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Gelatin Nanostructured Lipid Carriers Incorporating Nerve Growth Factor Inhibit Endoplasmic Reticulum Stress-Induced Apoptosis and Improve Recovery in Spinal Cord Injury

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Abstract

Clinical translation of growth factor therapies faces multiple challenges; the most significant one is the short half-life of the naked protein. Gelatin nanostructured lipid carriers (GNLs) had previously been used to encapsulate the basic fibroblast growth factor to enhance the functional recovery in hemiparkinsonian rats. In this research, we comparatively study the enhanced therapy between nerve growth factor (NGF) loaded GNLs (NGF-GNLs) and NGF only in spinal cord injury (SCI). The effects of NGF-GNLs and NGF only were tested by the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test, and footprint analysis. Western blot analysis and immunofluorescent staining were further performed to identify the expression of ER stress-related proteins, neuron-specific marker neuronal nuclei (NeuN), and growth-associated protein 43 (GAP43). Correlated downstream signals Akt/GSK-3β and ERK1/2 were also analyzed with or without inhibitors. Results showed that NGF-GNLs, compared to NGF only, enhanced the neuroprotection effect in SCI rats. The ER stress-induced apoptosis response proteins CHOP, GRP78 and caspase-12 inhibited by NGF-GNL treatment were more obvious. Meanwhile, NGF-GNLs in the recovery of SCI are related to the inhibition of ER stress-induced cell death via the activation of downstream signals PI3K/Akt/GSK-3β and ERK1/2.

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Acknowledgments

This work was supported by the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health talents (to J. X), National Natural Science Funding of China (81372112, 81200958, 81302775), Zhejiang Natural Science Funding (Y14H170008), State Key Basic Research Development Program (2012CB518105), Ningbo Natural Science Foundation (2012A610255), and Zhejiang undergraduate talent project (2014R413067).

Conflict of Interest

The authors declare no conflict of interest.

Statement on the Welfare of Animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at Wenzhou Medical University. This article does not contain any studies with human participants performed by any of the authors.

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    Authors and Affiliations

    1. Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

      Si-Pin Zhu & Hua-Zi Xu

    2. Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

      Si-Pin Zhu, Zhou-Guang Wang, Ying-Zheng Zhao, Jiang Wu, Hong-Xue Shi, Li-Bing Ye, Yi Cheng, Hong-Yu Zhang, **ao-Kun Li, Hua-Zi Xu & Jian **ao

    3. Department of Neurosurgery, Cixi People’s Hospital, Wenzhou Medical University, Ningbo, 315300, China

      Fen-Zan Wu & **aojie Wei

    4. Department of Neurology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, 316021, China

      Songbin He

    5. Institute of Basic Medical Science, Chinese PLA General Hospital, Bei**g, 100853, China

      **ao-Bing Fu

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    Si-Pin Zhu, Zhou-Guang Wang and Ying-Zheng Zhao contributed equally to this work.

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    Zhu, SP., Wang, ZG., Zhao, YZ. et al. Gelatin Nanostructured Lipid Carriers Incorporating Nerve Growth Factor Inhibit Endoplasmic Reticulum Stress-Induced Apoptosis and Improve Recovery in Spinal Cord Injury. Mol Neurobiol 53, 4375–4386 (2016). https://doi.org/10.1007/s12035-015-9372-2

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