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Age-Related Upregulation of Carboxyl Terminal Modulator Protein Contributes to the Decreased Brain Ischemic Tolerance in Older Rats

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Abstract

Stroke remains one of the leading causes of death worldwide. The underlying neuropathology for stroke is ischemic brain injury. Carboxyl terminal modulator protein (CTMP), an endogenous inhibitor of the prosurvival Akt, may increase brain ischemic injury in young animals. Aging decreases brain ischemic tolerance. We hypothesize that CTMP is increased with aging and that this increase contributes to the decreased brain ischemic tolerance. To address these hypotheses, we determined the expression of CTMP and its downstream proteins in the brain of various ages of rats (Fischer 344 and Sprague-Dawley rats). The role of CTMP in ischemic brain injury was investigated by RNA interference. Here, we showed that CTMP in the brain was increased with aging in rats. The phosphorylated/activated Akt was decreased with aging. Six- and 20-month-old rats had poorer neurological outcome than did 2-month-old rats after brain ischemia. The neurological outcome of 2-month-old rats was worsened by LY294002, an Akt inhibitor. The poor neurological outcome in 6-month-old rats was improved by silencing CTMP. CTMP was increased in ischemic penumbral brain tissues. Silencing this increase activated Akt. These results suggest that CTMP increase with aging contributes to the aging-dependent decrease of brain ischemic tolerance.

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Funding

This study was supported by grants (R01 GM098308 and R21 AG047472 to Z Zuo) from the National Institutes of Health, Bethesda, MD, the Robert M. Epstein Professorship endowment, University of Virginia, Charlottesville, VA, and the National Key Research and Development Program of China (2016YFC1300600).

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Authors and Affiliations

  1. Department of Anesthesiology, University of Virginia, 1 Hospital Drive, PO Box 800710, Charlottesville, VA, 22901, USA

    Jun Li, Weiran Shan & Zhiyi Zuo

  2. Department of Anesthesiology, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, 150001, China

    Jun Li

  3. Laboratory of RNA and Major Diseases of Brain and Heart and Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510120, China

    Zhiyi Zuo

Authors
  1. Jun Li
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  2. Weiran Shan
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Contributions

ZZ conceived the project. JL, WS, and ZZ designed the study. JL and WS performed the experiments. JL did the initial data analysis and drafted the manuscript. ZZ performed the final data analysis and rewrote the manuscript.

Corresponding author

Correspondence to Zhiyi Zuo.

Ethics declarations

The animal protocol was approved by the Institutional Animal Care and Use Committee of the University of Virginia (Charlottesville, VA, USA). All animal experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publications number 80-23) revised in 2011 and reported according to the ARRIVE guidelines.

Conflict of Interest

The authors declare that they have no competing interests.

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Li, J., Shan, W. & Zuo, Z. Age-Related Upregulation of Carboxyl Terminal Modulator Protein Contributes to the Decreased Brain Ischemic Tolerance in Older Rats. Mol Neurobiol 55, 6145–6154 (2018). https://doi.org/10.1007/s12035-017-0826-6

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  • DOI: https://doi.org/10.1007/s12035-017-0826-6

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