Recovery of post-stroke cognitive and motor deficiencies by Shuxuening injection via regulating hippocampal BDNF-mediated Neurotrophin/Trk Signaling

• Published in: Biomedicine & pharmacotherapy Vol. 141; p. 111828
• Main Authors: Li, Zhixiong, Wang, Huanyi, Xiao, Guangxu, Du, Hongxia, He, Shuang, Feng, Yuxin, Zhang, Boli, Zhu, Yan
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-09-2021; Elsevier
• Subjects: Animals; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - drug effects; Cell Line; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognitive dysfunction; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - therapeutic use; Gene Expression Regulation - drug effects; Hippocampus - metabolism; Ischemic stroke; Male; Mice; Mice, Inbred C57BL; Movement Disorders - drug therapy; Movement Disorders - etiology; Nerve Growth Factors - drug effects; Neurotrophin/Trk Signaling; Psychomotor Performance - drug effects; Receptor, trkA - drug effects; Recovery of Function; Shuxuening injection; Signal Transduction - drug effects; Stroke - complications; Stroke - psychology; Stroke Rehabilitation - methods; Transcriptome; CIRI; TTC; Mek3; SXNI; rBCF; PPI; CNS; GBE; WB; Ischemic stroke; Creb; DEGs; mNSS; OGD/R; FBS; RT-PCR; IF; p-Erk; Cognitive dysfunction; MCAO; Shuxuening injection; MWM; AD; BDNF; H&E; Neurotrophin/Trk Signaling; GFAP; Ngfr p75; PA; TrkB; Brain-derived neurotrophic factor; PD; IPA; HD; ELISA; TCM
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111828

A mild ischemic stroke may cause both debilitating locomotor and cognitive decline, for which the mechanism is not fully understood, and no therapies are currently available. In this study, a nonfatal stroke model was constructed in mice by a modified middle cerebral artery occlusion (MCAO) procedure, allowing an extended recovery period up to 28 days. The extended MCAO model successfully mimicked phenotypes of a recovery phase post-stroke, including locomotor motor and cognitive deficiencies, which were effectively improved after Shuxuening injection (SXNI) treatment. Tissue slices staining showed that SXNI repaired brain injury and reduced neuronal apoptosis, especially in the hippocampus CA3 region. Transcriptomics sequencing study revealed 565 differentially expressed genes (DEGs) in the ischemic brain after SXNI treatment. Integrated network pharmacological analysis identified Neurotrophin/Trk Signaling was the most relevant pathway, which involves 15 key genes. Related DEGs were further validated by RT-PCR. Western-blot analysis showed that SXNI reversed the abnormal expression of BDNF, TrkB, Mek3 and Jnk1after stroke. ELISA found that SXNI increased brain level of p-Erk and Creb. At sub-brain level, the expression of BDNF and TrkB was decreased and GFAP was increased on the hippocampal CA3 region in the post-stroke recovery phase and this abnormality was improved by SXNI. In vitro experiments also found that oxygen glucose deprivation reduced the expression of BDNF and TrkB, which was reversed by SXNI. In summary, we conclude that SXNI facilitates the recovery of cognitive and locomotor dysfunction by modulating Neurotrophin/Trk Signaling in a mouse model for the recovery phase of post-ischemic stroke.
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