title: Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat.
abstract: OBJECTIVE
  Neurocognitive disorders afflict approximately 20% of HIV-infected patients. HIV-1-infected cells in the brain shed viral proteins such as transactivator of transcription (Tat). Tat elicits cell death and synapse loss via processes initiated by NMDA receptor activation but mediated by separate downstream signalling pathways. Subunit selective NMDA receptor antagonists may differentially modulate survival relative to synaptic changes.
  
  
  METHODS
  Tat-evoked cell death was quantified by measuring propidium iodide uptake into rat hippocampal neurons in culture. The effects of Tat on synaptic changes were measured using an imaging-based assay that quantified clusters of the scaffolding protein postsynaptic density 95 fused to green fluorescent protein.
  
  
  RESULTS
  Dizocilpine, a non-competitive NMDA receptor antagonist, inhibited Tat-induced synapse loss, subsequent synapse recovery and Tat-induced cell death with comparable potencies. Memantine (10 µM) and ifenprodil (10 µM), which preferentially inhibit GluN2B-containing NMDA receptors, protected from Tat-induced cell death with no effect on synapse loss. Surprisingly, memantine and ifenprodil induced synapse recovery in the presence of Tat. In contrast, the GluN2A-prefering antagonist TCN201 prevented synapse loss and recovery with no effect on cell death.
  
  
  CONCLUSIONS
  Synapse loss is a protective mechanism that enables the cell to cope with excess excitatory input. Thus, memantine and ifenprodil are promising neuroprotective drugs because they spare synaptic changes and promote survival. These GluN2B-preferring drugs induced recovery from Tat-evoked synapse loss, suggesting that synaptic pharmacology changed during the neurotoxic process. NMDA receptor subtypes differentially participate in the adaptation and death induced by excitotoxic insult.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Shin
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: S A
authors.initials: SA
authors.lastname: Thayer
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008559:Memantine / Q000494:pharmacology; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism / Q000633:toxicity*; D006834:Hydrazines; D000096926:Benzenesulfonamides
chemical_list: D003470:Culture Media; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D008559:Memantine; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D054322:tat Gene Products, Human Immunodeficiency Virus; C574512:TCN 201; D006834:Hydrazines; D000096926:Benzenesulfonamides; C010739:ifenprodil