1. Academic Validation
  2. Restoration of early deficiency of axonal guidance signaling by guanxinning injection as a novel therapeutic option for acute ischemic stroke

Restoration of early deficiency of axonal guidance signaling by guanxinning injection as a novel therapeutic option for acute ischemic stroke

  • Pharmacol Res. 2021 Mar;165:105460. doi: 10.1016/j.phrs.2021.105460.
Guangxu Xiao 1 Ming Lyu 2 Zhixiong Li 1 Linghua Cao 1 Xinyan Liu 1 Yule Wang 1 Shuang He 1 Zihao Chen 1 Hongxia Du 1 Yuxin Feng 1 Jigang Wang 3 Yan Zhu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin, 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, 220 Dongting Road, TEDA, Tianjin, 300457, China.
  • 2 State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin, 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, 220 Dongting Road, TEDA, Tianjin, 300457, China; Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
  • 3 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
  • 4 State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Beihua South Road, JingHai District, Tianjin, 301617, China; Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, 220 Dongting Road, TEDA, Tianjin, 300457, China. Electronic address: yanzhu.harvard@icloud.com.
Abstract

Despite of its high morbidity and mortality, there is still a lack of effective treatment for ischemic stroke in part due to our incomplete understanding of molecular mechanisms of its pathogenesis. In this study, we demonstrate that SHH-PTCH1-GLI1-mediated axonal guidance signaling and its related neurogenesis, a central pathway for neuronal development, also plays a critical role in early stage of an acute stroke model. Specifically, in vivo, we evaluated the effect of GXNI on ischemic stroke mice via using the middle cerebral artery embolization model, and found that GXNI significantly alleviated cerebral ischemic reperfusion (I/R) injury by reducing the volume of cerebral infarction, neurological deficit score and cerebral edema, reversing the BBB permeability and histopathological changes. A combined approach of RNA-seq and network pharmacology analysis was used to reveal the underlying mechanisms of GXNI followed by RT-PCR, immunohistochemistry and western blotting validation. It was pointed out that axon guidance signaling pathway played the most prominent role in GXNI action with Shh, Ptch1, and Gli1 genes as the critical contributors in brain protection. In addition, GXNI markedly prevented primary cortical neuron cells from oxygen-glucose deprivation/reoxygenation damage in vitro, and promoted axon growth and synaptogenesis of damaged neurons, which further confirmed the results of in vivo experiments. Moreover, due to the inhibition of the SHH-PTCH1-GLI1 signaling pathway by cyclopropylamine, the effect of GXNI was significantly weakened. Hence, our study provides a novel option for the clinical treatment of acute ischemic stroke by GXNI via SHH-PTCH1-GLI1-mediated axonal guidance signaling, a neuronal development pathway previously considered for after-stroke recovery.

Keywords

Acute ischemic stroke; Axonal guidance signaling; Cerebral ischemia-reperfusion injury; Guanxinning injection; Neuroprotection; Oxygen-glucose deprivation/reoxygenation.

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