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Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain

Gene Therapy volume 16, pages 840–848 (2009)Cite this article

Abstract

To study the effects of excision repair cross-complementing 1 (ERCC1) on the pathophysiological process of brain ischemia, we examined the changes in ERCC1 expression, as well as the functional significance of ERCC1 in the rat brain following middle cerebral artery occlusion (MCAO). The results were as follows: (1) ERCC1 immunopositive cells were widely distributed in various brain regions. ERCC1 expression was localized to the nuclei of neurons and astrocytes. (2) ERCC1 expression, as determined by western blot, increased at 3 days, remaining until 14 days, in the ipsilateral cortex and striatum following MCAO. Immunohistochemical analysis demonstrated that ischemia induced increased ERCC1 expression within the periinfarct core, with increasingly less expression toward the core. (3) Knockdown of ERCC1 expression by intraventricular injection of antisense plasmids increased DNA damage and infarct volume in the ischemic brain. (4) ERCC1 overproduction, by injection of expression plasmids, significantly reduced infarct volume and the accumulation of DNA-damaged neurons. Taken together, these results indicate that both endogenous ERCC1 and exogenous ERCC1 have an important neuroprotective function in the brain. In addition, administration of ERCC1 to the brain could prove to be a successful strategy for neuronal protection against ischemic injury.

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Abbreviations

BER:

base excision repair

DSB:

DNA double-strand break

ERCC1:

excision repair cross-complementing 1

IP:

ischemic preconditioning

MCAO:

middle cerebral artery occlusion

NER:

nucleotide excision repair

PCNA:

proliferating cell nuclear antigen

SSB:

DNA single-strand break

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Acknowledgements

This work was supported in part by grants from the National Basic Research Program of China (nos. 2006CB504100 and 2006CB943702), National Natural Science Foundation of China (no. 30770660) and Shanghai Metropolitan Fund for Research and Development (nos. 04DZ14005 and 07DZ14005).

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  1. K-Y He and S-Z Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Institute of Biomedical Sciences, State Key Laboratory of Medical Neurobiology, Shanghai Medical College of Fudan University, Shanghai, PR China

    K-Y He, S-Z Yang, D-H Shen, L-M Zhang, S-D Lu & F-Y Sun

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Correspondence to F-Y Sun.

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He, KY., Yang, SZ., Shen, DH. et al. Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain. Gene Ther 16, 840–848 (2009). https://doi.org/10.1038/gt.2009.48

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