Thermosensitive heparin-poloxamer hydrogels enhance the effects of GDNF on neuronal circuit remodeling and neuroprotection after spinal cord injury
Ying-Zheng Zhao
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Hainan Medical College, Haikou, Hainan, 570102 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorXi Jiang
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
Zhejiang University Mingzhou Hospital, Zhejiang, 315104 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorQian Lin
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, 40202
These authors contributed equally to this work.
Search for more papers by this authorHe-Lin Xu
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Search for more papers by this authorYa-Dong Huang
Biopharmaceutical R&D Center of Jinan University, Guangzhou, Guangdong, 510000 People's Republic of China
Search for more papers by this authorCorresponding Author
Cui-Tao Lu
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Correspondence to: Cui-Tao Lu; e-mail: [email protected] or Jun Cai; e-mail: [email protected]Search for more papers by this authorCorresponding Author
Jun Cai
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, 40202
Correspondence to: Cui-Tao Lu; e-mail: [email protected] or Jun Cai; e-mail: [email protected]Search for more papers by this authorYing-Zheng Zhao
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Hainan Medical College, Haikou, Hainan, 570102 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorXi Jiang
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
Zhejiang University Mingzhou Hospital, Zhejiang, 315104 People's Republic of China
These authors contributed equally to this work.
Search for more papers by this authorQian Lin
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, 40202
These authors contributed equally to this work.
Search for more papers by this authorHe-Lin Xu
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Search for more papers by this authorYa-Dong Huang
Biopharmaceutical R&D Center of Jinan University, Guangzhou, Guangdong, 510000 People's Republic of China
Search for more papers by this authorCorresponding Author
Cui-Tao Lu
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035 People's Republic of China
Correspondence to: Cui-Tao Lu; e-mail: [email protected] or Jun Cai; e-mail: [email protected]Search for more papers by this authorCorresponding Author
Jun Cai
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000 People's Republic of China
Kosair Children's Hospital Research Institute at the Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky, 40202
Correspondence to: Cui-Tao Lu; e-mail: [email protected] or Jun Cai; e-mail: [email protected]Search for more papers by this authorAbstract
Traumatic spinal cord injury (SCI) results in paraplegia or quadriplegia, and currently, therapeutic interventions for axonal regeneration after SCI are not clinically available. Animal studies have revealed that glial cell-derived neurotrophic factor (GDNF) plays multiple beneficial roles in neuroprotection, glial scarring remodeling, axon regeneration and remyelination in SCI. However, the poor physicochemical stability of GDNF, as well as its limited ability to cross the blood–spinal cord barrier, hampers the development of GDNF as an effective therapeutic intervention in clinical practice. In this study, a novel temperature-sensitive heparin–poloxamer (HP) hydrogel with high GDNF-binding affinity was developed. HP hydrogels showed a supporting scaffold for GDNF when it was injected into the lesion epicenter after SCI. GDNF-HP by orthotopic injection on lesioned spinal cord promoted the beneficial effects of GDNF on neural stem cell proliferation, reactive astrogliosis inhibition, axonal regeneration or plasticity, neuroprotection against cell apoptosis, and body functional recovery. Most interestingly, GDNF demonstrated a bidirectional regulation of autophagy, which inhibited cell apoptosis at different stages of SCI. Furthermore, the HP hydrogel promoted the inhibition of autophagy-induced apoptosis by GDNF in SCI. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2816–2829, 2017.
Supporting Information
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