Neuroprotection against traumatic brain Injury by a peptide derived from the Collapsin Response Mediator Protein 2 (CRMP2)

Joel M. Brittain, Liang Chen, Sarah M. Wilson, Tatiana Brustovetsky, Xiang Gao, Nicole M. Ashpole, Andrei I. Molosh, Haitao You, Andy Hudmon, Anantha Shekhar, Fletcher A. White, Gerald W. Zamponi, Nickolay Brustovetsky, Jinhui Chen, Rajesh Khanna

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Neurological disabilities following traumatic brain injury (TBI) may be due to excitotoxic neuronal loss. The excitotoxic loss of neurons following TBI occurs largely due to hyperactivation of N-methyl-D-aspartate receptors (NMDARs), leading to toxic levels of intracellular Ca 2+. The axon guidance and outgrowth protein collapsin response mediator protein 2 (CRMP2) has been linked to NMDAR trafficking and may be involved in neuronal survival following excitotoxicity. Lentivirus-mediated CRMP2 knockdown or treatment with a CRMP2 peptide fused to HIV TAT protein (TAT-CBD3) blocked neuronal death following glutamate exposure probably via blunting toxicity from delayed calcium deregulation. Application of TAT-CBD3 attenuated postsynaptic NMDAR-mediated currents in cortical slices. In exploring modulation of NMDARs by TAT-CBD3, we found that TAT-CBD3 induced NR2B internalization in dendritic spines without altering somal NR2B surface expression. Furthermore, TAT-CBD3 reduced NMDA-mediated Ca 2+influx and currents in cultured neurons. Systemic administration of TAT-CBD3 following a controlled cortical impact model of TBI decreased hippocampal neuronal death. These findings support TAT-CBD3 as a novel neuroprotective agent that may increase neuronal survival following injury by reducing surface expression of dendritic NR2B receptors.

Original languageEnglish (US)
Pages (from-to)37778-37792
Number of pages15
JournalJournal of Biological Chemistry
Volume286
Issue number43
DOIs
StatePublished - Oct 28 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Brittain, J. M., Chen, L., Wilson, S. M., Brustovetsky, T., Gao, X., Ashpole, N. M., Molosh, A. I., You, H., Hudmon, A., Shekhar, A., White, F. A., Zamponi, G. W., Brustovetsky, N., Chen, J., & Khanna, R. (2011). Neuroprotection against traumatic brain Injury by a peptide derived from the Collapsin Response Mediator Protein 2 (CRMP2). Journal of Biological Chemistry, 286(43), 37778-37792. https://doi.org/10.1074/jbc.M111.255455