A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats.

Elina Rubin,Agnese C Pippione,Stefano Sainas,Carlo Cifani,Abed N Azab,Marco L Lolli,Matthew Boyko,Massimo Collino,Jacob Kaplanski,Donatella Boschi,Naim Abu-Freha,Giacomo Einaudi

doi:10.3390/brainsci12010035

Elina Rubin, Agnese C Pippione + Show 10 more

Open Access

https://doi.org/10.3390/brainsci12010035

Copy DOI

Abstract

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

Highlights

A large body of data indicates that activation of nuclear factor (NF)-κB contributes to the pathophysiology of ischemic stroke and, inhibition of NF-κB has been suggested as a potential therapeutic strategy against post-stroke brain inflammation [32,33,34]
The difference between vehicle-treated and MEDS-23-treated middle cerebral artery occlusion (MCAO)-operated rats was not significant (p = 0.6). These findings indicate that early administration of a NF-κB inhibitor and its subsequent continuation is capable of mitigating the severity of neurological deficits in post-stroke rats
This study demonstrated that chronic treatment with the potent NF-κB inhibitor

Summary

Introduction

Stroke is the second leading cause of death worldwide, causing 5.5 million deaths in. More than half of stroke survivors are left with a disability and a third are dependent on others for the tasks of daily living [1]. Ischemic stroke is the most prevalent type of stroke among adults and accounts for more than 80% of all stroke cases [2]. The primary underlying cause of ischemic stroke is cerebral infarction (for example, due to embolism or atherosclerotic stenosis) [3]. Hypoxia and hypoglycemia start the ischemic cascade that leads to acute cell death (necrosis) and delayed programmed cell death (apoptosis). Despite the use of acute therapeutic interventions aimed at rapid reperfusion of tissue surrounding the ischemic core, various types of deficits originating from stroke necessitate long-term rehabilitation processes [3,4,5]

Objectives

Methods

Results

Conclusion