Hydroxysafflor Yellow A and Tenuigenin Exhibit Neuroprotection Effects Against Focal Cerebral Ischemia Via Differential Regulation of JAK2/STAT3 and SOCS3 Signaling Interaction

Lu Yu; Cheng Zhang; Lingling Gu; Hong Chen; Yan Huo; Shuyan Wang; Jie Tao; Chuan Xu; Qiujuan Zhang; Mingliang Ma; Jun Zhang

doi:10.1007/s12035-023-03896-6

Hydroxysafflor Yellow A and Tenuigenin Exhibit Neuroprotection Effects Against Focal Cerebral Ischemia Via Differential Regulation of JAK2/STAT3 and SOCS3 Signaling Interaction

Mol Neurobiol. 2024 Jan 12. doi: 10.1007/s12035-023-03896-6. Online ahead of print.

Authors

Lu Yu^#¹, Cheng Zhang^#², Lingling Gu^#², Hong Chen³, Yan Huo⁴, Shuyan Wang⁵, Jie Tao¹, Chuan Xu⁶, Qiujuan Zhang⁷, Mingliang Ma^{8

9}, Jun Zhang¹⁰

Affiliations

¹ Comprehensive Department of Traditional Chinese Medicine, Department of Neurology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
² Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China.
³ Department of Clinical Laboratory, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
⁴ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
⁵ Department of Anesthesiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
⁶ Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
⁷ Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China. qiujuanzhang0000@hotmail.com.
⁸ Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China. mlma@brain.ecnu.edu.cn.
⁹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. mlma@brain.ecnu.edu.cn.
¹⁰ Department of Clinical Laboratory, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. zhangjun@51mch.com.

^# Contributed equally.

PMID: 38214838
DOI: 10.1007/s12035-023-03896-6

Abstract

Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke.

Keywords: Cerebral ischemia; Combination; Differential regulatory mechanisms; Hydroxysafflor yellow A; Synergistic effect; Tenuigenin.

Abstract

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