Skip to main content
SpringerLink
Log in

Anti-inflammatory agent, OKN-007, reverses long-term neuroinflammatory responses in a rat encephalopathy model as assessed by multi-parametric MRI: implications for aging-associated neuroinflammation

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Lipopolysaccharide (LPS)–induced encephalopathy induces neuroinflammation. Long-term neuroinflammation is associated with aging and subsequent cognitive impairment (CI). We treated rats that had LPS-induced neuroinflammation with OKN-007, with an anti-inflammatory agent currently considered an anti-cancer investigational new drug in clinical trials for glioblastoma (GBM). Contrast-enhanced magnetic resonance imaging (MRI) (CE-MRI), perfusion MRI, and MR spectroscopy were used as methods to assess long-term (up to 6 weeks post-LPS) alterations in blood-brain barrier (BBB) permeability, microvascularity, and metabolism, respectively, and the therapeutic effect of OKN-007. A free radical–targeted molecular MRI approach was also used to detect the effect of OKN-007 on brain free radical levels at 24 h and 1 week post-LPS injection. OKN-007 was able to reduce BBB permeability in the cerebral cortex and hippocampus at 1 week post-LPS using CE-MRI. OKN-007 was able to restore vascular perfusion rates by reducing LPS-induced increased relative cerebral blood flow (rCBF) in the cortex and hippocampus regions at all time points studied (1, 3, and 6 weeks post-LPS). OKN-007 was also able to restore LPS-induced brain metabolite depletions. NAA/Cho, Cr/Cho, and Myo-Ins/Cho metabolite ratios at 1, 3, and 6 weeks post-LPS were all restored to normal levels following OKN-007 treatment. OKN-007 also reduced LPS-induced free radical levels at 24 h and 1 week post-LPS, as detected by free radical–targeted MRI. LPS-exposed rats were compared with saline-treated controls and LPS + OKN-007-treated animals. We clearly demonstrated that OKN-007 restores LPS-induced BBB dysfunction, impaired vascularity, and decreased brain metabolites, all long-term neuroinflammatory indicators, as well as decreases free radicals in a LPS-induced neuroinflammation model. OKN-007 should be considered an anti-inflammatory agent for age-associated neuroinflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Banks WA, Erickson MA (2010) The blood-brain barrier and immune function and dysfunction. Neurobiol Dis 37:26–32

    Article  CAS  PubMed  Google Scholar 

  • Berg RM, Moller K, Bailey DM (2011) Neuro-oxidative-nitrosative stress in sepsis. J Cereb Blood Flow Metab 31:1532–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bettio LEB, Rajendran L, Gil-Mohapel J (2017) The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev 79:66–86

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Carvalho C, Moreira PI (2018) Oxidative stress: a major player in cerebrovascular alterations associated to neurodegenerative events. Front Physiol 9:806

    Article  PubMed  PubMed Central  Google Scholar 

  • Clausen F, Marklund N, Lewen A, Hillered L (2008) The nitrone free radical scavenger NXY-059 is neuroprotective when administered after traumatic brain injury in the rat. J Neurotrauma 25:1449–1457

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Culot M, Mysiorek C, Renftel M, Roussel BD, Hommet Y, Vivien D, Cecchelli R, Fenart L, Berezowski V, Dehouck MP, Lundquist S (2009) Cerebrovascular protection as a possible mechanism for the protective effects of NXY-059 in preclinical models: an in vitro study. Brain Res 1294:144–152

    Article  CAS  PubMed  Google Scholar 

  • 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 7:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Edenius C, Strid S, Borga O, Breitholtz-Emanuelsson A, Vallen KL, Fransson B (2002) Pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent, in healthy young and elderly subjects. J Stroke Cerebrovasc Dis 11:34–43

    Article  PubMed  Google Scholar 

  • Erdő F, Denes L, de Lange E (2017) Age-associated physiological and pathological changes at the blood-brain barrier: a review. J Cereb Blood Flow Metab 37:4–24

