PSD-95 uncoupling from NMDA receptors by Tat- N-dimer ameliorates neuronal depolarization in cortical spreading depression

J Cereb Blood Flow Metab. 2017 May;37(5):1820-1828. doi: 10.1177/0271678X16645595. Epub 2016 Jan 1.


Cortical spreading depression is associated with activation of NMDA receptors, which interact with the postsynaptic density protein 95 (PSD-95) that binds to nitric oxide synthase (nNOS). Here, we tested whether inhibition of the nNOS/PSD-95/NMDA receptor complex formation by anti-ischemic compound, UCCB01-144 (Tat- N-dimer) ameliorates the persistent effects of cortical spreading depression on cortical function. Using in vivo two-photon microscopy in somatosensory cortex in mice, we show that fluorescently labelled Tat- N-dimer readily crosses blood-brain barrier and accumulates in nerve cells during the first hour after i.v. injection. The Tat- N-dimer suppressed stimulation-evoked synaptic activity by 2-20%, while cortical blood flow and cerebral oxygen metabolic (CMRO2) responses were preserved. During cortical spreading depression, the Tat- N-dimer reduced the average amplitude of the negative shift in direct current potential by 33% (4.1 mV). Furthermore, the compound diminished the average depression of spontaneous electrocorticographic activity by 11% during first 40 min of post-cortical spreading depression recovery, but did not mitigate the suppressing effect of cortical spreading depression on cortical blood flow and CMRO2. We suggest that uncoupling of PSD-95 from NMDA receptors reduces overall neuronal excitability and the amplitude of the spreading depolarization wave. These findings may be of interest for understanding the neuroprotective effects of the nNOS/PSD-95 uncoupling in stroke.

Keywords: Cortical spreading depression; NMDAR; Tat-N-dimer; UCCB01-144; postsynaptic density protein 95; spreading depolarization; stroke.

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / physiopathology
  • Cerebrovascular Circulation / drug effects
  • Cerebrovascular Circulation / physiology
  • Cortical Spreading Depression / drug effects*
  • Cortical Spreading Depression / physiology
  • Disks Large Homolog 4 Protein
  • Guanylate Kinases / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Neurons / drug effects*
  • Neurons / physiology
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / pharmacology*
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synaptic Potentials / drug effects


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Neuroprotective Agents
  • Peptides
  • Receptors, N-Methyl-D-Aspartate
  • Tat-NPEG4(IETDV)2
  • Guanylate Kinases