title: Chronic memantine does not block 3-nitropropionic acid-delayed ischaemic tolerance in rat hippocampal slices ex vivo.
abstract: The moderate affinity uncompetitive NMDA receptor antagonist memantine, at concentrations found to be neuroprotective in animal models of chronic excitotoxicity, did not reduce ischaemic tolerance induced chemically with 3 nitropropionic acid (3-NP), but actually tended to enhance this effect ex vivo. Injection of 3-NP (20 mg/kg i.p.)--24 h prior to the in vitro experiment--significantly protected against hypoxia/hypoglycaemia-induced suppression of extracellular field excitatory postsynaptic potentials (fEPSPs) in rat hippocampal slices (62.2% vs. control of 16.8%), whereas 3 days pre-treatment with memantine (20 mg/kg/day--Alzet minipumps) tended to enhance recovery further following 3-NP preconditioning (89.7%). This low dose of memantine had no effect on fEPSPs in the absence of preconditioning. As expected, 3 days pre-treatment with a high dose of (+)MK-801 (dizocilpine; 2 mg/kg/day--Alzet minipumps) tended to reduce ischaemic tolerance following 3-NP preconditioning (45.3%). We conclude that although NMDA receptors do seem to be involved in chemically-induced ischaemic tolerance, semi-chronic pre-treatment with therapeutically-relevant doses of memantine does not block ischaemic tolerance.
authors.affiliation: Department of Preclinical Research & Development, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt/Main, Germany.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Frankiewicz
authors.forename: Chris G
authors.initials: CG
authors.lastname: Parsons
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008559:Memantine / Q000008:administration & dosage*; D009574:Nitro Compounds; D011422:Propionates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid; D008559:Memantine