NeuroRx 2(1): 120-128

Neuroprotection in Experimental Stroke with Targeted Neurotrophins

Department of Radiology, Wayne State University School of Medicine, Children's Hospital of Michigan, PET Center, Detroit, Michigan 48201

Address correspondence and reprint requests to Dr. Dafang Wu, M.D., Ph.D., Children's Hospital of Michigan, PET Center, Room GP-112, 3901 Beaubien Boulevard, Detroit, MI 48201. E-mail: ude.enyaw.tep@uwd.

Abstract

Summary: More than 30 neurotrophins have been identified, and many of them have neuroprotective effects in brain ischemia or injury. However, all the clinical trials with several neurotrophins for the treatment of acute ischemic stroke or neurodegenerative diseases have failed so far, primarily because of their poor blood-brain barrier (BBB) permeability. This article is an overview of recent progress in the research focused on BBB targeted neurotrophins using a chimeric peptide approach, in which antitransferrin receptor antibody was used as a BBB delivery vector, and neurotrophin peptide was conjugated to the antibody via the avidin/biotin technology. Vasoactive intestinal peptide was the first model chimeric peptide to show an enhanced CNS effect after noninvasive peripheral administration. Brain-derived neurotrophic factor (BDNF) chimeric peptide was neuroprotective in rats subjected to transient forebrain ischemia, permanent focal ischemia, or transient focal ischemia. Delayed treatments with the BDNF chimeric peptide showed an effective time window of 1–2 h after ischemia. Basic FGF chimeric peptide was highly effective in the reduction of infarct volume in the rat model of permanent focal ischemia, with lowest effective dose of 1 μg per rat. Future studies in this exciting area include genetically engineered fusion proteins or humanized antibodies for BBB drug targeting with less immunogenicity and reduced working burden in the chemical conjugation, the use of antihuman insulin receptor antibody for higher BBB delivery efficiency, and combination therapies using chimeric neurotrophins plus other neuroprotectants to achieve additive or synergistic effects.

Keywords: Blood-brain barrier, neurotrophins, drug targeting, transferrin receptor, ischemic stroke, neuroprotection

Abstract

Acknowledgments

The author is grateful to the guidance and inspiration provided by Dr. William Pardridge, M.D. A Scientist Development Grant to the author from the American Heart Association, Western States Affiliate, supported the bFGF work cited in this article. This work was supported in part by National Institutes of Health Grant NS34698.

Acknowledgments

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