Free Radic Biol Med 87:157–168. https://doi.org/10.1016/j.freeradbiomed.2015.06.026
Cunningham C, Hennessy E (2015) Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimers Res Ther 7(1):33. https://doi.org/10.1186/s13195-015-0117-2
Gao R, Ji MH, Gao DP, Yang RH, Zhang SG, Yang JJ, Shen JC (2017) Neuroinflammation-induced downregulation of hippocampal neuregulin 1-ErbB4 signaling in the parvalbumin interneurons might contribute to cognitive impairment in a mouse model of sepsis-associated encephalopathy. Inflammation 40(2):387–400. https://doi.org/10.1007/s10753-016-0484-2
Gomez-Mejiba SE, Zhai Z, Akram H, Deterding LJ, Hensley K, Smith N, Towner RA, Tomer KB, Mason RP, Ramirez DC (2009) Immuno-spin trapping of protein and DNA radicals: “tagging” free radicals to locate and understand the redox process. Free Radic Biol Med 46(7):853–865. https://doi.org/10.1016/j.freeradbiomed.2008.12.020
Gomez-Mejiba SE, Zhai Z, Della-Vedova MC, Muñoz MD, Chatterjee S, Towner RA, Hensley K, Floyd RA, Mason RP, Ramirez DC (2014) Immuno-spin trapping from biochemistry to medicine: advances, challenges, and pitfalls. Focus on protein-centered radicals. Biochim Biophys Acta 1840(2):722–729. https://doi.org/10.1016/j.bbagen.2013.04.039
Hamed SA, Hamed EA, Abdella MM (2009) Septic encephalopathy: relationship to serum and cerebrospinal fluid levels of adhesion molecules, lipid peroxides and S-100B protein. Neuropediatrics 40(2):66–72. https://doi.org/10.1055/s-0029-1231054
Handa O, Stephen J, Cepinskas G (2008) Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis. Am J Physiol Heart Circ Physiol 295(4):H1712–H1719. https://doi.org/10.1152/ajpheart.00476.2008
Hernandes MS, D’Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, Castro-Faria-Neto HC, Cunha FQ, Britto LR, Bozza FA (2014) The role of Nox2-derived ROS in the development of cognitive impairment after sepsis. J Neuroinflammation 11(1):36. https://doi.org/10.1186/1742-2094-11-36
Jacob A, Brorson JR, Alexander JJ (2011) Septic encephalopathy: inflammation in man and mouse. Neurochem Int 58(4):472–476. https://doi.org/10.1016/j.neuint.2011.01.004
Jain NK, Patil CS, Kulkarni SK, Singh A (2002) Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide-induced cognitive dysfunction in mice. Behav Brain Res 133(2):369–376. https://doi.org/10.1016/S0166-4328(02)00025-6
Khoo NK, Cantu-Medellin N, St Croix C, Kelley EE (2015) In vivo immuno-spin trapping: imaging the footprints of oxidative stress. Curr Protoc Cytom 74:12.42.1–12.4211
Lyu J, Zheng G, Chen Z, Wang B, Tao S, Xiang D, Xie M, Huang J, Liu C, Zeng Q (2015) Sepsis-induced brain mitochondrial dysfunction is associated with altered mitochondrial Src and PTP1B levels. Brain Res 1620:130–138. https://doi.org/10.1016/j.brainres.2015.04.062
Mason RP (2004) Using anti-5,5-dimethyl-1-pyrroline N-oxide (anti-DMPO) to detect protein radicals in time and space with immuno-spin trapping. Free Radic Biol Med 36(10):1214–1223. https://doi.org/10.1016/j.freeradbiomed.2004.02.077
Mason RP (2016) Imaging free radicals in organelles, cells, tissue, and in vivo with immuno-spin trapping. Redox Biol 8:422–429. https://doi.org/10.1016/j.redox.2016.04.003
Michels M, Danielslki LG, Vieira A, Florentino D, Dall’lgna D, Gallant L, Sonai B, Vuolo F, Mina F, Pescador B, Dominguini D, Barichello T, Quevedo J, Dal-Pizzol F, Petronilho F (2015) CD40-CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-term cognitive dysfunction after sepsis. Mol Med 21:219–226. https://doi.org/10.2119/molmed.2015.00070
Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL et al (2012) The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 185(12):1307–1315
