Overexpression of netrin-1 improves neurological outcomes in mice following transient middle cerebral artery occlusion

Abstract

Netrin-1 (NT-1) is one of the axon-guiding molecules that are critical for neuronal development. Because of its structural homology to the endothelial mitogens, NT-1 may have similar effects on vascular network formation. NT-1 was shown to be able to stimulate the proliferation and migration of human cerebral endothelial cells in vitro and also promote focal neovascularization in adult brain in vivo. In the present study, we reported the delivery of NT-1 using an adeno-associated virus (AAV) vector (AAV-NT-1) into mouse brain followed by transient middle cerebral artery occlusion (tMCAO). We found that AAV vectors did not elicit a detectable inflammatory response, cell loss or neuronal damage after brain transduction. The level of NT-1 was increased in the AAV-NT-1-transduced tMCAO mice compared with the control mice. Furthermore, the neurobehavioral outcomes were significantly improved in AAV-NT-1-transduced mice compared with the control animals (P<0.05) 7 days after tMCAO. Our data suggests that NT-1 plays a neuronal function recovery role in ischemic brain and that NT-1 gene transfer might present a valuable approach to treat brain ischemic disorders.

Key words： adeno-associated virus; angiogenesis; gene transfer; ischemia; middle cerebral artery occlusion; netrin-1

Acknowledgments

This study is supported by the National Basic Research Program 2011CB504405 (Guo-yuan yang, Yongting Wang) and the National Natural Science Foundation of China (#30973097). The authors thank Ms. Karana Shun and Yan Wang for their editorial assistance and staff of the Neuroscience and Neuroengineering Center for their collaborative support.

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