Abstract
Ergothioneine (ET) is a naturally occurring antioxidant and cytoprotective agent that is synthesized by fungi and certain bacteria. Recent studies have shown a beneficial effect of ET on neurological functions, including cognition and animal models of depression. The aim of this study is to elucidate a possible effect of ET in rodent models of stroke. Post-ischemic intracerebroventricular (i.c.v.) infusion of ET significantly reduced brain infarct volume by as early as 1 day after infusion in rats, as shown by triphenyltetrazolium chloride (TTC) assay. There was a dose-dependent increase in protection, from 50 to 200 ng of ET infusion. These results suggest that ET could have a protective effect on CNS neurons. We next elucidated the effect of systemic ET on brain infarct volume in mice after stroke. Daily i.p. injection of 35 mg/kg ET (the first dose being administered 3 h after stroke) had no significant effect on infarct volume. However, daily i.p. injections of 70 mg/kg, 100 mg/kg, 125 mg/kg and 150 mg/kg ET, with the first dose administered 3 h after stroke, significantly decreased infarct volume at 7 days after vessel occlusion in mice. In order to elucidate at what time interval during the 7 days there could be effective protection, a second set of experiments was carried out in mice, using one of the effective loading protocols, i.e. 125 mg/kg i.p. ET but the brains were analyzed at 1, 4 and 7 days post-stroke by MRI. We found that ET was already protective against neuronal injury and decreased the size of the brain infarct from as early as 1 day post-stroke. Behavioral experiments carried out on a third set of mice (using 125 mg/kg i.p. ET) showed that this was accompanied by significant improvements in certain behaviors (pole test) at 1 day after stroke. Together, results of this study indicate that i.c.v. and systemic ET are effective in reducing brain infarct volume after stroke in rodent models.
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Acknowledgements
The authors wish to thank Tetrahedron (Paris, France) for provision of the l-ergothioneine used in these studies. This work was supported by grants from the Ministry of Education, Singapore (R-181-000-183-114, WYO), HCLA (Catalyst Grant, HLCA21Jan-0019, WYO); and grants from the Ministry of Science and Technology (MoST) and Academia Sinica, Taiwan (TNL). We thank the Animal Image Facility (AIF), Academia Sinica and Taiwan Animal Consortium for the technical support in MRI analysis. We thank Professor Barry Halliwell, Department of Biochemistry, National University of Singapore for valuable discussion and suggestions on the manuscript.
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WYO, DMKL, IKMC and TNL wrote and edited the main manuscript text. MHK and WMC prepared figures. All authors reviewed the manuscript.
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Ong, WY., Kao, MH., Cheung, WM. et al. Protective Effect of Ergothioneine Against Stroke in Rodent Models. Neuromol Med 25, 205–216 (2023). https://doi.org/10.1007/s12017-022-08727-w
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DOI: https://doi.org/10.1007/s12017-022-08727-w