Format

Send to

Choose Destination
Geroscience. 2019 Sep 2. doi: 10.1007/s11357-019-00094-y. [Epub ahead of print]

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.

Author information

1
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK, 73104, USA. Rheal-Towner@omrf.org.
2
Oklahoma Nathan Shock Aging Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Rheal-Towner@omrf.org.
3
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Rheal-Towner@omrf.org.
4
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK, 73104, USA.
5
Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA.
6
Department of Radiology and Imaging Sciences, University of Utah School of Medicine, Salt Lake City, UT, USA.

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.

KEYWORDS:

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

PMID:
31478121
DOI:
10.1007/s11357-019-00094-y

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center