Moran JP, Dalrymple-Alford JC (2003) Perirhinal cortex and anterior thalamic lesions: comparative effects on learning and memory. Behav Neurosci 117(6):1326–1341. https://doi.org/10.1037/0735-7044.117.6.1326
Murray C, Sanderson DJ, Barkus C, Deacon RM, Rawlins JN, Bannerman DM, Cunningham C (2012) Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol Aging 33(603–16):e3
Ning Q, Liu Z, Wang X, Zhang R, Zhang J, Yang M, Sun H, Han F, Zhao W, Zhang X (2017) Neurodegenerative changes and neuroapoptosis induced by systemic lipopolysaccharide administration are reversed by dexmedetomidine treatment in mice. Neurol Res 39(4):357–366. https://doi.org/10.1080/01616412.2017.1281197
Oedekoven CS, Jansen A, Keidel JL, Kircher T, Leube D (2015) The influence of age and mild cognitive impairment on associative memory performance and underlying brain networks. Brain Imaging Behav 9(4):776–789. https://doi.org/10.1007/s11682-014-9335-7
Ory D, Planas A, Dresselaers T, Gsell W, Postnov A, Celen S, Casteels C, Himmelreich U, Debyser Z, Van Laere K, Verbruggen A, Bormans G (2015) PET imaging of TSPOI in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide. Nucl Med Biol 42(10):753–761. https://doi.org/10.1016/j.nucmedbio.2015.06.010
Percheron G (2003) Thalamus. In: Paxinos G, May J (eds) The human nervous system, 2nd edn. Elsevier, Amsterdam, pp 592–675
Pierrakos C, Attou R, Decorte L, Velissaris D, Cudia A, Gottignies P, Devriendt J, Tsolaki M, De Bels D (2017) Cerebral perfusion alterations and cognitive decline in critically ill sepsis survivors. Acta Clin Belg 72(1):39–44. https://doi.org/10.1080/17843286.2016.1191851
Ramirez DC, Mason RP (2005) Immuno-spin trapping: detection of protein-centered radicals. Curr Protoc Toxicol 17:17
Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Schafers M, Kummer MP, Klockgether T, Heneka MT (2008) Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 5(1):38. https://doi.org/10.1186/1742-2094-5-38
Shipp S (2007) Structure and function of the cerebral cortex. Curr Biol 17(12):R443–R449. https://doi.org/10.1016/j.cub.2007.03.044
Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99(2):195–231. https://doi.org/10.1037/0033-295X.99.2.195
Sumbria RK, Grigoryan MM, Vasilevko V, Krasieva TB, Scadeng M, Dvornikova AK, Paganini-Hill A, Kim R, Cribbs DH, Fisher MJ (2016) A murine model of inflammation-induced cerebral microbleeds. J Neuroinflammation 13(1):218. https://doi.org/10.1186/s12974-016-0693-5
Sun J, Zhang S, Zhang X, Zhang X, Dong H, Qian Y (2015) IL-17A is implicated in lipopolysaccharide-induced neuroinflammation and cognitive impairment in aged rats via microglial activation. J Neuroinflammation 12(1):165. https://doi.org/10.1186/s12974-015-0394-5
Taccone FS, Scolletta S, Franchi F, Donadello K, Oddo M (2013) Brain perfusion in sepsis. Curr Vasc Pharmacol 11(2):170–186
Takechi R, Lam V, Brook E, Giles C, Fimognari N, Mooranian A, Al-Salami H, Coulson SH, Nesbit M, Mamo JCL (2017) Blood-brain barrier dysfunction precedes cognitive decline and neurodegeneration in diabetic insulin resistant mouse model: an implication for causal link. Front Aging Neurosci 9:399. https://doi.org/10.3389/fnagi.2017.00399
Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to gognitive impairement and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312(1):H1–H20. https://doi.org/10.1152/ajpheart.00581.2016
Towner R, Smith N (2017) In vivo and in situ detection of macromolecular free radicals using immune-spin trapping and molecular MRI. Antioxid Redox Signal. https://doi.org/10.1089/ars.2017.7390
