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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 volume 41, pages 483–494 (2019)Cite this article

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.

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Funding

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

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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

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  1. Rheal A. Towner
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  2. Debra Saunders
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  3. Nataliya Smith
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  4. Rafal Gulej
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  6. Brandy Lawrence
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  7. Kathryn A. Morton
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Correspondence to Rheal A. Towner.

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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.

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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

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Keywords

  • Neuroinflammation
  • Encephalopathy
  • Contrast-enhanced magnetic resonance imaging (CE-MRI)
  • Perfusion imaging
  • MR spectroscopy
  • Free radical–targeted imaging
  • OKN-007