Ruscogenin timing administration mitigates cerebral ischemia-reperfusion injury through regulating circadian genes and activating Nrf2 pathway

Sanli Zhang; Yan Yu; Mingyue Sheng; Xun Chen; Qi Wu; Junping Kou; Gangling Chen

doi:10.1016/j.phymed.2023.155028

Ruscogenin timing administration mitigates cerebral ischemia-reperfusion injury through regulating circadian genes and activating Nrf2 pathway

Phytomedicine. 2023 Nov:120:155028. doi: 10.1016/j.phymed.2023.155028. Epub 2023 Aug 20.

Authors

Sanli Zhang¹, Yan Yu¹, Mingyue Sheng¹, Xun Chen¹, Qi Wu², Junping Kou³, Gangling Chen⁴

Affiliations

¹ Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, 639 Longmian Road, Nanjing, Jiangsu 211198, China.
² State Key Laboratory of Natural Medicines, Research Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing , Jiangsu 211198, China. Electronic address: christina_576636@126.com.
³ Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, 639 Longmian Road, Nanjing, Jiangsu 211198, China. Electronic address: junpingkou@cpu.edu.cn.
⁴ Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, Jiangsu 211198, China; State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, 639 Longmian Road, Nanjing, Jiangsu 211198, China. Electronic address: chengangling@cpu.edu.cn.

PMID: 37659295
DOI: 10.1016/j.phymed.2023.155028

Abstract

Background: Ruscogenin (Rus), a steroidal sapogenin extracted from Ophiopogon japonicus (L. f.) Ker-Gawl., has the effect of alleviating cerebral ischemia-reperfusion injury (IRI), acute lung injury. At present, the chronopharmacological effects of Rus are still unknown.

Purpose: This study explored the alleviating effect and mechanism of Rus timing administration on mice cerebral IRI.

Methods: The animals in different groups were administrated Rus (10 mg/kg) by gavage at four time points (23:00-01:00, 05:00-07:00, 11:00-13:00, 17:00-19:00) respectively for 3 days. On the 4th day, middle cerebral artery occlusion (MCAO) surgery was operated during 5:00-7:00. Behavioral tests were executed and the brain was collected for infarct volume, qPCR and immunoblot detection. The levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin-1beta (IL-1β) and inducible nitric oxide synthase (iNOS) were detected by qPCR. Glutathione (GSH), superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in serum and cerebral cortex were detected. The clock genes were tested by western blot. Based on these results, 17:00-19:00 was selected to administrate Rus for further mechanism study and Nrf2 blocker group was administrated all-trans-retinoic acid (ATRA) at 14:00 for 3 days.

Results: Administration of Rus reduced cerebral infarcted volume, ameliorated the behavior score and upregulated the mRNA and protein expression of Per1, Bmal1, Clock, Rev-erbα, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), quinone oxidoreductase 1 (NQO1). Administration of Rus during 17:00-19:00 had better preventive effect than other three time points. Combined administration of ATRA blunted the preventive effect of Rus.

Conclusion: The preventive effect of Rus is affected by the time of administration, which was regulated by Nrf2 pathway. Taken together, we provide solid evidence to suggest that different administration time point affect the effectiveness of Rus in alleviating IRI.

Keywords: Cerebral ischemia; Circadian gene; Oxidative stress; Ruscogenin; Timing administration.

MeSH terms

Acute Lung Injury*
Animals
Blotting, Western
Glutathione
Mice
NF-E2-Related Factor 2* / genetics
Tumor Necrosis Factor-alpha

Substances

ruscogenin
NF-E2-Related Factor 2
Tumor Necrosis Factor-alpha
Glutathione