Towner RA, Smith N, Saunders D, Henderson M, Downum K, Lupu F, Silasi-Mansat R, Ramirez DC, Gomez-Mejiba SE, Bonini MG, Ehrenshaft M, Mason RP (2012) In vivo imaging of immuno-spin trapped radicals with molecular MRI in a mouse diabetes model. Diabetes 61(10):2405–2413. https://doi.org/10.2337/db11-1540
Towner RA, Garteiser P, Bozza F, Smith N, Saunders D, d’Avila JCP, Magno F, Oliveira MF, Ehrenshaft M, Lupu F, Silasi-Mansat R, Ramirez DC, Gomez-Mejiba SE, Mason RP, Faria-Neto HCC (2013a) In vivo detection of free radicals in mouse septic encephalopathy using molecular MRI and immuno-spin-trapping. Free Radic Biol Med 65:828–837. https://doi.org/10.1016/j.freeradbiomed.2013.08.172
Towner RA, Smith N, Saunders D, De Souza PC, Henry L, Lupu F, Silasi-Mansat R, Ehrenshaft M, Mason RP, Gomez-Mejiba SE, Ramirez DC (2013b) Combined molecular MRI and immuno-spin-trapping for in vivo detection of free radicals in orthotopic mouse GL261 gliomas. Biochim Biophys Acta 1832(12):2153–2161. https://doi.org/10.1016/j.bbadis.2013.08.004
Towner RA, Smith N, Saunders D, Lupu F, Silasi-Mansat R, West M, Ramirez DC, Gomez-Mejiba SE, Bonini MG, Mason RP, Ehrenshaft M, Hensley K (2013c) In vivo detection of free radicals using molecular MRI and immuno-spin-trapping in a mouse model for amyotrophic lateral sclerosis. (ALS) Free Radic Biol Med 63:351–360. https://doi.org/10.1016/j.freeradbiomed.2013.05.026
Towner RA, Smith N, Saunders D, Carrizales J, Lupu F, Silasi-Mansat R, Ehrenshaft M, Mason RP (2015) In vivo targeted molecular magnetic resonance imaging of free radicals in diabetic cardiomyopathy within mice. Free Radic Res 49(9):1140–1146. https://doi.org/10.3109/10715762.2015.1050587
Wang Y, Chen Z, Zhang Y, Fang S, Zeng Q (2014) Mitochondrial biogenesis of astrocytes is increased under experimental septic conditions. Chin Med J 127(10):1837–1842
Wen M, Lian Z, Huang L, Zhu S, Hu B, Han Y, Deng Y, Zeng H (2017) Magnetic resonance spectroscopy for assessment of brain injury in the rat model of sepsis. Exp Ther Med 14(5):4118–4124. https://doi.org/10.3892/etm.2017.5034
Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM (1988) Haemophilus influenza lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest 82(4):1339–1346. https://doi.org/10.1172/JCI113736
Wu J, Zhang M, Hao S, Jia M, Ji M, Qui L, Sun X, Yang J, Li K (2015) Mitochondria-targeted peptide reverses mitochondrial dysfunction and cognitive deficits in sepsis-associated encephalopathy. Mol Neurobiol 52(1):783–791. https://doi.org/10.1007/s12035-014-8918-z
Yamanaka D, Kawano T, Nishigaki A, Aoyama B, Tateiwa H, Shigematsu-Locatelli M, Locatelli FM, Yokoyama M (2017) Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats. J Anesth 31(1):25–35. https://doi.org/10.1007/s00540-016-2264-4
Zhen H, Zhao L, Ling Z, Kuo L, Xue X, Feng J (2017) Wip1 regulates blood-brain barrier function and neuroinflammation induced by lipopolysaccharide via the sonic hedgehog signaling signaling pathway. Mol Immunol 93:31–37
Zhou T, Zhao L, Zhan R, He Q, Tong Y, Tian X, Wang H, Zhang T, Fu Y, Sun Y, Xu F, Guo X, Fan D, Han H, Chui D (2014) Blood-brain barrier dysfunction in mice induced by lipopolysaccharide is attenuated by dapsone. Biochem Biophys Res Commun 453(3):419–424. https://doi.org/10.1016/j.bbrc.2014.09.093
Ziaja M (2013) Septic encephalopathy. Curr Neurol Neurosci Rep 13(10):383. https://doi.org/10.1007/s11910-013-0383-y
Funding
Grant funding was provided by the National Institutes of Health (NIH) grant R01 NS092458.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Towner, R.A., Saunders, D., Smith, N. et al. Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model. GeroScience 40, 49–60 (2018). https://doi.org/10.1007/s11357-018-0009-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-018-0009-z