    Article  PubMed  Google Scholar 

  • Floyd RA, Kopke RD, Choi CH, Foster SB, Doblas S, Towner RA (2008) Nitrones as therapeutics. Free Radic Biol Med 45(10):1361–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Floyd RA, Chandru HK, He T, Towner R (2011) Anti-cancer activity of nitrones and observations on mechanism of action. Anti Cancer Agents Med Chem 11(4):373–379

    Article  CAS  Google Scholar 

  • Floyd RA, Castro Faria Neto HC, Zimmerman GA, Hensley K, Towner RA (2013) Nitrone-based therapeutics for neurodegenerative diseases. Their use alone or in combination with lanthionines. Free Radic Biol Med 62:145–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 46:853–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Hernández-Zimbrón LF, Perez-Hernández M, Torres-Romero A, Gorostieta-Salas E, Gonzalez-Salinas R, Gulias-Cañizo R, Quiroz-Mercado H, Zenteno E (2017) Markers of Alzheimer’s disease in primary visual cortex in normal aging in mice. Biomed Res Int 2017(3706018):1–10

    Article  CAS  Google Scholar 

  • Jacobs KR, Lim CK, Blennow K, Zetterberg H, Chatterjee P, Martins RN, Brew BJ, Guillemin GJ, Lovejoy DB (2019) Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer’s disease and relationship to amyloid-β and tau. Neurobiol Aging 80:11–20

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Kirk RA, Kesner RP, Wang L-M, Wu Q, Towner RA, Hoffman JM, Morton KA (2019) Lipopolysaccharide exposure in a rat sepsis model results in hippocampal amyloid-β plaque and phosphorylated tau deposition and corresponding behavioral deficits. GeroScience. (in press)

  • Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK (1999) Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 19:778–787

    Article  CAS  PubMed  Google Scholar 

  • Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM, Diener HC, Grotta JC, Ashwood TJ, Hardemark HG, Svensson HH, Rodichok L, Wasiewski WW, Ahlberg G (2007) Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT trial. Stroke 38:2262–2269

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Maghsudi H, Schütze M, Maudsley AA, Daak M, Lanfermann H, Ding XQ (2019) Age-related brain metabolic changes up to the seventh decade in healthy humans: whole-brain magnetic resonance spectroscopic imaging study. Clin Neuroradiol. https://doi.org/10.1007/s00062-019-00814.z

  • 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 36:1214–1223

    Article  CAS  PubMed  Google Scholar 

  • Mason RP (2016) Imaging free radicals in organelles, cells, tissue, and in vivo with immuno-spin trapping. Redox Biol 8:422–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Poon HF, Calabrese V, Scapagnini G, Butterfield DA (2004) Free radicals and brain aging. Clin Geriatr Med 20:329–359

    Article  PubMed  Google Scholar 

  • Ramirez DC, Mason RP (2005) Immuno-spin trapping: detection of protein-centered radicals. Curr Protoc Toxicol 17:17

    Google Scholar 

  • 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 5:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shipp S (2007) Structure and function of the cerebral cortex. Curr Biol 17(12):R443–R449

    Article  CAS  PubMed  Google Scholar 

  • Sumbria RK, Grigoryan MM, Vasilevko V, Paganini-Hill A, Kilday K, Kim R, Cribbs DH, Fisher MJ (2018) Aging exacerbates development of cerebral microbleeds in a mouse model. J Neuroinflammation 15:69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • 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 12:165

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taccone FS, Scolletta S, Franchi F, Donadello K, Oddo M (2013) Brain perfusion in sepsis. Curr Vasc Pharmacol 11(2):170–186

    CAS  PubMed  Google Scholar 

  • Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A (2017) Impaired neurovascular coupling in aging and Alzheimer’s disease: contribution of astrocyte dysfunction and endothelial impairment to cognitive decline. Exp Gerontol 94:52–58

