Neuroprotection after status epilepticus by targeting protein interactions with postsynaptic density protein 95.
N-methyl-D-aspartate receptors (NMDARs) mediate essential neuronal excitation, but overactivation of NMDARs results in excitotoxic cell death in a variety of pathologic conditions, including status epilepticus (SE). Although NMDAR antagonists attenuate SE-induced brain injury, undesirable side effects have limited their clinical efficacy. Tat-NR2B9c was designed to disrupt protein interactions involving postsynaptic density protein 95 in the NMDAR signaling complex while not interfering with function of the NMDAR ion channel. We examined the ability of Tat-NR2B9c to provide neuroprotection in the hippocampus of rats after 60 minutes of SE induced by the repeated injection of low doses of pilocarpine (10 mg/kg). Tat-NR2B9c was administered 3hours after the termination of SE, and neuronal densities were assessed 14 days later by stereologic analysis of NeuN-positive cells. After SE, pyramidal cell densities were reduced by 70% in CA1, 34% in CA3, 58% in CA4, and 88% in the piriform cortex. In Tat-NR2B9c-treated rats, neuronal densities in CA1, a subregion of CA3, and CA4 were decreased by only 38%, 4%, and 26%, respectively. Tat-NR2B9c did not reduce cell loss in the posterior piriform cortex. The results indicate that targeted disruption of the NMDAR signaling complex represents a potential therapeutic approach for limiting neuronal cell loss after SE.
Dykstra
Crystal M
CM
Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada.
Ratnam
Melanie
M
Gurd
James W
JW
D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D010862:Pilocarpine; D017966:Pyramidal Cells / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D010862:Pilocarpine; C542597:Tat-NR2B9c