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PEGylated rhFGF-2 Conveys Long-term Neuroprotection and Improves Neuronal Function in a Rat Model of Parkinson’s Disease

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Abstract

Fibroblast growth factor 2 (FGF-2) has a neurotrophic effect on dopaminergic neurons in vitro and in vivo, and exhibits beneficial effects in animal models of neurodegenerative disorders such as Parkinson’s disease (PD). The poor stability and short half-life of FGF-2, however, have hampered its clinical use for neurological diseases. In the present study, we modified native recombinant human FGF-2 (rhFGF-2) by covalently attaching polyethylene glycol (PEG) polymers, named PEGylation, to enhance its neuroprotection efficacy in 6-hydroxydopamine (6-OHDA)-induced model of PD. In vitro, PEG-rhFGF-2 performed better biostability in 6-OHDA-induced PC-12 cells than native rhFGF-2. The in vivo data showed that, compared with native rhFGF-2, PEGylated rhFGF-2 was more efficacious in preventing 6-OHDA-induced lesion upon tyrosine hydroxylase-positive neurons in the substantia nigra (SN), improving the apomorphine-induced rotational behavior and the 6-OHDA-induced decline in tissue concentration of dopamine (DA) and its metabolites. Importantly, our data showed that the superior pharmacological activity of PEGylated rhFGF-2 is probably due to its greater permeability through the blood–brain barrier and better in vivo stability compared to native rhFGF-2. The enhanced stability and bioavailability of PEGylated rhFGF-2 make this molecule a great therapeutic candidate for neurodegenerative diseases such as PD and mood disorders.

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Acknowledgments

The authors are thankful to Dr. Regina Goetz and Moosa Mohammadi for critically reading the manuscript and making thoughtful suggestions. This work was supported, in part, by grants from Natural Science Foundation of China, 81102486, 81010012 (to Z.H. and X.L.); Zhejiang Key Group Project in Scientific Innovation 2010R10042-01 (to Z.H.); Ningbo Natural Science Foundation (2013A610272 to C.Y.).

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Authors and Affiliations

  1. The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325035, China

    Guanghui Zhu

  2. School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, China

    Guanghui Zhu, Lu Shi, Yan Wang, Jianlou Niu & Zhifeng Huang

  3. Department of Neuroscience, Jinhua Renmin Hospital, Jinhua, 321000, China

    Ganping Chen

  4. University of Louisville School of Medicine, Louisville, KY, 40202, USA

    Jenny Feng & Wenke Feng

  5. Department of Pharmacy, Ningbo Women & Children’s Hospital, Ningbo, 315012, China

    Chaohui Ye

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  1. Guanghui Zhu
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  5. Yan Wang
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Correspondence to Jianlou Niu or Zhifeng Huang.

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Guanghui Zhu, Ganping Chen, Lu Shi, and Jenny Feng contributed equally to this work.

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Zhu, G., Chen, G., Shi, L. et al. PEGylated rhFGF-2 Conveys Long-term Neuroprotection and Improves Neuronal Function in a Rat Model of Parkinson’s Disease. Mol Neurobiol 51, 32–42 (2015). https://doi.org/10.1007/s12035-014-8750-5

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  • DOI: https://doi.org/10.1007/s12035-014-8750-5

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