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

Abstract

Lipopolysaccharide (LPS)-induced encephalopathy induces neuroinflammation. Long-term neuroinflammation is associated with aging and subsequent cognitive impairment (CI). We treated rats that had LPSinduced neuroinflammation with OKN-007, with an anti-inflammatory agent currently considered an anticancer 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 longterm (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 radicaltargeted 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.

Age‐related alterations in the cerebrovasculature affect neurovascular coupling and BOLD fMRI responses: Insights from animal models of aging

“…Additionally, genetic IGF-1 deficiency was shown to impair vascular function Csiszar et al, 2008;, including neurovascular coupling responses in rodent models . A recent (Towner et al, 2018) and (Towner et al, 2019). BOLD fMRI data are unpublished study suggested that systemic circulating IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice (Farias Quipildor et al, 2019).…”

“…Long‐term neuroinflammation is associated with aging and subsequent cognitive impairment (CI). A recent study used parametric MRI approaches to assess cerebrovascular, blood–brain‐barrier (BBB), metabolic and free radical level changes associated with LPS‐augmented neuroinflammation, and found that LPS‐exposed rat brains had decreased relative cerebral blood flow (rCBF), increased BBB disruption, decreased N‐acetyl aspartate (NAA; a neuronal marker), and increased levels of free radicals detected in vivo, compared to saline‐treated controls (Figure 2) (Towner et al., 2018), (Towner et al., 2019). These findings imply that increased neuroinflammation results in cerebrovascular, neuronal metabolic and free radical changes, which are similar to the mechanistic alterations underlying age‐related BOLD fMRI change.…”

“…All data were obtained 6 weeks post‐LPS or saline treatments. Data modified from references (Towner et al., 2018) and (Towner et al., 2019). BOLD fMRI data are unpublished…”

A tale of two multi‐focal therapies for glioblastoma: An antibody targeting ELTD1 and nitrone‐based OKN‐007

“…OKN has been shown to be an anti‐inflammatory agent for age‐associated neuroinflammation in a lipopolysaccharide (LPS)‐induced encephalopathy rat model. 43 Currently, there is little data regarding the relationship between ELTD1 and inflammation, but future studies are needed to investigate this relationship. Further studies are being conducted to determine if Notch1 may be the master regulator of anti‐ELTD1 in GBM.…”

“…to be an anti-inflammatory agent for age-associated neuroinflammation in a lipopolysaccharide (LPS)-induced encephalopathy rat model. 43 Currently, there is little data regarding the relationship be- be the master regulator of ELTD1. For instance, our data have demonstrated that key genes targeted by anti-ELTD1 antibody therapy, such as c-MET, Ki-67, BMP2 and VEGFR2 are all correlated with Notch1.…”