title: Neuroprotection against traumatic brain injury by a peptide derived from the collapsin response mediator protein 2 (CRMP2).
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.
authors.affiliation: Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Brittain
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Tatiana
authors.initials: T
authors.lastname: Brustovetsky
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Ashpole
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Molosh
authors.forename: Haitao
authors.initials: H
authors.lastname: You
authors.forename: Andy
authors.initials: A
authors.lastname: Hudmon
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
authors.forename: Jinhui
authors.initials: J
authors.lastname: Chen
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C095114:collapsin response mediator protein-2; D054322:tat Gene Products, Human Immunodeficiency Virus; D002118:Calcium