title: Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats.
abstract: OBJECTIVE
  Previous studies reported that Tat-NR2B9c, a peptide disrupting the N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction, reduced ischemic damage in the acute phase after stroke. However, its effect in the subacute phase is unknown. The aim of this study is to determine whether disrupting the N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction in the subacute phase promotes recovery after stroke.
  
  
  METHODS
  Studies were performed on Sprague-Dawley rats or nNOS(-/-) mice, and experimental ischemic stroke was induced by middle cerebral artery occlusion. Animals were treated with drugs starting at day 4 after ischemia. Sensorimotor functions and spatial learning and memory ability were assessed after drug treatment. Then, rats were euthanized for morphological observation and biochemical tests.
  
  
  RESULTS
  Disrupting the N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction with Tat-HA-NR2B9c significantly ameliorated the ischemia-induced impairments of spatial memory and sensorimotor functions in rats during subacute stage but did not improve stroke outcome in nNOS(-/-) mice. Consistent with the functional recovery, Tat-HA-NR2B9c substantially increased neurogenesis in the dentate gyrus and dendritic spine density of mature neurons in the motor cortex of rats, meanwhile, reversed the ischemia-induced formation of S-nitrosylation-cyclin-dependent kinase 5 and increased cyclin-dependent kinase 5 activity in ipsilateral hippocampus. However, directly blocking N-methyl-d-aspartate receptors with MK-801 or Ro 25-6981 did not show the beneficial effects above.
  
  
  CONCLUSIONS
  Dissociating N-methyl-d-aspartate receptor-postsynaptic density protein-95 coupling by Tat-HA-NR2B9c in the subacute phase after stroke promotes functional recovery, probably because of that it increases neurogenesis and dendritic spine density of mature neurons via regulating cyclin-dependent kinase 5 in the ischemic brain.
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Hai-Hui
authors: HH
authors: Zhou
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Ying
authors: Y
authors: Tang
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Xin-Yong
authors: XY
authors: Zhang
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Chun-Xia
authors: CX
authors: Luo
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Li-Yan
authors: LY
authors: Gao
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Hai-Yin
authors: HY
authors: Wu
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China.
authors: Lei
authors: L
authors: Chang
authors: From the Department of Pharmacology, School of Pharmacy (H.-H.Z., Y.T., X.-Y.Z., C.-X.L., L.-Y.G., H.-Y.W., L.C., D.-Y.Z.), Institution of Stem Cells and Neuroregeneration (C.-X.L., H.-Y.W., D.-Y.Z.), Nanjing Medical University, Nanjing, China. dyzhu@njmu.edu.cn.
authors: Dong-Ya
authors: DY
authors: Zhu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D049229:Dendritic Spines / Q000648:ultrastructure; D018891:Dentate Gyrus / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D009044:Motor Cortex / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012677:Sensation / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000517:prevention & control
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010455:Peptides; C542597:Tat-NR2B9c; D052248:Nitric Oxide Synthase Type I; D051360:Cyclin-Dependent Kinase 5
keywords: Tat-NR2B9c; cyclin-dependent kinase 5; nitrosation; regeneration; stroke