title: Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain.
abstract: The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20mg/kg, i.p.), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5-10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, St. Louis, MO 63110, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Creeley
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Anthony
authors.initials: A
authors.lastname: Nardi
authors.forename: Nuri B
authors.initials: NB
authors.lastname: Farber
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D016923:Cell Death / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000009:adverse effects*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005260:Female; D007189:Indans / Q000009:adverse effects*; D008559:Memantine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology*; D010880:Piperidines / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D008559:Memantine