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Tilorone, an oral antiviral agent utilized in humans, preconditions against transient ischemia in mice

PUBLICATION: 
Journal Article
Authors: 
Yujia Zhai, Yingxin Chen, Saravanan S. Karuppagounder, Amit Kumar, Nandini Kundu, Ishraq Alim, Stephanie Taylor, Craig E. Brown, Xiang Luo, Yi-Fang Li, Dawei Lian, Yang Chen, Hilda Ahnstedt, Louise D. McCullough, Rong-Rong He, Rajiv R. Ratan
Year Published: 
2020
Publisher: 
Conditioning Medicine 2020. 3(1): 1-8.
Full-Text on Conditioning Medicine

Abstract

An antiviral drug, Tilorone, which is currently used in humans in Europe and Russia, was recently examined as a preconditioning treatment for stroke by Ratan Lab of the Burke Neurological Institute in collaboration with researchers at Jinan University, University of Victoria, Guangzhou University of Chinese Medicine, and McGovern Medical School. It has been shown to inhibit Ebola-induced death in mice. Among antivirals being tested, it’s safe and ethical re-evaluation for COVID-19 should be considered. Burke Neurological Institute would be happy to share expertise with the drug in animals for anyone who might be interested in moving this forward in a rigorous way. 

Tilorone, an antiviral immunomodulator currently used in humans, was previously identified in a cell based screen for activators of hypoxia-inducible factor transcriptional activity. It reduced infarct size by 80% in a rat model of permanent stroke when delivered 24 hours prior to ischemia. Despite these robust preconditioning effects, its efficacy against stroke in mice are unclear and accordingly the use of transgenics to probe its mechanism of action have not been undertaken. Systemic (intraperitoneal; IP) delivery of tilorone (100 mg/kg) reduced infarct size by nearly 70% in a murine model of transient focal ischemia. This protective dose induced alterations in interferon (IFN)-associated mRNAs in the brain and peripheral organs. Forced expression of one of these genes, IFN-induced protein with tetratricopeptide repeats 1 (Ifit1), prevented oxygen-glucose deprivation induced death in hippocampal neuroblasts. In contrast to prior studies, tilorone significantly reduced hypoxia-associated mRNAs including vascular endothelial growth factor (VEGF). Additionally, tilorone was neither effective when delivered intracerebroventricularly, nor did it protect against permanent focal ischemia. Together, these studies suggest that tilorone is a clinically-used inducer of the IFN antiviral response that can precondition mice from deleterious effects of transient ischemic stroke via effects that require a non-CNS site of action. Future studies can now leverage transgenic mice to examine a model where tilorone, a known intercalator, stabilizes DNA to trigger activation of cytosolic DNA sensing and antiviral, homeostatic transcription leading to reduced metabolic demand prior to stroke and subsequent neuroprotection.

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