title: Delayed preconditioning with NMDA receptor antagonists in a rat model of perinatal asphyxia.
abstract: BACKGROUND
  In vitro experiments have demonstrated that preconditioning primary neuronal cultures by temporary application of NMDA receptor antagonists induces long-term tolerance against lethal insults. In the present study we tested whether similar effects also occur in brain submitted to ischemia in vivo and whether the potential benefit outweighs the danger of enhancing the constitutive apoptosis in the developing brain.
  
  
  METHODS
  Memantine in pharmacologically relevant doses of 5 mg/kg or (+)MK-801 (3 mg/kg) was administered i.p. 24, 48, 72 and 96 h before 3-min global forebrain ischemia in adult Mongolian gerbils or prior to hypoxia/ischemia in 7-day-old rats. Neuronal loss in the hippocampal CA1 in gerbils or weight deficit of the ischemic hemispheres in the rat pups was evaluated after 14 days. Also, the number of apoptotic neurons in the immature rat brain was evaluated.
  
  
  RESULTS
  In gerbils only the application of (+)MK-801 24 h before ischemia resulted in significant prevention of the loss of pyramidal neurons. In rat pups administration of (+)MK-801 at all studied times before hypoxia-ischemia, or pretreatment with memantine or with hypoxia taken as a positive control 48 to 92 h before the insult, significantly reduced brain damage. Both NMDA receptor antagonists equally reduced the number of apoptotic neurons after hypoxia-ischemia, while (+)MK-801-evoked potentiation of constitutive apoptosis greatly exceeded the effect of memantine.
  
  
  CONCLUSIONS
  We ascribe neuroprotection induced in the immature rats by the pretreatment with both NMDA receptor antagonists 48 to 92 h before hypoxia-ischemia to tolerance evoked by preconditioning, while the neuroprotective effect of (+)MK-801 applied 24 h before the insults may be attributed to direct consequences of the inhibition of NMDA receptors. This is the first report demonstrating the phenomenon of inducing tolerance against hypoxia-ischemia in vivo in developing rat brain by preconditioning with NMDA receptor antagonists.
authors.affiliation: Dorota Makarewicz, PhD, Laboratory of Pharmaconeurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, phone/fax: +48 22 608 66 23, phone +48 22 608 65 78, e-mail: dorota.makarewicz@gmail.com.
authors.forename: Dorota
authors.initials: D
authors.lastname: Makarewicz
authors.forename: Dorota
authors.initials: D
authors.lastname: Sulejczak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Duszczyk
authors.forename: Michał
authors.initials: M
authors.lastname: Małek
authors.forename: Marta
authors.initials: M
authors.lastname: Słomka
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Lazarewicz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum / Q000150:complications; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000517:prevention & control*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005849:Gerbillinae; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D008559:Memantine