    Article  CAS  PubMed  Google Scholar 

  • Timmers M, Tesseur I, Bogert J, Zetterberg H, Blennow K, Börjesson-Hanson A, Baquero M, Boada M, Randolph C, Tritsmans L, Van Nueten L, Engelborghs S, Streffer JR (2019) Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer’s disease. Neurobiol Aging 79:131–141

    Article  PubMed  Google Scholar 

  • Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment 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

    Article  PubMed  Google Scholar 

  • 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 28(15):1404–1415

    Article  PubMed  CAS  Google Scholar 

  • 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 61:2405–2413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 Radica Biol Med 65:828–837

    Article  CAS  Google Scholar 

  • 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 1832:2153–2161

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 49:1140–1146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Towner RA, Saunders D, Smith N, Towler W, Cruz M, Do S, Maher JE, Whitaker K, Lerner M, Morton KA (2018) Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model. GeroScience 40(1):49–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Towner RA, Smith N, Saunders D, Brown CA, Cai X, Ziegler J, Mallory S, Dozmorov MG, Coutinho De Souza P, Wiley G, Kim K, Kang S, Kong DS, Kim YT, Fung KM, Wren JD, Battiste J (2019) OKN-007 increases temozolomide (TMZ) sensitivity and suppresses TMZ-resistant glioblastoma (GBM) tumor growth. Transl Oncol 12(2):320–335

    Article  PubMed  Google Scholar 

  • Tsukamoto H, Takeuchi S, Kubota K, Kobayashi Y, Kozakai S, Ukai I, Shichiku A, Okubo M, Numasaki M, Kanemitsu Y, Matsumoto Y, Nochi T, Watanabe K, Aso H, Tomioka Y (2018) Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent toll-like receptor 4 internalization and LPS-induced TBK1-IKKϵ-IRF3 axis activation. J Biol Chem 293(26):10186–10201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Wang LM, Wu Q, Kirk RA, Horn KP, Ebada Salem AH, Hoffman JM, Yap JT, Sonnen JA, Towner RA, Bozza FA, Rodrigues RS, Morton KA (2018) Lipopolysaccharide endotoxemia induces amyloid-β and p-tau formation in the rat brain. Am J Nucl Med Mol Imaging 8(2):86–99

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wemer J, Cheng YF, Nilsson D, Reinholdsson I, Fransson B, Vallen KL, Nyman L, Eriksson C, Bjorck S, Schulman S (2006) Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects. Curr Med Res Opin 22:1813–1823

    Article  CAS  PubMed  Google Scholar 

  • 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 82:1339–1346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 Anesh 31:25–35

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Grant funding was provided by National Institutes of Health (NIH) grants R01 NS092458 and S10OD023508.

Author information

Authors and Affiliations

  1. Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK, 73104, USA

    Rheal A. Towner, Debra Saunders, Nataliya Smith, Rafal Gulej, Tyler McKenzie & Brandy Lawrence

  2. Oklahoma Nathan Shock Aging Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Rheal A. Towner

  3. Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Rheal A. Towner

  4. Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA

    Brandy Lawrence

  5. Department of Radiology and Imaging Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA

    Kathryn A. Morton

Authors
  1. Rheal A. Towner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Debra Saunders
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nataliya Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rafal Gulej
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tyler McKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brandy Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kathryn A. Morton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rheal A. Towner.

Ethics declarations

Animal experiments were performed with the approval and strict adherence to the policies of the Oklahoma Medical Research Foundation Institutional Animal Care and Use Committee, which specifically approved this study, with adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Towner, R.A., Saunders, D., Smith, N. et al. Anti-inflammatory agent, OKN-007, reverses long-term neuroinflammatory responses in a rat encephalopathy model as assessed by multi-parametric MRI: implications for aging-associated neuroinflammation. GeroScience 41, 483–494 (2019). https://doi.org/10.1007/s11357-019-00094-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-019-00094-y

Keywords

Search

Navigation