CXCR4 antagonist AMD3100 reverses the neurogenesis and behavioral recovery promoted by forced limb-use in stroke rats

Article type: Research Article

Authors: Zhao, Shanshan^a | Qu, Huiling^a | Zhao, Yi^b | Xiao, Ting^{c; d} | Zhao, Mei^e | Li, Yong^f | Jolkkonen, Jukka^g | Cao, Yunpeng^{a; *} | Zhao, Chuansheng^{a; *}

Affiliations: [a] Department of Neurology, The First Hospital of China Medical University, Shenyang, China | [b] Department of Obstetrics, The First Hospital of China Medical University, Shenyang, China | [c] Department of Dermatology, The First Hospital of China Medical University, Shenyang, China | [d] Key Laboratory of Immunodermatology, Ministry of Health, Ministry of Education, Shenyang, China | [e] Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, China | [f] Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China | [g] Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland

Correspondence: [*] Corresponding author: Yunpeng Cao, No.155, North Nanjing Street, Heping District, Shenyang 110001, Liaoning, PR China. Tel.: +86 24 83283026; Fax: +86 24 83282315; E-mail: [email protected]

Correspondence: [*] Corresponding author: Chuansheng Zhao, No.155, North Nanjing Street, Heping District, Shenyang 110001, Liaoning, PR China. Tel.: +86 24 83283026; Fax: +86 24 83282315; E-mail: [email protected]

Abstract: Purpose:Forced limb-use can enhance neurogenesis and behavioral recovery as well as increasing the level of stromal cell-derived factor-1 (SDF-1) in stroke rats. We examined whether the SDF-1/CXCR4 pathway is involved in the enhanced neurogenesis and promoted behavioral recovery induced by forced limb-use in the chronic phase of stroke. Methods:The CXCR4 antagonist, AMD3100, was used to block the SDF-1/CXCR4 pathway in the ischemic rats. Brain ischemia was induced by endothelin-1. One week after ischemia, the unimpaired forelimb of rats was immobilized for 3 weeks. The proliferation, migration, and survival of DCX-positive cells in the subventricular zone (SVZ), and the dendritic complexity of DCX-positive cells in the dentate gyrus (DG), as well as the inflammatory response in the infarcted striatum were analyzed by immunohistochemistry. Functional recovery was assessed in beam-walking and water maze tests. Results:Forced limb-use enhanced the proliferation, migration, dendritic complexity and the survival of newborn neurons. Furthermore, forced limb-use suppressed the inflammatory response and improved both motor and cognitive functions after stroke. AMD3100 significantly abrogated the enhanced neurogenesis and behavioral recovery induced by forced limb-use without influencing the inflammatory response. Conclusions:SDF-1/CXCR4 pathway seems to be involved in the enhancement of neurogenesis and behavioral recovery induced by post-stroke forced limb-use.

Keywords: Forced limb-use, neurogenesis, stroke, stromal cell-derived factor-1, functional recovery

DOI: 10.3233/RNN-150515

Journal: Restorative Neurology and Neuroscience, vol. 33, no. 6, pp. 809-821, 2015