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A Small Organic Compound Mimicking the L1 Cell Adhesion Molecule Promotes Functional Recovery after Spinal Cord Injury in Zebrafish

Abstract

Tacrine is a small organic compound that was discovered to mimic the functions of the neural cell adhesion molecule L1 by promoting the cognate functions of L1 in vitro, such as neuronal survival, neuronal migration, neurite outgrowth, and myelination. Based on studies indicating that L1 enhances functional recovery in different central and peripheral nervous system disease paradigms of rodents, it deemed interesting to investigate the beneficial role of tacrine in the attractive zebrafish animal model, by evaluating functional recovery after spinal cord injury. To this aim, larval and adult zebrafish were exposed to tacrine treatment after spinal cord injury and monitored for locomotor recovery and axonal regrowth. Tacrine promoted the rapid recovery of locomotor activities in both larval and adult zebrafish, enhanced regrowth of severed axons and myelination, and reduced astrogliosis in the spinal cords. Tacrine treatment upregulated the expression of L1.1 (a homolog of the mammalian recognition molecule L1) and enhanced the L1.1-mediated intracellular signaling cascades in the injured spinal cords. These observations lead to the hope that, in combination with other therapeutic approaches, this old drug may become a useful reagent to ameliorate the deficits resulting from acute and chronic injuries of the mammalian nervous system.

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Abbreviations

CNS:

Central nervous system

dpf:

Days post-fertilization

FDA:

Food and Drug Administration

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GFAP:

Glial fibrillary acidic protein

MBP:

Myelin basic protein

mTOR:

Mechanistic target of rapamycin

PBS:

Phosphate-buffered saline

PTEN:

Phosphatase and tensin homologue

SCI:

Spinal cord injury

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Acknowledgements

We are grateful to Professor Junhui Bian, Dean of Shantou University Medical College, and Dr. Frieda Law, advisor of Li Kashing Foundation for their support. This work was funded by the Li Kashing Foundation and the National Natural Science Foundation of China (Grant #31271580).

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Correspondence to Yanqin Shen or Melitta Schachner.

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Sudhanshu Sahu, Rong Li, and Junkai Hu contributed to this work equally.

Prof. Melitta Schachner is the first corresponding author.

Dr. Yanqin Shen is the co-corresponding author.

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Sahu, S., Zhang, Z., Li, R. et al. A Small Organic Compound Mimicking the L1 Cell Adhesion Molecule Promotes Functional Recovery after Spinal Cord Injury in Zebrafish. Mol Neurobiol 55, 859–878 (2018). https://doi.org/10.1007/s12035-016-0254-z

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Keywords

  • Cell adhesion molecule L1
  • Tacrine
  • Spinal cord injury
  • Axonal regrowth
  • Zebrafish